Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[F:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:29]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([F:26])[CH:28]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3-fluoro-4-methoxyphenylmagnesium bromide. Yield: 57 mg of a white solid. 1H NMR (400 MHz, CDCl3): δ 4.0 (s, 3H), 5.5 (s, 2H), 6.9-7.0 (m, 2H), 7.3-7.4 (m, 1H), 7.4-7.6 (m, 3H), 7.6-7.7 (m, 3H), 8.3 (s, 1H), 8.4-8.5 (m, 1H). LC-MSD, m/z for C23H16BrFN2O3 [M+H]+=467.0, 469.0; HPLC retention time: 2.3 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH2:12][CH2:13][OH:14])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1.[C:15]([OH:19])([CH3:18])(C)C.CC(C)([O-:23])C.[K+].Cl>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([CH2:12][CH2:13][O:14][CH2:18][C:15]([OH:19])=[O:23])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1cc2occc2cc1CCO
Reactant: CC(C)(C)O
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2occc2cc1CCOCC(=O)O
Reaction time: 0.5 h

Procedure:
1.75 g of 2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol was dissolved in a mixed solution consisting of 7.0 ml of tert-butanol and 1.75 ml of N,N-dimethylformamide. Thereafter, 2.2 g of 1-chloroacetylpiperidine and 1.54 g of potassium tert-butoxide were added to the obtained solution, while cooling on ice. The obtained mixture was stirred at the same temperature for 30 minutes and then at a room temperature for 2 hours. Thereafter, water and ethyl acetate were added to the reaction mixture. The pH of the obtained mixture was adjusted to pH 1 by addition of 6 mol/l hydrochloric acid, and an organic layer was separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was then distilled away under a reduced pressure. The residue was dissolved in 10.5 ml of a 90% aqueous ethanol solution. Thereafter, 0.91 g of sodium hydroxide was added thereto, and the obtained mixture was then heated to reflux for 3 hours. After cooling, water and ethyl acetate were added to the reaction mixture. The pH of the obtained mixture was adjusted to pH 1 by addition of 6 mol/l hydrochloric acid, and an organic layer was separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was then distilled away under a reduced pressure. Thereafter, diisopropyl ether was added to the residue, and precipitated crystals were then collected by filtration. The obtained crystals were washed with diisopropyl ether and then dried, so as to obtain 1.42 g of a yellow crystal, 2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]#[N:11].[CH2:12](N)[CH2:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]1[NH:14][CH2:13][CH2:12][N:11]=1
Reactant: NCCN
Reactant: Cc1cccc(Br)c1CC#N
Product: Cc1cccc(Br)c1CC1=NCCN1

Procedure:
2-(2-Bromo-6-methyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-bromo-6-methylphenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): off-white solid;
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14](=[O:21])OCC(Cl)(Cl)Cl)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:22]1([C:28]2[N:32]=[C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[S:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([N:36]3[CH2:37][CH2:38][N:33]([C:31]4[S:30][N:29]=[C:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:32]=4)[CH2:34][CH2:35]3)=[O:21])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(NC(=O)OCC(Cl)(Cl)Cl)ccc21
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)N1CCc2cc(NC(=O)N3CCN(c4nc(-c5ccccc5)ns4)CC3)ccc21

Procedure:
A solution of 2,2,2-trichloroethyl (1-acetyl-2,3-dihydro-1H-indol-5-yl)carbamate (200 mg, 0.569 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (140 mg, 0.569 mmol), diisopropylethylamine (0.198 ml, 1.14 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 48 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (110.0 mg, 43.1%) as a solid.
Reaction SMILES: [OH:1][CH:2]([C:6]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CN(C=O)C.[H-].[Na+].[CH3:43][O:44][C:45]1[CH:50]=[C:49]([CH3:51])[N:48]=[C:47](S(C)(=O)=O)[N:46]=1>O>[CH3:43][O:44][C:45]1[CH:50]=[C:49]([CH3:51])[N:48]=[C:47]([O:1][CH:2]([C:6]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:3]([OH:5])=[O:4])[N:46]=1
Reactant: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)O)cc1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(Oc2nc(C)cc(OC)n2)C(=O)O)cc1
Reaction time: 0.25 h
Yield: 23.7 %

Procedure:
1.8 g (3.8 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid were introduced into 20 ml of DMF, and 554 mg of NaH (50% suspension) were added. After the mixture had stirred for 15 minutes, 855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off and 540 mg (23%) of colorless powder were isolated after recrystallization from ether/n-hexane.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH2:9])=[NH:8].[Cl:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1.C([O-])(=O)C.[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[N:9]=[C:13]([C:12]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:11]=2[Cl:10])[C:21]2[C:22](=[O:26])[CH2:23][CH2:24][CH2:25][C:20]=2[NH:8]1
Reactant: N=C(N)c1nccs1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C1CCCC2=C1C(c1ccc(F)cc1Cl)=NC(c1nccs1)N2
Yield: 27 %

