Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[N:10][CH:11]=1)[CH3:2].[CH:14]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:12][C:7]1[C:6]([CH:5]([CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:11][N:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)Cc1cncnc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cncnc1Cl
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a stirred, cooled (−78° C. solution of 5.8 g (29 mmol) of ethyl(4-chloro-5-pyrimidinyl)acetate (see Step A, i-20) in 75 mL of anhydrous THF under an atmosphere of nitrogen was added 15.2 mL (30.4 mmol) of a 2.0 M solution of lithium diisopropylamide in anhydrous THF. The resulting mixture was stirred for 15 min then 2.26 mL (36.1 mmol) of iodomethane was added over 5 min. The reaction mixture was stirred for 15 min, allowed to warm to −20° C. over 45 min, then warmed to 0° C. for 15 min. The reaction mixture was then quenched with a saturated ammonium chloride solution and extracted with 50 mL of dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 20% ethyl acetate in hexanes mixture afforded the title compound (1.9 g, 31%). 1H-NMR (500 MHz, CD3OD) δ: 8.88 (s 1H), 8.74 (s, 1H), 4.17 (m, 2H), 1.58 (d, J=7 Hz, 3H), 1.29 (t, J=7 Hz, 3H). LC-MS: m/z (E/S) 215 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[NH:8][CH2:7][CH2:6]2.C1C=CC=CC=1.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>N1C=CC=CC=1>[CH:34]1([C:40]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)/[C:9]/2=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cc2c(cc1OC)C(=Cc1cc(OC)c(OC)c(OC)c1)NCC2
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)/C(=C/c1cc(OC)c(OC)c(OC)c1)N(C(=O)C1CCCCC1)CC2

