Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]([F:22])=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][NH2:25]>>[F:22][C:15]1[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]2[O:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:25][O:24][CH3:23])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: CON
Reactant: COC(=O)c1cc(F)cc2nc(-c3ccc(CBr)cc3)oc12
Product: CONCc1ccc(-c2nc3cc(F)cc(C(=O)OC)c3o2)cc1
Yield: 87 %

Procedure:
Following the experimental procedure as described in Example 144 C, and replacing methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate with methyl 2-(4-(bromomethyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxylate and substituting dimethylamine with methoxyamine, methyl 5-fluoro-2-(4-((methoxyamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (Yield: 87%. LC-MS (ESI) m/z: 331 (M+1)+) was made.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]([OH:16])(=O)[C:11]([CH3:14])([CH3:13])[CH3:12].[NH2:17][C:18]1[C:19]([C:24]([NH:26][NH2:27])=O)=[N:20][CH:21]=[CH:22][N:23]=1.CC1C=CC(S(Cl)(=O)=O)=CC=1>C(#N)C>[C:11]([C:10]1[O:16][C:24]([C:19]2[C:18]([NH2:17])=[N:23][CH:22]=[CH:21][N:20]=2)=[N:26][N:27]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)O
Reactant: NNC(=O)c1nccnc1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nnc(-c2nccnc2N)o1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (47.7 g, 148.69 mmol) was added portionwise over 15 minutes to a stirred suspension of N-ethyl-N-isopropylpropan-2-amine (70.6 mL, 405.51 mmol), pivalic acid (17.08 mL, 148.69 mmol) and 3-aminopyrazine-2-carbohydrazide (20.7 g, 135.17 mmol) in acetonitrile (350 mL) and the reaction mixture was stirred at 80° C. for 20 minutes (a solution was obtained). The reaction mixture was cooled to 0° C. and N-ethyl-N-isopropylpropan-2-amine (70.6 mL, 405.51 mmol), followed by 4-methylbenzene-1-sulfonyl chloride (77 g, 405.51 mmol) were added over a period of 15 minutes. The reaction mixture (yellow suspension) was brought to reflux (solubilisation) and then allowed to stir at room temperature for 14 hours affording a dark orange solution. The solution was concentrated. The residue was diluted with dichloromethane, washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 40% ethyl acetate in dichloromethane. The solvent was evaporated to dryness. The resulting mixture was triturated with ether (100 mL), filtered, washed with the minimum of ether and dried to afford 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (20.8 g, 70.2%) as a pale yellow soild: 1H NMR Spectrum; (CDCl3) 1.53 (9H, s), 1.58-1.68 (2H, m), 6.67 (2H, s), 8.13 (2H, dt); Mass Spectrum [M+H]+=220.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH3:41]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH3:41])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
General Procedure A. To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 40 mg, 0.092 mmol) in DMF (2.0 ml) was added K2CO3 (39 mg, 0.28 mmol) and iodoethane (22 μl, 0.28 mmol). The reaction was stirred at room temperature for 48 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([C:21]([NH:23][C:24](=[CH2:29])[C:25]([O:27]C)=[O:26])=[O:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.O.O.[OH-].[Li+].Cl>C1COCC1>[C:1]1([CH3:31])[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([C:21]([NH:23][C:24](=[CH2:29])[C:25]([OH:27])=[O:26])=[O:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:6]=1
Reactant: C=C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C)cc3)cc2)no1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C)cc3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
Methyl 2-(3-(4-(3-p-tolylureido)phenyl)isoxazole-5-carboxamido)acrylate (125 mg, 0.298 mmol) was dissolved in THF and water in 2:1 ratio. Lithium hydroxide monohydrate (19 mg, 0.447 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. Crude compound was purified by washing with methanol to get 60 mg (50%) white solid as the required compound. MS: ES (+): m/z 407(M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 9.732 (s, 1H), 8.989 (s, 1H), 8.714 (s, 1H), 7.894 (d, 2H), 7.784 (s, 1H), 7.638 (d, 2H), 7.377 (d, 2H), 7.121 (d, 2H), 6.232 (s, 1H), 5.921 (s, 1H), 5.918 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2C(Cl)=NC=[N:8][C:7]=2[CH:6]=[CH:5]1)[CH:2]=[CH2:3].[H-].[Na+].CI.[CH3:18][N:19]([CH:21]=[O:22])[CH3:20]>O>[CH2:1]([N:4]1[C:12]2[C:21](=[O:22])[N:19]([CH3:20])[CH:18]=[N:8][C:7]=2[CH:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: CN(C)C=O
Reactant: C=CCn1ccc2ncnc(Cl)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: C=CCn1ccc2ncn(C)c(=O)c21
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a room temperature solution of 5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (220 mg, 1.3 mmol, 1 equiv.) in 3 mL of DMF was added 60% NaH (100 mg, 2.5 mmol, 2 equiv.) followed by MeI (0.18 ml, 1.8 mmol, 1.5 equiv.). After 30 minutes, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-90% CH3CN/water+0.1% TFA). The desired fractions were combined and concentrated to remove CH3CN. The remaining aqueous mixture was extracted with EtOAc, dried, filtered, and evaporated to provide 152 mg (64%) of 5-allyl-3-methyl-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one as a yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[C:3]#[N:4].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:21][C:20](=[O:29])[NH:1][C:2]([C:3]#[N:4])([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a, 5.01 g, 30.9 mmol) in dry THF (119 mL) was added DIEA (12.1 mL, 67.9 mmol) and benzyl carbonochloridate (CAN 501-53-1, 5.57 mL, 37.1 mmol). Reaction was stirred at 45° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (8.12, 89%) as a yellow oil. MS (ESI, m/z): 297.5 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]5[NH:22][CH:23]=[CH:24][C:20]=5[C:19]([O:25][CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32](O)(=[O:36])[C@@H:33]([CH3:35])[OH:34].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[OH:34][C@H:33]([CH3:35])[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([O:25][C:19]2[C:20]3[CH:24]=[CH:23][NH:22][C:21]=3[N:16]3[N:15]=[CH:14][C:13]([C:10]4[CH:11]=[N:12][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)=[C:17]3[N:18]=2)[CH2:27][CH2:28]1)=[O:36]
Reactant: c1ccc(-c2ccc(-c3cnn4c3nc(OC3CCNCC3)c3cc[nH]c34)cn2)cc1
Reactant: C[C@@H](O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@@H](O)C(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (Int-11e, 95.8 mg, 0.23 mmoL), D-(−)-lactic acid (25 mg, 0.28 mmoL), EDC (89 mg, 0.47 mmoL), HOBt (63 mg, 0.47 mmoL) and DIEA (244 uL, 1.46 mmoL) in DMF (4 mL) were stirred at room temperature for 2 hr. Purification with prep-LC provided (R)-2-hydroxy-1-(4-(3-(6-phenylpyridin-3-yl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-5-yloxy)piperidin-1-yl)propan-1-one (35): LCMS tR=3.48 Min (10 min run, UV254nm). Mass calculated for, M+482.2, observed m/z 483.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([O:16][CH3:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].C[O-].[Na+].[CH:24](OCC)=O.S(=O)(=O)(O)O>O1CCCC1.O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18](=[O:20])[CH:19]=[CH:24][NH:1]2)=[CH:4][C:5]=1[O:16][CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Reactant: CCOC=O
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
1-[2-Amino-4-(benzyloxy)-5-methoxyphenyl]-1-ethanone (24.95 g) was dissolved in tetrahydrofuran (450 ml), and sodium methoxide (24.87 g) was added to the solution. The mixture was stirred at room temperature for one hr. Ethyl formate (37.07 ml) was then added thereto, and the mixture was stirred at room temperature for 2 hr. Water (150 ml) was then added thereto, and the mixture was stirred overnight. The reaction solution was adjusted to pH 4 by the addition of concentrated sulfuric acid at 0° C. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (10/1) to give 17.16 g (yield 66%) of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][S:28][CH2:29][C@H:30]([OH:33])[CH2:31][OH:32])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:34](Cl)(=[O:48])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C(OC[C@@H](OC(=O)CCCCCCCCCCC)CSC[C@H](NC([O:80][CH2:81][CH:82]1[C:94]2[CH:93]=[CH:92][CH:91]=[CH:90][C:89]=2[C:88]2[C:83]1=[CH:84][CH:85]=[CH:86][CH:87]=2)=O)C(OC(C)(C)C)=O)(=O)CCCCCCCCCCC>>[C:34]([O:32][CH2:31][C@@H:30]([O:33][C:81](=[O:80])[CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:94][CH2:93][CH2:92][CH2:91][CH3:90])[CH2:29][S:28][CH2:27][C@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])(=[O:48])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Reactant: CCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCC

Procedure:
The product was prepared from (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((R)-2,3-dihydroxypropylthio)propanoate (10, 1 eq) and tetradecanoyl chloride (3.7 eq) following the procedure described for compound 11.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:20]=[CH:19][C:18]2[S:17](=[O:22])(=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10](C(OC(C)(C)C)=O)[C:9]=2[CH:8]=1)=O)C.[F:30][C:31]1([F:39])[CH2:36][CH2:35][CH:34]([CH2:37]I)[CH2:33][CH2:32]1.FC1(F)CCC(C(OCC)=O)CC1.[I-].[CH2:54]([N:61]1[CH:65]=[CH:64][C:63]([NH2:66])=[N:62]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[CH2:54]([N:61]1[CH:65]=[CH:64][C:63]([NH:66][C:4](=[O:3])[CH:6]([C:7]2[CH:20]=[CH:19][C:18]3[S:17](=[O:22])(=[O:21])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[CH:8]=2)[CH2:37][CH:34]2[CH2:35][CH2:36][C:31]([F:39])([F:30])[CH2:32][CH2:33]2)=[N:62]1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: FC1(F)CCC(CI)CC1
Reactant: Nc1ccn(Cc2ccccc2)n1
Reactant: CCOC(=O)Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)c1ccccc1S2(=O)=O
Agent: CCOC(=O)C1CCC(F)(F)CC1
Agent: [I-]
Product: O=C(Nc1ccn(Cc2ccccc2)n1)C(CC1CCC(F)(F)CC1)c1ccc2c(c1)Nc1ccccc1S2(=O)=O

