Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C@@H:17]([NH2:24])[C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[CH:6]=[CH:7][C:8]=1[F:9].C(OC(N[C@@](C1C=CC=CC=1C1C=CC(F)=C(Cl)C=1)(C)C(O)=O)=O)(C)(C)C.[CH3:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=2)=[CH:56][C:55]=1[C:70](O)=[O:71]>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C@@H:17]([NH:24][C:70]([C:55]2[CH:56]=[C:57]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([F:67])([F:69])[F:68])=[CH:62][CH:61]=3)[CH:58]=[CH:59][C:54]=2[O:53][CH3:52])=[O:71])[C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reactant: Cc1noc([C@H](N)Cc2ccccc2-c2ccc(F)c(Cl)c2)n1
Agent: CC(C)(C)OC(=O)N[C@@](C)(C(=O)O)c1ccccc1-c1ccc(F)c(Cl)c1
Agent: Cl
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccccc1-c1ccc(F)c(Cl)c1)c1nc(C)no1
Yield: 66.4 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.081 g) was prepared from 2-(3′-Chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride salt (0.075 g, 0.2 mmol) which was prepared from 2-(R)-tert-Butoxycarbonylamino-2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-propionic acid following general procedure N and 4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.06 g, 0.2 mmol) following general procedure A.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1>O>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([O-:35])=[O:34])=[CH:36][CH:37]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Solvent: O
Product: O=C([O-])COc1ccc(Cl)cc1

Procedure:
4 g of the salt are prepared, according to the method of the example 19.a, starting from 3.36 g of apovincamine and 1.86 g of p-chlorophenoxyacetic acid. The melting point of the salt is about 120° C. and it is insoluble in water; the content of apovincamine is 64%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[N:29]1([C:33]([C:35]2[CH:36]=[CH:37][C:38](Cl)=[N:39][CH:40]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([C:33]([C:35]2[CH:36]=[CH:37][C:38]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:39][CH:40]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 65.7 %

Procedure:
Potassium carbonate (0.181 g, 1.31 mmol) was added to a mixture of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.2 g, 0.66 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (129 mg, 0.66 mmol) in acetonitrile (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Biotage initiator Microwave’ for 6 hours. The mixture was allowed to reach RT and pressure and was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (5×50 mL) brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-5% methanol in ethyl acetate, to give the desired compound (202 mg). 1H NMR δ (CDCl3): 1.33 (d, 3H), 2.38 (quin, 2H), 3.40 (s, 3H), 3.61-3.47 (m, 2H), 3.74 (s, 3H), 4.42-4.18 (m, 4H), 4.58 (sextet, 1H), 6.80 (d, 1H), 6.91 (t, 1H), 6.97 (d, 1H), 7.21 (t, 1H), 7.26 (d, 1H), 7.33 (t, 1H), 8.09-8.05 (m, 1H), 8.42 (d, 1H), 8.92 (s, 1H); m/z 466 (M+H)+
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:11]#[N:12])=[CH:6][CH:5]=1.CN(C=O)C.Cl.Cl[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CCCCCC.CCOCC.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:11]#[N:12])([CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:27][N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)=[CH:8][CH:9]=1
Reactant: N#CC(CCc1cccs1)c1ccc(Cl)cc1
Reactant: ClCn1cncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(CCc1cccs1)(Cn1cncn1)c1ccc(Cl)cc1

Procedure:
To a flask under a nitrogen atmosphere was added, with stirring, 1.5 g. (0.036 mole) of 60% sodium hydride, washed twice with hexane to remove the original mineral oil, in 30 ml. of dry DMF. To this slurry at room temperature was added 3.36 g. (12.8 mmoles) of 2-(4-chlorophenyl)-4-(2-thienyl)butyronitrile in 30 ml. of DMF over 10 minutes. After stirring for 30 minutes, 2.15 g. (14.08 mmoles) of 1-(chloromethyl)-1,2,4-triazole hydrochloride was added in two portions and stirred for another 60 minutes. Water, 20 ml., was then added followed by 100 ml. of ether. The ether layer was washed twice with 50 ml. portions of water and the water washes further extracted with 50 ml. of ether. The combined ether extracts were chromatographed on 50 g. of silica gel. The product was eluted with ethyl acetate yielding 1.17 g. of product as a thick brown oil.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])=[O:16])([O:3][CH3:4])=[O:2].Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:26][CH2:27][CH2:28][C:29]#[N:30])=[O:16])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCC(=O)Nc1ccccc1O
Reactant: N#CCCCBr
Product: COC(=O)CCCCCCCCCCC(=O)Nc1ccccc1OCCCC#N