Procedure:
To a suspension of 5 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline in 50 parts of benzene is added 15 parts of pyridine, followed by 3 parts of cyclohexanecarbonyl chloride. The resultant mixture is heated at the boiling point under reflux in a nitrogen atmosphere for 2 hours, then cooled, consecutively washed with water and aqueous 5% sodium becarbonate, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of ethyl acetate and ether to afford (Z)-2-cyclohexanecarbonyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline melting at 162°-164°.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[N:8]C(=O)C(F)(F)F)[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[N:4]=1)[CH3:2].[OH-].[Na+].O>O1CCCC1>[CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 5-ethyl-3-(4-iodobenzyl)-2-trifluoroacetylimino-1,3,4-thiadiazoline (44.1 g) in tetrahydrofuran (300 ml) was added 2N sodium hydroxide (100 ml), followed by stirring at room temperature overnight. Water (300 ml) was added to the reaction mixture, followed by extraction with chloroform (250 ml) twice. The organic layers were washed with a saturated aqueous sodium hydrogencarbonate and were dried over anhydrous magnesium sulfate, followed by removal through distillation. The oily substance so obtained was crystallized from diisopropyl ether, whereby 32.3 g of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:20])[CH2:16][C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:15][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Reactant: CC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 457 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 277 mg of 3-pentyn-1-ol, to which 132 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 467 mg of 4-(2-fluorophenyl)-6-(3-pentynyloxy)pyrimidine (the present compound (153)).
Reaction SMILES: ClC1C=C2C(C(N3CCN(C(NC4C=CC(C(F)(F)F)=CC=4)=O)CC3)=CC=N2)=CC=1.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C.[C:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]=[C:67]=[O:68])=[CH:62][CH:61]=1)(=[O:59])[CH3:58]>C(Cl)Cl.CO>[C:57]([C:60]1[CH:65]=[CH:64][C:63]([NH:66][C:67]([N:45]2[CH2:46][CH2:47][N:42]([C:36]3[C:35]4[C:40](=[CH:41][C:32]([Cl:31])=[CH:33][CH:34]=4)[N:39]=[CH:38][CH:37]=3)[CH2:43][CH2:44]2)=[O:68])=[CH:62][CH:61]=1)(=[O:59])[CH3:58]
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CC(=O)c1ccc(N=C=O)cc1
Agent: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (250 mg, 1.01 mmol), diisopropyl(ethyl)amine (261 mg, 2.02 mmol), and 4-acetylphenyl isocyanate (195 mg, 1.21 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.C([Sn]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(CCCC)CCCC)CCC>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a slurry of anhydrous LiCl (46 mg, 1.1 mmol) and tetrakis(triphenylphosphine)-palladium(0)(24 mg, 0.02 mmol) in dry dioxane (3 mL) was added a solution of Methyl (1RS,2RS,3RS)-3-(4Methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (95 mg, 0.16 mmol) and tri(but-1-yl)stannylbenzene (319 mg, 0.87 mmol) in dioxane (1 mL). The mixture was refluxed under Argon for 17 h, cooled to room temperature, diluted with ethyl acetate (5 ml) and the resulting solution washed sequentially with brine and water. The organic layer was dried (MgSO4 anhydrous), filtered through a short pad of silica gel and concentrated in vacuo to yield an oil. The product was purified by flash column chromatography (silica gel, gradient elution from hexanes to 10% ethyl acetate/hexanes) to afford the title compound as a white solid. (92 mg, 86%).
Reaction SMILES: C(O)C.C([O:11][C:12](=[O:29])[C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[O:21]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].O1CCCC1>[C:19]([C:17]1[CH:18]=[C:13]([C:12]([OH:29])=[O:11])[C:14]([OH:21])=[CH:15][CH:16]=1)#[N:20]
Reactant: N#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(O)c(C(=O)O)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethanol (10 mL) and tetrahydrofuran (10 mL) were added to 2-benzyloxy-5-cyanobenzoic acid benzyl ester (446 mg, 1.3 mmol) and 5% palladium on carbon (45 mg), and the mixture was hydrogenated at room temperature for 2 hours. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure to give the title compound (212 mg, 100.0%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24][N:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:16]2[C:11]([C:12]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:14]=[CH:15]2)=[N:10]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: Fc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccc(F)cc2Cl)cc1
Temperature: 120 °C
Yield: 42.2 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-7-trifluoromethyl-1H-indazole (6.43 g, 23 mmol) in 20 mL DMF was added 2-chloro-4-fluoro benzyl bromide (7.0 g, 31 mmol). The reaction mixture was heated overnight at 120° C. After cooling to room temperature, ethyl acetate was added and the solution was washed three times with brine. The organic layer was dried over NaSO4 and concentrated. Flash chromatography (hexane/CH2Cl2, 1:1, as eluent) afforded 4.1 g of pure product. Three grams (3 g) of product were recrystallized from 10 mL of isopropanol to recover 1.98 g of crystalline product, mp 78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[O:15])[CH2:10]1.[ClH:38].C(O)C>CCOC(C)=O>[ClH:1].[ClH:38].[Cl:1][C:2]1[CH:3]=[C:4](/[CH:26]=[CH:27]/[C:28]([NH:30][OH:31])=[O:29])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:20][CH2:21]2)=[O:15])[CH2:10]1
Reactant: CN(C)C[C@H]1CC[C@H](C(=O)N2CC[C@@H](Nc3ncc(/C=C/C(=O)NOC4CCCCO4)cc3Cl)C2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C[C@H]1CC[C@H](C(=O)N2CC[C@@H](Nc3ncc(/C=C/C(=O)NO)cc3Cl)C2)CC1
Reaction time: 3 h

