Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9](Cl)=[O:10].[Cl:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[CH:22]([OH:25])[C:23]#[CH:24])=[CH:16][CH:15]=1.N1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([O:25][CH:22]([C:23]#[CH:24])[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([O:18][C:17]2[CH:29]=[CH:30][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:20]=1)=[O:10]
Reactant: C#CC(O)c1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C#CC(OC(=O)C1C(C=C(Cl)Cl)C1(C)C)c1cccc(Oc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
In 120 ml of dry benzene was dissolved 11.4 g of 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (cis-/trans-ratio=50:50, approx.) followed by addition of 12.9 g. of 3-(4-chlorophenoxy)-α-ethynylbenzyl alcohol and further by dropwise addition of 7.9 g of pyridine. The mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was diluted with 100 g of water and the benzene layer was separated, washed with dilute hydrochloric acid and water and dried over anhydrous magnesium sulfate. The low-boiling fraction was then distilled off under reduced pressure to recover an oil. This oily product was purified by preparative liquid chromatograpy [column: Water's Associates' Prep LC/System 500, Prep PAK® 500/SILICA; solvent system: diethyl ether:n-hexane=2:98]. The above procedure yielded 20.2 g of 3-(4-chlorophenoxy)-α-ethynylbenzyl 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (yield 90%). The separation of cis- and trans-isomers from each other can be effected by the above-mentioned preparative liquid chromatography. The NMR spectra of such isomers are indicated below.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:32](=[O:33])[C:31]([CH3:34])=[CH:30][N:12]([C@@H:13]2[O:20][C@H:17]([CH2:18][OH:19])[C@@:15]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([OH:16])[CH2:14]2)[C:11]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.P(=O)(O)(O)[OH:52]>CS(C)=O>[CH2:1]([O:8][CH2:9][N:10]1[C:32](=[O:33])[C:31]([CH3:34])=[CH:30][N:12]([C@@H:13]2[O:20][C@H:17]([C:18](=[O:52])[OH:19])[C@@:15]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([OH:16])[CH2:14]2)[C:11]1=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(O)(O)O
Reactant: Cc1cn([C@H]2C[C@@](O)(COCc3ccccc3)[C@@H](CO)O2)c(=O)n(COCc2ccccc2)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: Cc1cn([C@H]2C[C@@](O)(COCc3ccccc3)[C@@H](C(=O)O)O2)c(=O)n(COCc2ccccc2)c1=O

Procedure:
A solution of 3-benzyloxymethyl-3′-benzyloxymethylthymidine (14.5 g, 30 mmol) in DMSO (200 ml) was treated with DCC (33 g, 160 mmol) and phosphoric acid 85% (2.0 g) for 16 h. The reaction mixture was filtered and concentrated in vacuo. The resultant oil was chromatographed on silica gel (EtOAc/hexane, 7/3) to afford the product as a viscous oil, 11 g (76%). 1H NMR (CDCl3) 1.92 (s, 3H, C5-CH3), 2.20-2.52 (m, 2H, C2′H), 4.09 (m, 1H, C4′H), 4.49 (m, 1H, C3′H), 4.62 (s, 2H, NCH2O), 6.28 (t, 1H, C1′H) 7.24-7.51 (M, 11H, ArH, CH═), 9.65 (s, 1H, CHO). Anal. Calcd. for C26H28N2O7: C, 64.99; H, 5.87; N, 5.83. Found: C, 64.68; H, 5.95; N, 6.01.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4- carboxylic acid was prepared starting from 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (17.4 g, 40 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 10.8 g (66%); colorlesssolid; mp 154° C.; MS: 408 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.[CH:16]1[CH:21]=[CH:20][C:19](/[C:22](/C2C=CC([N+]([O-])=O)=CC=2)=[N:23]/O)=[CH:18][CH:17]=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(N)C1C=CC=CC=1>>[CH2:22]([NH:23][C:13]([CH:9]1[N:8]([S:40]([C:37]2[CH:38]=[CH:39][C:34]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:35][CH:36]=2)(=[O:42])=[O:41])[CH2:12][CH2:11][S:10]1)=[O:15])[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, [1,1′-biphenyl]-4-sulfonyl chloride and benzylamine, the title compound was obtained in 97% purity by HPLC.
Reaction SMILES: [CH2:1]([C:6]1[CH:22]=[CH:21][C:9]([C:10](=[O:20])[CH2:11][C:12]2[CH:13]=C([CH:17]=[CH:18][CH:19]=2)C#N)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:23]([OH:26])(=[O:25])[CH3:24]>S(=O)(=O)(O)O.O>[CH2:1]([C:6]1[CH:22]=[CH:21][C:9]([C:10](=[O:20])[CH2:11][C:12]2[CH:13]=[C:24]([CH:17]=[CH:18][CH:19]=2)[C:23]([OH:26])=[O:25])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)O
Reactant: CCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCc1ccc(C(=O)Cc2cccc(C(=O)O)c2)cc1