Procedure:
When (44) and 4-bromobutyronitrile are reacted under the conditions of step (A), above, (45) is obtained as a waxy solid. Conversely, reacting (44) with ethyl 4-bromobutyrate as in step (A) yields (8).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1>>[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Fc1cccc(N2CCNCC2)n1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=109-111° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH2:23][O:24]C)[N:22]=2)[CH2:14][CH2:13]1)=[O:10].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH2:23][OH:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1COC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CO
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
Ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-(methoxymethyl)-1,3-thiazole-5-carboxylate (Example 276; 50 mg; 0.105 mmol) was dissolved in anhydrous DCM and cooled to −78° C. 1 M Boron tribromide/DCM (105 μl; 0.105 mmol) was added dropwise. The mixture was stirred at −78° C. for 15 min, then at room temperature for 4 h. The mixture was diluted with DCM, washed with water and dried over Na2SO4. Organic phase was concentrated in vacuo giving the title compound (20 mg).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC2CNCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (2.00 g) in MeOH was added a catalytic amount of 20% Pd(OH)2/C. The suspension was stirred for 2 h at room temperature under H2 and filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 227.6 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH3:12])[C:6]=2[N:7]=1.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>CN(C=O)C>[CH2:14]([NH:17][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:15]=[CH2:16]
Reactant: CCc1csc2c(Cl)nc(Cl)nc12
Reactant: C=CCN
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(CC)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
In 6 ml of DMF, 500 mg (2.1 mmol) of 2,4-dichloro-7-etylthieno[3,2-d]pyrimidine was dissolved, and then 269 mg (4.7 mmol) of allylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 483 mg (yield: 88.8%) of the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Br:17])=[CH:12][C:13]([Cl:16])=[C:14]([Br:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:16][C:13]1[CH:12]=[C:11]([Br:17])[C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[C:14]=1[Br:15]
Reactant: CC(N)(C#N)Cn1nc2c(Br)cc(Cl)c(Br)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2c(Br)cc(Cl)c(Br)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-4,7-dibromo-2H-benzotriazol-2-yl)-2-methylpropionitrile (44 mg, described in Example 53) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (15 mg, 22%). MS (ES): M/Z [M−H]=594. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.43 (d, J=13.4 Hz, 1H), 5.61 (d, J=13.3 Hz, 1H), 7.88 (q, J=8.5 Hz, 4H), 8.04 (s, 1H) and 8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[N:28](C)[CH:29]=[O:30].[NH4+].[Cl-]>C1COCC1>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[C:29]([NH2:28])=[O:30])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CCCCn2ccnc2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NC(=O)c1nccn1CCCCc1ccccc1
Temperature: -78 °C

Procedure:
Reaction under N2 atmosphere. A mixture of DIPA (0.455 mol) in THF (500 ml) was stirred at −78° C. Butyllithium, 2.5M/hexane (0.390 mol) was added dropwise at −40° C. The mixture was stirred for 15 min, then re-cooled to −78° C. A solution of 1-(4-phenylbutyl)-1H-imidazole, prepared according to the procedure described in J. Chem. Soc., Perkin Trans., 1 (1975), 17, 1670–1671, (0.325 mol) in THF (350 ml) was added dropwise at −60° C. The mixture was stirred for one hour, then re-cooled to −78° C. This mixture was added dropwise to a mixture of N,N-dimethylformamide (0.390 mol, dry, p.a.) in THF (500 ml), stirred at −78° C. The reaction mixture was stirred for one hour at −78° C., then allowed to warm to room temperature while stirring overnight. A saturated aqueous NH4Cl solution (400 ml) was added and this mixture was extracted with THF. The separated organic layer was dried, filtered and the solvent evaporated, yielding 74.2 g of 1-(4-phenylbutyl)-1H-imidazole-2-carboxamide (interm. 18).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[CH3:8].[CH:14]1([CH3:26])[CH2:19][CH2:18][CH:17]([CH:20]([CH3:22])[CH3:21])[CH:16]([C:23](Cl)=[O:24])[CH2:15]1>O.CCOCC>[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:23]([CH:16]1[CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:19][CH:14]([CH3:26])[CH2:15]1)=[O:24])[CH3:8]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CNC(=O)C1CC(C)CCC1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium bicarbonate (8.4 g., 0.1 mole) and glycine ethyl ester hydrochloride (7 g. 0.05 mole) were dissolved in water (100 ml.), and a solution of p-menth-3-oyl chloride (10 g., 0.05 mole) in ether (50 ml.) was added and the mixture stirred vigorously at room temperature for 2 hours. At the end of this time the ether layer was separated and dried (MgSO4). Removal of the solvent left an oily solid (12.3 g.). This was distilled under reduced pressure to yield N-p-menth-3-oylglycine ethyl ester, bp. 150- 2°/0.1 mm. as a colourless liquid which rapidly solidified.
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+].[C:5]1([CH2:11][N:12]2[C:16](=O)C(C(C)C)[N:14](C)[S:13]2(=[O:23])=[O:22])C=CC=[CH:7][CH:6]=1>CO.[Pd]>[CH2:5]([CH:11]1[N:12]([CH3:16])[S:13](=[O:23])(=[O:22])[NH:14][C:1]1=[O:3])[CH2:6][CH3:7]
Reactant: CC(C)C1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CCCC1C(=O)NS(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a suspension of 3.5 g of 10% Pd/C in 150 ml of methanol containing ammonium formate (15 g) was added a solution of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.1 g) in 50 ml of methanol under nitrogen. The mixture was stirred at room temperature for 7 hours, filtered through a pad of CELITE® and the residue was washed with methanol. The combined filtrate was concentrated in vacuo to afford 4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide 2-ammonium salt (Formula IV: R1 =H; R2 =isopropyl; R3 =methyl; as NH4+ salt).
Reaction SMILES: [S:1]1[CH:3]([C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2]1>C1C=CC=CC=1>[CH2:6]([CH:5]1[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:3][CH2:2][S:1]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC=C(CCCCC)C1CS1
Solvent: c1ccccc1
Product: CCCCCCC1SCC=C1CCCCC
Yield: 65 %