Procedure:
2-thiazolecarboxamidine hydrochloride (Schaefer P. C., Peters G. A., et al.) 2.164 mmol, 2-chloro-4-fluorobenzaldehyde 2.164 mmol, 1,3-cyclohexanedione 2.164 mmol and sodium acetate 3.2 mmol were reacted in 8 ml anhydrous ethanol under refluxing for 18 hr, and condensed, to which ethyl acetate and water and 1N HCl were added and the layers were separated. The water layer was adjusted with concentrated NaOH solution until pH value to be basic, then ethyl acetate was added again and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a yellow crystal of 0.21 g (yield 27%); 1H-NMR (400 MHz, CDCl3-d1) δ 7.86 (m, 1H, ArH); 7.73-7.52 (m, 1H, ArH); 7.24-7.21 (m, 1H, ArH); 7.15-7.12 (m, 1H, ArH); 6.94-6.92 (m, 1H, ArH); 6.11 (s, 1H, CH); 2.80-2.47 (m, 2H, CH2); 2.14-2.11 (m, 2H, CH2). HREI: 361.0450 (M+).
Reaction SMILES: [F:1][C:2]([F:30])([O:9][C:10]([F:29])([F:28])[C:11]([F:27])([F:26])[O:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.[C:31]1([CH3:41])[C:32]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:31]1([CH3:41])[C:32]([S:37]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:30])[O:9][C:10]([F:28])([F:29])[C:11]([F:26])([F:27])[O:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])(=[O:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OCCCCCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)CCCCCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
This hexanol (1.2 g, 2.45 Moles)was combined with toluene sulfonyl chloride (0.5 g, 2.58 mmoles), N,N-diisopropylethyl amine (0.85 mL, 4.9 mmoles), and N,N-dimethylaminopyridine (12 mg, 0.98 mmole) in dichloromethane (10 mL). After stirring for 10 hours at room temperature, the desired product, 1-toluenesulfonyl-6,6-difluoro-6-(perfluoro-2-butoxyethoxy)hexane, was isolated by column chromatography (and its structure confirmed by infrared spectroscopy).
Reaction SMILES: [S:1]([O-:17])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:3])=[O:2].[Na+:18].[ClH:19]>>[S:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([OH:17])(=[O:2])=[O:3].[Cl-:19].[Na+:18]
Reactant: Cl
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCOS(=O)(=O)O
Product: [Cl-]

Procedure:
A second mixture was made using the amounts as above, but using sodium lauryl sulfate as a surfactant to form the emulsion. Immediately after homogenization, 300 g of the emulsion was mixed with 3 g of 5 N hydrochloric acid. The hydrochloric acid reacted with the sodium lauryl sulfate to give hydrogen lauryl sulfate as the catalyst and sodium chloride. After 4 days at 22° C. for polymerization and crosslinking, the emulsion was neutralized in the same manner as above.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:48])([CH3:47])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:46])([C@@:13]3([CH3:45])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[C:51]([NH:54][C:55]1([C:70]([O:72][CH3:73])=[O:71])[CH2:60][CH2:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH2:56]1)(=[O:53])[CH3:52]>>[C:51]([NH:54][C:55]1([C:70]([O:72][CH3:73])=[O:71])[CH2:60][CH2:59][C:58]([C:7]2[C:8]([CH3:48])([CH3:47])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:46])([C@@:13]4([CH3:45])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:37][CH2:36]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:57][CH2:56]1)(=[O:53])[CH3:52]
Reactant: COC(=O)C1(NC(C)=O)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(NC(C)=O)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 58.3 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a, 5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (triflate-2) and methyl 1-acetamido-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as the reactants. The product was obtained as a mixture of diastereomers in 58.3% yield. MS: m/e 794.6 (M+H)+, 2.718 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.71 (d, J=5.5 Hz, 1H), 5.28 (br. s., 1H), 5.22 (s, 1H), 4.73 (br. s., 1H), 4.60 (br. s., 1H), 3.75 (s, 3H), 3.15 (d, J=10.5 Hz, 2H), 2.92-2.79 (m, 4H), 2.73-2.53 (m, 4H), 2.52-2.22 (m, 7H), 2.20-2.08 (m, 5H), 2.03 (br. s., 1H), 2.00 (d, J=1.8 Hz, 3H), 1.98-1.75 (m, 7H), 1.70 (s, 3H), 1.68-1.20 (m, 15H), 1.14-1.04 (m, 6H), 1.00-0.91 (m, 6H), 0.86 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[C:39]([O:41][CH3:42])=[O:40].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH2:27][O:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=2[C:39]([O:41][CH3:42])=[O:40])=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)c(C(=O)OC)c1
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 4-[N′-(2-methylphenyl)ureido]phenylacetic acid (2.32 g, 5.15 mmol), dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate (1.51 g, 5.15 mmol) in DMF (20 mL) was added Et3N (1.0 mL, 6.65 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc. The solution was washed with brine, dried over MgSO4, and evaporated off in vacuo. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (10:1, v/v) as eluent to give 1.58 g (55%) dimethyl 4-[1-[4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate as a yellow crystalline solid. 1H-NMR (CDCl3) δ1.87-2.25 (m, total 7 H), 3.50-3.65 (m, 4 H), 3.85 (s, 3 H), 3.89 (s, 3 H), 4.18-4.31 (m, 2 H), 4.44 (m, 1 H), 6.95-8.45 (m, total 13 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1)#[N:23]
Reactant: N#Cc1ccccc1B(O)O
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Product: N#Cc1ccccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 272 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2-cyanophenylboronic acid. colorless crystals (yield 6%). MS (APCI−): 356 (M−H).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][OH:7].C(Cl)(Cl)Cl.[OH-:14].[Na+]>CC(C)=O>[OH:7][CH2:6][CH2:5][N:4]1[CH2:3][C:2]([CH3:9])([CH3:8])[NH:1][C:2]([CH3:9])([CH3:8])[C:3]1=[O:14]
Reactant: CC(C)(N)CNCCO
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Temperature: 0 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
To a solution of 2-((2-amino-2-methylpropyl)amino)ethanol (12 g, 91 mmol) in 90 mL of acetone was added chloroform (10.9 mL, 136 mmol) and the solution was cooled to 0° C. with an external ice bath. A solution of NaOH (50% by weight, 43.6 g, 545 mmol) was added slowly to the cold solution over several minutes and the resultant solution was stirred at 0° C. for 2 hours then allowed to warm to room temperature and stirred for an additional 18 hr. The crude reaction mixture was filtered to remove solids, washing with acetone, and the solution was concentrated to 20 g of a clear oil. A portion of the crude material was purified by a bulb-to-bulb distillation under reduced pressure to give 1.45 g of a clear oil, which was used directly in the next step without further purification. LRMS (ESI/APCI) m/z 201 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[CH2:10]([NH:17][C:7](=[O:9])[C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[NH:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CC[C@H](C(=O)NCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Oxo-D-proline (5.0 g), benzylamine (4.65 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.5 g) and 1-hydroxybenzotriazole (6.3 g) were mixed in acetonitrile (100 mL) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 3 hr. The mixture was diluted with ethyl acetate (200 mL), and washed successively with 1M hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (4.02 g) as a white powder.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8]1)(=O)=O.[I-:21].[Na+]>CC(C)=O>[I:21][CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8]1
Reactant: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1Cc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@@H]1CO[C@H](CI)CN1Cc1ccccc1
Yield: 66.7 %