Procedure:
First, 3-cyanophenylacetic acid (3 g, 0.019 mol) is heated under reflux in thionyl chloride (50 ml) for 90 minutes. The excess thionyl chloride is then removed by distillation and the residual acid chloride added in one portion to a solution. 1-phenylpentane (2.76 g, 0,019 moles) in methylene chloride (10 ml). Anhydrous aluminum chloride (2.98 g) is added in small portions over 10 minutes. The reaction mixture is then heated under reflux for 1 hour, cooled and poured into a mixture of ice water (250 ml) and concentrated hydrochloric acid (50 ml). The mixture is extracted with ether (2×100 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica (hexane: ethyl acetate at 90:10 ) to yield 3-(4-pentylphenacyl) benzonitrile (1.13 g, m.p. 73° C.). This nitrile is heated under reflux in a mixture of 75% sulfuric acid (8 g) and acetic acid (8 g) for 90 minutes. The reaction mixture is then diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane to provide 3-(4-pentylphenacyl)benzoic acid (0.97 g), m.p. 109°-111° C., which was identified by IR and NMR spectroscopy.
Reaction SMILES: C([O:5][CH2:6][C@@H:7]([C:16]1[O:20][N:19]=[C:18]([C@@H:21]2[CH2:25][C:24](=[N:26][O:27][CH3:28])[CH2:23][N:22]2[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[O:30])[N:17]=1)[NH:8]C(OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:28][O:27][N:26]=[C:24]1[CH2:25][CH2:21][N:22]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[O:30])[CH2:23]1.[CH3:28][O:27][N:26]=[C:24]1[CH2:25][C@@H:21]([C:18]2[N:17]=[C:16]([C@@H:7]([NH2:8])[CH2:6][OH:5])[O:20][N:19]=2)[N:22]([C:29]([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)=[O:30])[CH2:23]1
Reactant: CON=C1C[C@@H](c2noc([C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C1CCN(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc([C@@H](N)CO)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
4-{[(2S,4EZ)-2-(5-{(1S)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]ethyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl (100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for 1 hour. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and solvent removal afforded two products, which were separated and purified by flash-chromatography to give the desired products as mixtures of E-/Z-isomers, (3EZ,5S)-5-{5-[(1S)-1-amino-2-tert-butoxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl-3-pyrrolidinone O-methyloxime in 20% yield (80.8% purity by HPLC), and (3EZ,5S)-5-{5-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime in 30% yield (98.1% purity by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[C:34](Cl)=[O:35]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][NH:17][C:34]([C:26]3[O:25][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[CH:27]=3)=[O:35])[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C2(CNC(=O)c3cc4ccccc4o3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 78 %

Procedure:
C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (141 mg, 0.600 mmol) was dissolved in anhydrous 1,4-dioxane (2 mL) containing triethylamine (167 μL, 1.20 mmol). Benzofuran -2-carbonyl chloride (108 mg, 0.600 mmol) was then added and the reaction mixture was allowed to stir for 16 hours. The reaction mixture was filtered, evaporated to dryness, and purified by column chromatography on silica gel using a gradient of 5-50% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.1775 g, 0.4678 mmol, 78.0%) ESI-MS m/z calc. 379.5, found 380.2 (M+1)+. Retention time of 3.36 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.57-2.03 (m, 8H), 3.46 (d, J=6.4 Hz, 2H), 3.72 (s, 6H), 6.81-6.89 (m, 3H), 7.31 (t, J=7.5 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.48 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.94 (t, J=6.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 23.1, 35.3, 47.2, 51.8, 55.5, 109.2, 111.5, 111.6, 111.7, 118.8, 122.6, 123.6, 126.7, 127.1, 139.3, 147.1, 148.3, 149.1, 154.1, 158.2.
Reaction SMILES: [OH-:1].[K+].[CH:3]1([CH:6]([CH:10]2[CH2:12][CH2:11]2)[CH2:7][C:8]#N)[CH2:5][CH2:4]1.N.Cl.[OH2:15]>C(O)COCCO>[CH:3]1([CH:6]([CH:10]2[CH2:12][CH2:11]2)[CH2:7][C:8]([OH:15])=[O:1])[CH2:5][CH2:4]1
Reactant: N#CCC(C1CC1)C1CC1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: N
Agent: [K+]
Solvent: OCCOCCO
Product: O=C(O)CC(C1CC1)C1CC1
Yield: 83 %