Procedure:
Analogously to Example 36 and Example 44, tert-butyl 2-ethoxycarbonylmethyl-5,5-dioxo-5H-phenothiazine-10-carboxylate, 1,1-difluoro-4-iodomethylcyclohexane (prepared from commercially available ethyl 4,4-difluoro-cyclohexanecarboxylate analogously to the synthesis of the iodide described in Example 40) and 1-benzyl-1H-pyrazole-3-ylamine give N-(1-benzyl-1H-pyrazol-3-yl)-3-(4,4-difluorocyclohexyl)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)propionamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][N:21]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35]>CCO>[Cl-:35].[Cl-:35].[CH2:1]([NH+:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][NH3+:21])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCC(c3ccc(NN=C(c4ccccc4)c4ccccc4)cc3)C2)cc1
Reactant: Cl
Solvent: CCO
Product: [Cl-]
Product: [NH3+]Nc1ccc(C2CCC[NH+](Cc3ccccc3)C2)cc1
Yield: 80 %

Procedure:
A suspension of (F2) in EtOH/conc. HCl (1:10, 0.8 M solution) was stirred overnight at RT. Then, the reaction mixture was extracted with Et2O (3×) and the aqueous phase was concentrated under reduced pressure and dried under high vacuum pump to afford (80%) the title compound as a beige solid. 1H NMR (300 MHz, DMSO-d6, 300K) δ 10.84 (1H, s), 10.16 (3H, s), 8.22 (1H, s), 7.66-7.55 (2H, m), 7.48-7.39 (3H, m), 7.15 (2H, d, J=8.1 Hz), 6.95 (2H, d, J=8.1 Hz), 4.28 (2H, s), 3.38-3.22 (2H, m), 3.20-3.06 (1H, m), 3.05-2.80 (2H, m), 2.04-1.76 (3H, m), 1.69-1.52 (1H, m). MS (ES+) C18H25Cl2N3 required: 281, found: 282 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][CH2:28][OH:29])C>CS(C)=O>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][CH2:28][OH:29])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#CCCO
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: CS(C)=O
Product: O=c1cc(CCO)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 5-hydroxy-pent-2-ynoic acid ethyl ester employing the procedure described in Example 105. [αa]D25 +6.40 (c 0.5, DMSO).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=S)=[CH:4][CH:3]=1.CI.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>CC#N.CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:25]\[C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:4][CH:3]=1
Reactant: S=c1ccccn1-c1ccc(I)cc1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CI
Solvent: CC#N
Product: COc1ccc(/N=c2\ccccn2-c2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (192 mg, 0.61 mmol) in CH3CN (5 mL), CH3I (0.40 mL, 6.4 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo to give a solid. The solid was dissolved in DMF (3 mL). To the solution, p-anisidine (317 mg, 2.6 mmol) was added. After being stirred at 100° C. overnight, the mixture was purified by HPLC to give (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)-4-methoxybenzenamine (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([CH:22]=[C:23]([C:32]#[N:33])[C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=4)=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.[C-:34]#[N:35].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([C:22]([C:34]#[N:35])=[C:23]([C:32]#[N:33])[C:24]4[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=4)=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c3ccccc3c3cc(C=C(C#N)c4cc(F)cc(F)c4)ccc32)cc1
Reactant: [C-]#N
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2c3ccccc3c3cc(C(C#N)=C(C#N)c4cc(F)cc(F)c4)ccc32)cc1
Reaction time: 0.17 h