Procedure:
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (530 mg) and 2N HCl/Ethanol (5 ml) was stirred for 3 hrs. EtOAc (10 ml) and IPE (50 ml) was added and stirred. After 1 hour, precipitate was filtered and dried to give 462 mg (89%) of (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C:25]([OH:27])=O.[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[NH:36][NH2:37]>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C:25]([NH:37][NH:36][C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:27]
Reactant: Cc1ccc(C(CCCCl)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
IPEA (4.04 mL), HOBt (1.82 g) and EDC (2.59 g) were added to a solution of 5-chloro-2-p-tolylpentanoic acid (1.53 g) and tert-butyl carbazate (1.07 g) in DMF (25 mL), and the reaction solution was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.77 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:27][NH2:28]>CO>[CH3:27][NH:28][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccsc1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccsc1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a stirred solution of 4-(1-(4-(2-chloroethoxy)phenyl)-2-(thiophen-3-yl)but-1-enyl)phenol (0.3 g, 1.0 eq) in 10 mL MeOH was added 10 mL MeNH2 (30% in water). The mixture was refluxed at 80° C. overnight, and purified by column chromatography with CH2Cl2:MeOH(NH3)=10:1 to give the desired product (185 mg, 63% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.00-7.12 (m, 3H), 6.90-6.95 (m, 1H), 6.80-6.89 (m, 2H), 6.72-6.79 (m, 2H), 6.68-6.72 (m, 1H), 6.58 (d, J=8.8 Hz, 1H), 6.53 (d, J=8.8 Hz, 1H), 4.09 (t, J=5.2 Hz, 1H), 3.99 (t, J=5.2 Hz, 1H), 3.00 (t, J=5.2 Hz, 1H), 2.94 (t, J=5.2 Hz, 1H), 2.40-2.54 (m, 5H), 0.98 (t, J=5.2 Hz, 3H); m/z=380[M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:27])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:15]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:27])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:36])[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CSCc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Solvent: ClCCl
Product: COC(=O)CS(=O)Cc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Yield: 31.1 %

Procedure:
To a solution of 0.17 g of 4-hydroxy-3-[3-[3-[(methoxycarbonylmethylthio)methyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 4 ml of methylene chloride was added 0.076 g of m-chloroperbenzoic acid in portions under ice-cooling. After stirred under ice-cooling, the solvent was distilled off under reduced pressure, water was added to the residue, this was extracted with ethyl acetate, washed with an aqueous sodium bicarbonate solution, and further washed with an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.055 g of 4-hydroxy-3-[3-[3-[(methoxycarbonylmethylsulfinyl)methyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (77a)] as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].I[CH2:13][CH3:14]>>[CH2:13]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[CH3:14]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (1.5 g), in dimethylformylamide (30 mL), 60% sodium hydride (0.50 g) was added portion-wise at 0° C. then warmed to ambient temperature. Iodoethane (3.5 mL) was added to the mixture at 0° C. then stirred for 16 h at room temperature. The reaction mixture was filtered then the filtrate was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O (×2) then brine and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAc/Et2O (1:1) as eluent to give the subtitle compound as clear, colourless oil. Yield: 1 g
Reaction SMILES: C(O)C#C.[CH2:5]([OH:19])[C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].COCCO[AlH2-]OCCOC.[Na+]>CCOCC>[CH2:5]([OH:19])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCC#CCO
Agent: C#CCO
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCC/C=C/CO

Procedure:
trans-2-Tetradecen-1-ol was prepared by reduction of the propargyl alcohol by the method described by Jones and Denmark (Org. Syn., 1985, 64, 182-8) using 8.0 g (38 mmole) of 2-tetradecyn-1-ol in 30 ml of ether and 16 ml (55 mmole) of Red-Al in 40 ml of ether. Kugelrohr distillation afforded 7.67 g of clear oil. 1H NMR δ5.66 (m, 2), 4.08 (d, 2, J=5 Hz) 2.03 (dd, 2, J=6, 13 Hz), 1.60 (br, 1), 1.4-1.2 (m, 18), 0.88 (t, 3, J=7 HZ).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15].Cl>>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Agent: Cl
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 0.21 h