Procedure:
45 g of potassium hydroxide are dissolved in 65 ml of water. 100 ml of diethylene glycol are added to the above solution followed by 30 g of the product obtained in stage A. The mixture is refluxed until the evolution of ammonia ceases. After cooling, 700 ml of water are added and the mixture is acidified with 12N hydrochloric acid. After extraction with ether, the ethereal phases are pooled, washed with water until neutral, dried and evaporated. The expected product is obtained after distillation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:17](=[O:20])[CH:18]=[CH:19][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To compound of Step A (161.0 g, 561.8 mmol) in DMF (800 mL) is added methyl acrylate (58.0 g, 674.2 mmol), TEA (170.5 g, 1685.4 mmol) and dichlorobis(triphenylphosphine)palladium(II) (7.9 g, 11.2 mmol). The mixture is heated at 80° C. for about 32 hours. The mixture is cooled, diluted with 1000 mL of EtOAc and washed with 10% aqueous sodium bisulfate. The aqueous portion is extracted three times with EtOAc and the combined organics are dried (Na2SO4) and concentrated to dryness. The residue is dissolved in a small amount of DCM and filtered through 7 inch of silica gel in a 2 L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent is concentrated to dryness and recrystallized from EtOAc/hexanes to afford about 116.9 g (71%) of Step B compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[C:4]([CH3:18])[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[F-].[Cs+]>COCCOC.O>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[C:4]([CH3:18])[CH:3]=1
Reactant: COCCCc1ccccc1B(O)O
Reactant: Cc1cc(Br)ccc1C(C#N)Cc1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cccnc2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution 2-(4-bromo-2-methylphenyl)-3-pyridin-3-ylpropanenitrile (1 eq.) from step 1 and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 (1.2 eq.) in DME (0.1M) at room temperature was added palladium tetrakistriphenyl phosphine (Pd(PPh3)4; 0.05 eq.) and CsF (2.4 eq.). The mixture was refluxed for 2 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with water, brine, dried over Na2SO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 65% in 30 min) afforded the desired compound.
Reaction SMILES: Cl.Cl.C(C1C=C(/[CH:12]=[CH:13]/[CH2:14][N:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH2:37][CH2:36][CH2:35][N:34]=4)[CH2:29][CH2:28]3)=[C:22]([C:38](=[O:40])[NH2:39])[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])C=CC=1)(=N)N.[C:41]([O:49]C1C=CC([N+]([O-])=O)=CC=1)(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([N:61]([CH2:64][CH3:65])CC)C>ClCCl.C(#N)C.O>[C:41]([NH:15][C:20]1[C:65]([CH:64]=[NH:61])=[C:24](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH2:37][CH2:36][CH2:35][N:34]=4)[CH2:29][CH2:28]3)=[C:22]([C:38](=[O:40])[NH2:39])[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:23]=[CH:22][CH:21]=1)(=[O:49])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: CS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C3=NCCC3)CC2)c(C(N)=O)c1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)N(C/C=C/c1cccc(NC(=O)c2ccccc2)c1C=N)c1ccc(OC2CCN(C3=NCCC3)CC2)c(C(N)=O)c1
Yield: 75 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-carbamoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidin-4-yloxy]phenyl]methanesulfonamide dihydrochloride (0.30 g) obtained in example 99(b) in a mixture of dichloromethane (4 ml) and acetonitrile (4 ml) were added successively 4-nitrophenyl benzoate (0.15 g) and triethylamine (0.28 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight. After stirring, the reaction mixture was diluted with dichloromethane, and the organic layer was washed successively with a 0.5N aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (50:0˜47:3). The purified solid obtained was dissolved in water and then lyophilized to afford the title compound (0.24 g, yield: 75%) as a pale yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18](=O)[CH3:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>ClCCCl>[F:1][C:2]1[C:3]([NH:17][C:18](=[S:30])[CH3:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)Nc1nc(OCc2ccc(F)cc2)ncc1F
Solvent: ClCCCl
Product: CC(=S)Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 100 °C
Yield: 3.2 %