Procedure:
0.50 g (1.15 mmol) of N-(4-methoxyphenyl)-3-(2-cyano-2-(3,5-difluorophenyl)ethenyl) carbazole and 5 ml of N,N-dimethylformamide as solvent were placed in a 200 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.06 g (1.15 mmol) of sodium cyanide and 0.5 ml of water, which was stirred for 10 minutes. Further, 0.51 g (1.15 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 20 ml of chloroform was added. To the resultant solution was added 20 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a vermilion solid. The vermilion solid was recrystallized in the presence of ethanol to obtain 0.10 g of a vermilion crystal. The yield of the synthesized orange crystal was 19%, and its melting point was 140-142° C. The IR chart is shown in FIG. 23.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].C=[CH:10][CH2:11][CH:12]([OH:16])[CH2:13][CH:14]=[CH2:15].[CH2:17](N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:16][CH:12]([CH:11]=[CH2:10])[CH2:13][CH2:14][CH:15]=[CH2:17])=[O:7]
Reactant: O=C(Cl)CCCCBr
Reactant: CCN(CC)CC
Reactant: C=CCC(O)CC=C
Solvent: ClCCl
Product: C=CCCC(C=C)OC(=O)CCCCBr
Reaction time: 2 h
Yield: 47.5 %

Procedure:
5-Bromopentanoyl chloride (3.0 g, 0.015 mol) was added dropwise to 1,6-heptadien-4-ol (1.5 g, 0.013 mol) and triethylamine (1.4 g, 0.014 mol) in DCM (25 cm3). The mixture was stirred for 2 h and washed with dilute hydrochloric acid (20%, 50 cm3), saturated aqueous potassium carbonate solution (50 cm3), water (50 cm3) then dried (MgSO4) and concentrated to a brown oil. The product was purified by dry flash chromatography [silica gel, DCM] to yield a pale yellow oil (1.7 g, yield 48%). Purity >92% (GC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5](Cl)=[O:6].[OH:20]S(O)(=O)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]([OH:20])=[O:6]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1Br
Reactant: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(C(=O)O)cc1Br
Temperature: 0 °C
Reaction time: 48 h

Procedure:
540 mg (≃0.002 mole) of ##STR17## C5H11 and 700 mg (≃0.002 mole) of 3-bromo-4 octyloxybenzoic acid chloride are charged in a reactor containing 10 ml of pyridine and kept at ambient temperature for 48 hours. The reaction mixture is then poured into a solution containing 10 ml of concentrated H2SO4 and 100 g of ice. The organic fraction is extracted three times with ether then washed three times with water and finally dried on anhydrous Na2SO4. The solvent is evaporated and the product is recrystallised three times in ethanol. 850 ml of product are obtained. The molar efficiency is 73%. Step (d) of substituting the cyanide group for the bromine group
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=[O:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.OS([O-])=O.[Na+]>ClCCl.CCOCC>[CH3:12]/[C:7](/[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:1])=[CH:8]/[C:9]([OH:11])=[O:10]
Reactant: C/C(=C/C(=O)O)CCCCC(O)c1ccc2ccccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(=C/C(=O)O)CCCCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of 192 (98 mg, 0.33 mmol) in dry dichloromethane (6 mL) was added a solution of Dess-Martin reagent (162 mg, 0.38 mmol) in dry dichloromethane (1 mL) via cannula. The mixture was stirred at room temperature for 24 hours. The mixture was diluted with ether and NaHSO3 (221 mg) in aqueous solution was added with stirring until the phases are homogeneous. The product was extracted, washed with 5% KHSO4, brine, dried over Na2SO4, and finally isolated by chromatography over silica gel (hexanes:Et2O: 4:1 to 1:1) to give 193 in 94% yield. 13CNMR: (75 MHz, CD3OD) δ: 25.2, 25.3, 28.7, 33.7, 39.1, 117.4, 124.7, 127.8, 128.7, 129.0, 129.5, 130.6, 131.0, 137.8, 161.9, 170.1. MS (ESI)=297 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: COc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 94.4 %

Procedure:
Using 4-bromo-2-methoxybenzoic acid (2.31 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.91 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.81 g) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[CH3:15][C:16]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])[CH3:17]>O1CCOCC1>[C:16]([O:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:21])([CH3:18])([CH3:17])[CH3:15]
Reactant: NCCCC(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCC(=O)O
Temperature: -20 °C
Yield: 51.9 %

Procedure:
Prepared as described for L2 from stirring 4-aminobutyric acid (3.94 g, 38.2 mmol) in 50% aqueous dioxane with triethylamine (8.0 mL, 57 mmol) and BOC-ON (10.4 g, 42.2 mmol). A yellow oil was obtained that solidified upon addition of hexanes and cooling to −20° C. to yield a cream solid (4.03 g, 51.8%). 1H NMR (d6-DMSO, 300 MHz): δ 1.36 (s, 9H, CH3), 1.57 (m, 2H, CH2), 2.17 (t, 2H, CH2), 2.90 (m, 2H, CH2), 6.80 (t, 1H, NH).