Procedure:
A solution of 1,2-epithio-3-pentyl-3-decene (20 mg, 83 □mol) and Cu(hfacac)2 (4.1 mg, 8.3 μmol) in benzene (8.3 mL) was heated to 80° C. for 4.5 h under N2. After cooling, concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (hexanes) to give 2-Hexyl-3-pentyl-2,5-dihydrothiophene (13 mg, 65%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH2:22]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3([CH2:8][NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)[CH3:23]
Reactant: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Reactant: CCN1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1CCC(Oc2ccc(C3(CNc4ccccn4)CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2.6 %

Procedure:
To a solution of 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (250 mg, 0.881 mmol), 1-ethylpiperidin-4-ol (103 mg, 0.8 mmol) and triphenylphosphine (231 mg, 0.881 mmol) in THF (5 ml) at 0° C. under nitrogen was added dropwise diisopropyl azodicarboxylate (95% solution, 183 μl, 0.881 mmol). Reaction was stirred for 10 minutes then warmed to room temperature for 72 hours until complete. THF was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml). The organic layer was separated, dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (100:0:0 to 96:4:0.4 by volume) to give the title compound (8.2 mg, 23%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.05 (t, 3H), 1.80-1.98 (m, 4H), 2.00-2.18 (m, 4H), 2.28-2.42 (m, 2H), 2.44-2.54 (q, 2H), 2.72-2.86 (m, 2H), 3.50 (d, 2H), 3.55-3.62 (m, 2H), 3.78-3.88 (m, 2H), 4.00-4.08 (m, 1H), 4.30-4.39 (m, 1H), 6.22 (d, 1H), 6.50 (t, 1H), 6.90 (d, 2H), 7.23 (d, 2H), 7.30 (t, 1H), 8.01 (d, 1H). LRMS APCI+ m/z 396 [MH]+. HRMS ESI+ m/z 396.2641 [MH]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH2:24][CH2:25][OH:26])[CH2:22][N:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:20](=[O:34])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH2:24][CH:25]=[O:26])[CH2:22][N:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:20](=[O:34])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CC=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (0.608 mL, 6.97 mmol) in dichloromethane (40 mL) at -78° C. was added DMSO (0.990 mL, 13.9 mmol) over 2-3 minutes. The solution was stirred for 10 minutes, then a solution of the alcohol from Step E of Example 43 (2.06 g, 5.81 mmol) in 10 mL of dichloromethane was added over 5 minutes, keeping the reaction temperature below -70° C. The reaction was stirred for 10 minutes, then triethylamine (2.43 mL) was added, and the reaction was stirred at -78° C. for 5 minutes, then allowed to warm to room temperature. After 45 minutes, the solution was poured into dichloromethane, and washed with sat. NH4Cl soln., 10% citric acid soln., water, and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled aldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(#N)C>[Br:24][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:16])=[N:5][C:6]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1cc(Cl)c(Br)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-6-(2-phenylethynyl)pyridin-2-amine B3a (1.0 g, 4.37 mmol), NBS (778 mg, 4.37 mmol) and ACN (20 ml) is stirred for 3 h at RT in the dark. The mixture is concentrated in vacuo and the product purified NP chromatography. Yield: 1.0 g (74%). HPLC-MS: M+H=307/309.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][C:16](=[O:34])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][C:16](=[O:34])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CC(=O)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
2-Methyl-2-{[4-(2-oxo-2-{[4′-(trifluoromethyl)biphenyl-4-yl]amino}ethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (540 mg) obtained in Example 458-2 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (290 mg) as a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9](/[CH:11]=[C:12]2/[C:13](=[O:18])[NH:14][C:15](=[O:17])[S:16]/2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C([O-])(=O)C.[NH4+:23]>CS(C)=O>[NH2:23][C:5]1[N:10]=[C:9](/[CH:11]=[C:12]2/[C:13](=[O:18])[NH:14][C:15](=[O:17])[S:16]/2)[CH:8]=[CH:7][N:6]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1nccc(/C=C2\SC(=O)NC2=O)n1
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Temperature: 100 °C
Yield: 67 %

Procedure:
(Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows. A 40 mL round bottomed vial was charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (203 mg, 0.712 mmol), DMSO (3 mL), ammonium acetate (543 mg, 7.04 mmol, 10 equiv.) and heated at 100° C. for 2 h. The reaction was concentrated under reduced pressure using the Genevac. The residue was partitioned between 3 mL of DCE and 3 mL of H2O and the aqueous layer was back extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure to provide the desired product. (114 mg, 0.477 mmol, 67.0% yield). LC-MS m/z 223 (M+1).