Procedure:
N-(5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl)acetamide (50 mg, 0.42 mmol) was stirred in a Biotage Initiator® microwave vessel with 1,2-dichloroethane (3 mL) and Lawesson's reagent (170 mg, 0.42 mmol). The vessel was heated in a Biotage Initiator® microwave to 100° C. for 5 minutes then cooled room temperature, filtered, and diluted with CH2Cl2. The reaction mixture was then washed brine, and the layers were separated. The organic extract was dried onto silica and purified by flash chromatography. The product-containing fractions were then evaporated to dryness and purified again by reverse-phase HPLC to give 4 mg of N-(5-fluoro-2-(4-fluorobenzyl-oxy)pyrimidin-4-yl)ethanethioamide (4%) as a yellow glass: 1H NMR (CDCl3) δ 9.34 (b, 1H), 8.29 (d, J=3 Hz, 1H), 7.41 (m, 2H), 7.06 (m, 2H), 5.33 (s, 2H), 3.13 (s, 3H); HPLC-MS (ESI): m/z 294 (ES−).
Reaction SMILES: C(N(CC)C(Cl)=O)C.[CH2:9]([N:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:12][CH3:13])[CH3:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[CH2:9]([N:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:12][CH3:13])[CH3:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38][C:17]([NH:16][C:14]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])=[O:15])=[S:18])=[CH:39][CH:40]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN(CC)C(=O)Cl
Agent: CCN(CC)C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
(Diethylamino)methanoyl isothiocyanate was prepared using commercially available N,N-diethylcarbamic chloride (80 mg) as a starting compound according to the description of the literature. (Diethylamino)methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (42 mg, yield 55%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][C:19](=[O:20])[N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CBr)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCN(c3ccccc3)CC2)cc1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.582 g) in dimethylformamide (8 mL) under argon was treated with 55% sodium hydride (0.131 g), stirred for 30 minutes in a ice-water bath and then 1-(bromoacetyl)-4-phenyl-piperazine (1.0 g) in dimethylformamide (5 mL) was added. The solution was stirred at room temperature for 18 hours and worked up as in Example 20. The crude product was purified by HPLC (ethyl acetate-hexane; 1:1) to yield 0.8 g of 4-[2-oxo-2-(4-phenyl-1-piperazinyl)ethoxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].[CH3:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1S(C)(=O)=O.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:21]3[N:20]([CH3:19])[C:24]4=[N:25][CH:26]=[CH:27][CH:28]=[C:23]4[N:22]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1nc(-c2ccc(O)cc2)c2nccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccnc21
Temperature: 150 °C
Yield: 63.4 %

Procedure:
To a solution of 4-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)phenol (100 mg) and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (88 mg) in DMF (3 mL) was added NaH (60% in oil, 17 mg) at room temperature, and the mixture was heated at 150° C. for 1.5 h under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (98 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]([CH:21]([CH2:27][CH2:28][CH2:29]Cl)[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ClC1C=CC=CC=1>O>[C:14]1([C:13]2[N:1]([CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][CH:5]=3)[CH2:29][CH2:28][CH2:27][C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)C(CCCCl)C(=O)c1ccccc1
Solvent: Clc1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(c2ccccc2)N(CCc2c[nH]c3ccccc23)CCC1

Procedure:
0.273 g. (0.0017 mole) of tryptamine are added to a solution of 0.229 g. (0.00085 mole) of (±)-ethyl 2-benzoyl-5-chloro-valerate prepared according to Example 29 in 5 ml. of chlorobenzene, and the reaction mixture is heated on an oil bath of 150° C. for 5 hours, with stirring, while the water formed is allowed to distill off slowly together with chlorobenzene. After cooling the precipitate is filtered off, washed with chlorobenzene, and the combined chlorobenzene solution is evaporated from a bath of 40° C. on a rotating evaporator. The title compound is obtained by subjecting the residue to column chromatography on 40 g. of silica gel (Geduran Si 60, 0.063-0.200 mm.) using toluene containing 10% of diethyl amine as an eluting agent.