Procedure:
To a solution of [(2S,5R)-5-methyl-4-(phenylmethyl)-2-morpholinyl]methyl methanesulfonate (8.0 g, 26.7 mmol) in acetone (80 mL) stirred under nitrogen at room temp was added sodium iodide (20.03 g, 134 mmol), and the reaction mixture was stirred at reflux overnight. The reaction was cooled and concentrated under reduced pressure. Then to the residue was added water (50 mL) and CH2Cl2 (60 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (60 mL). The combined organic layers were washed with 1 M Na2S2O3 (2×30 mL), then water (20 mL), dried (Na2SO4), and concentrated to afford the crude product. Purification by silica gel chromatography (300-400 mesh), eluting with Hex/EtOAc (2:1 to 3:2) and monitoring in iodine afforded the title compound (5.9 g) as a yellow oil. LC-MS (ES) m/z=332 [M+H]+.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(NCC)C.CCN=C=NCCCN(C)C.Cl.[C:37]([N:44]([CH2:52][C:53]1[N:54]=[CH:55][C:56]([C:59](O)=[O:60])=[N:57][CH:58]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:37]([N:44]([CH2:52][C:53]1[N:54]=[CH:55][C:56]([C:59]([NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[O:60])=[N:57][CH:58]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1cnc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cn1
Reaction time: 1 h

Procedure:
The compound obtained in Example 8-6 (160 mg) was dissolved in DMF (3.2 ml) and diethylamine (0.32 ml) was added. After one hour, the reaction solution was concebtrated and the residue obtained was dissolved in DMF (1 ml). Then, WSCI hydrochloride (73 mg), DMAP (31 mg), and a solution of the compound obtained in Example 13-3 in DMF (1 ml) were sequentially added. After 15 hours, the reaction solution was concentrated. After the addition of chloroform and 1 mol/l hydrochloric acid, the residue was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was crude-purified by silica gel column chromatography (4 g, chloroform/ethyl acetate=1/2) to obtain the title compound (95.2 mg) as colorless syrup.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([S:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 177.2 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (1 g, 4.65 mmol) in EtOH (13 ml) was added to a solution of benzylmercaptan (0.65 ml, 5.53 mmol), Na2CO3 (0.64 g, 6.1 mmol) and water (3 ml) and the reaction was heated under reflux for 4 h. After cooling, the mixture was diluted with water. The resulting precipitate was collected by filtration, washed with n-hexane and dried to give the title compound (2.5 g, 88%). The structure was confirmed by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:6]
Reactant: NCC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccccc1)c1ccc(Cl)cc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-phenyl-ethylamine. LCMS (MH+): m/z=404.0, tR (minutes, Method D)=0.91
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[S:17][C:15]=2[N:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.