Procedure:
500 g of 4-chloro-3-nitrobenzoic acid and 2 L of mono methyl amine were added stirred for 10-15 minutes at 25° C. to 35° C. The reaction mixture was heated to 55° C. and maintained for 12 hours. The reaction mixture was dumped in ice-water and stirred for 15 minutes and pH was adjusted to 2 by conc. HCl. The reaction mixture was stirred for 15 minutes and filtered. The wet-cake was washed with water and dried to obtain 4-(methylamino)-3-nitrobenzoic acid of Formula (A).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:33])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)CCCCBr
Reactant: C=CCOC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Product: C=CCOC(=O)c1ccc(-c2ccc3cc(OCCCCC(=O)OCC)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Yield: 60.8 %

Procedure:
Following the procedure of Example 12(a), but reacting 2 g (4.5 mmol) of allyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 1.4 g (6.7 mmol) of ethyl 5-bromovalerate, 1.55 g (59%) of the expected compound was obtained, which compound had a melting point of 117°-8° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[S:31][CH2:30][CH2:29][NH:28][CH2:27]2)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[S:31][CH2:30][CH2:29][N:28]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=3)=[O:16])[CH2:27]2)[CH:21]=1
Reactant: c1cncc(C2CNCCS2)c1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCSC(c2cccnc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 2-pyridin-3-yl thiomorpholine hydrochloride (13.0 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (12.8 mg). Calcd for C20H16F3N3O2S: 419.0915, found 419.0914.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([S:20](Cl)(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:20]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CCCCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using butane sulfonyl chloride (72 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]butane-1-sulfonamide (0.026 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:39]=[CH:38][C:28]3[CH2:29][N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][N:33]([CH2:34][CH3:35])[C:27]=3[CH:26]=2)[C:21]([Cl:40])=[CH:20][N:19]=1>>[Cl:40][C:21]1[C:22]([NH:24][C:25]2[CH:39]=[CH:38][C:28]3[CH2:29][N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][N:33]([CH2:34][CH3:35])[C:27]=3[CH:26]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: CCN1CCN(CC)c2cc(Nc3nc(Cl)ncc3Cl)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc5c(c4)N(CC)CCN(CC)C5)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(1,4-diethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-8-yl)-amine in an analogous manner to example 712. Product was isolated as a tan solid (0.025 g, 16%). Mp 75-78° C.; LCMS (m/e) 549 (M); 1H-NMR (DMSO, 400 MHz) δ 9.12 (s, 1H), 8.67 (s, 1H), 8.09 (s, 1H), 7.25-7.19 (m, 4H), 7.04 (d, 2H, J=6.82 Hz), 6.90-6.83 (d, 1H, J=7.83 Hz), 3.63 (s, 2H), 3.56 (s, 2H), 3.09-3.00 (q, 2H, J=6.32 Hz), 2.92-2.83 (m, 4H), 2.80-2.70 (m, 3H), 2.47-2.31 (m, 4H), 1.09-1.02 (m, 12H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)=O)(C)(C)C>Cl.CCO>[OH:13][C:10]1([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CCOP(=O)(OCC)C1(O)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(OCC)C1(O)CCNC1

Procedure:
A solution of 1.78 g (5.5 mmol) of (R/S)-1-tert-butoxycarbonyl-3-hydroxy-pyrrolidin-3-yl phosphonic acid, diethyl ester (from Step C) in 2N HCl in EtOH was stirred at rt for 5.5 h. The reaction was concentrated from CH2Cl2 several times. The crude product was partitioned between aqueous NH4OH and CHCl3/isopropanol (3:1 v/v). After separating phases, the aqueous layer was extracted with 3× CHCl3/isopropanol (3:1 v/v). The combined organics were dried over Na2SO4 and concentrated. The residue was purified on a 40S Biotage column using 90:10:1 v/v/v CH2Cl2/MeOH/NH4OH as the eluant to afford the title compound as a light brown oil: 1H-NMR (500 MHz) δ 1.35 (t, J=7.0, 6H), 1.92 (m, 1H), 2.20 (m, 1H), 2.78-2.99 (m, 3H), 3.06 (dd, J=12.7, 3.7, 1H), 3.13 (dd, J=12.7, 6.2, 1H), 3.20 (m, 1H), 4.16-4.23 (m, 4H).