Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=O>C1COCC1>[CH3:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:9][NH:8][CH3:7])=[CH:12]1
Reactant: CNC(=O)c1cn(C)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cn(C)c2ccccc12
Reaction time: 23 h
Yield: 66.2 %

Procedure:
A solution of LiAlH4 in THF (1.0 M, 5.20 mL, 5.2 mmole) was slowly added via syringe to a solution of N,1-dimethyl-1H-indole-3-carboxamide (0.50 g, 2.6 mmole) in anhydrous THF (15 mL). Gas was evolved during the addition of the first 2 mL of LiAlH4 solution. When the addition was complete, the resulting light yellow solution was heated at gentle reflux. After 23 hr, the reaction was cooled in ice and quenched by the sequential dropwise addition of H2O (0.5 mL), 1.0 N NaOH (0.5 mL), and H2O (0.5 mL). The mixture was stirred for 15 min, then was filtered through Celite®, and the filter pad was washed thoroughly with THF. The filtrate was concentrated and the residue was flash chromatographed on silica gel (10% MeOH/CHCl3 containing 0.5% cone. NH4OH) to afford the title compound (0.30 g, 67%) as a light yellow oil: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][C:12](=O)[CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.NN.[OH-].[K+]>C(O)COCCO>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CC(=O)CC(c2ncccc2C)N1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Temperature: 125 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 3,3″-dimethyl-2′,3′,5′,6′-tetrahydro-1′H-[2,2′;6′,2″]terpyridin-4′-one (9.6 g, 34.1 mmol) in diethylene glycol (170 mL) was added hydrazine monohydrate (90 mL, 2.89 mol) and potassium hydroxide pellets (57.4 g, 1.02 mol) and the reaction stirred at 125° C. for 2 hours. 50 mL of hydrazine distilled off and water (200 mL) was added the remaining mixture. The solution was extracted with CH2Cl2 (4×300 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL) and washed with a saturated solution of NaHCO3 (3×100 mL) to remove the residual diethylene glycol. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 8.82 g (97%) of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine as yellow solid. 1H NMR (CDCl3) δ 1.50-1.65 (m, 2H), 1.75-1.95 (m, 3H), 2.13 (m, 1H), 2.37 (s, 6H), 3.09 (br t, 1H), 4.15-4.25 (m, 2H), 7.02 (dd, 2H, J=7.5, 4.8 Hz) 7.38 (d, 2H, J=7.5 Hz), 8.46 (br d, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[NH2:12][C:13]1[N:14]=[C:15]([NH2:24])[C:16]2[C:21]([CH2:22]Cl)=[CH:20][O:19][C:17]=2[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:12][C:13]1[N:14]=[C:15]([NH2:24])[C:16]2[C:21]([CH2:22][O:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:20][O:19][C:17]=2[N:18]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1nc(N)c2c(CCl)coc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc(N)c2c(COc3ccc4ccccc4c3)coc2n1
Temperature: 45 °C
Reaction time: 24 h
Yield: 23.3 %

Procedure:
To a 50 mL three neck round bottom flask was added in sequence anhydrous DMSO (4 mL), 2-naphthol (0.27 g), compound 117 (0.25 g) and anhydrous potassium carbonate (0.26 g). The reaction mixture was stirred at 45° C. for 24 h under nitrogen in the dark and then quenched with distilled water (12 mL). The resultant suspension was stirred at room temperature for 4 h, cooled to 5° C. and filtered. The sold was washed with cold water (2×5 mL) and then dissolved in MeOH. The solution was mixed with silica gel (1 g) and the mixture was evaporated under reduced pressure and dried in vacuo. The residue was ground into a fine powder and poured on top of a wet column of silica gel (30 g) and eluted with 3% MeOH in CHCl3. Fractions corresponding to a single spot of the product (TLC) were pooled and evaporated to afford 0.09 g compound 425 (23%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4](Cl)[N:3]=1.CC1C=CC=CC=1C.[NH:19]1[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1.[OH-].[Na+]>O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:19]2[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Reactant: C1=CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Temperature: 5 °C

Procedure:
155 G. of 2,4-diamino-6-chloropyrimidine-3-oxide are mixed and stirred under an argon atmosphere with 640 ml. of o-xylene and 260 ml. of 1,2,5,6-tetrahydropyridine. The mixture is then heated to reflux for 30 minutes, the internal temperature rising from 115° C. to 123° C. The mixture is then cooled to 5° C., treated with 40 g. of sodium hydroxide in 400 ml. of water and stirred at 5° C. for 1 hour. The precipitate formed is filtered off, washed with 200 ml. of water and recrystallized from 3000 ml. of water, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide having a melting point of 263°-265° C. (decomposition).
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[C:20](=[O:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:18](=[O:32])[N:17]([C:33]4[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=4[F:40])[C:16]=3[N:15]([CH3:41])[C:14](=[O:42])[C:13]=2[CH3:43])(=O)=O)=CC=1.N1C(C)=CC=CC=1C.[NH2:52][C:53]1[CH:54]=[C:55]([CH2:59][CH2:60][C:61]([NH2:63])=[O:62])[CH:56]=[CH:57][CH:58]=1.O>CC(N(C)C)=O>[F:40][C:34]1[CH:35]=[C:36]([I:39])[CH:37]=[CH:38][C:33]=1[N:17]1[C:16]2[N:15]([CH3:41])[C:14](=[O:42])[C:13]([CH3:43])=[C:12]([NH:52][C:53]3[CH:54]=[C:55]([CH2:59][CH2:60][C:61]([NH2:63])=[O:62])[CH:56]=[CH:57][CH:58]=3)[C:21]=2[C:20](=[O:22])[N:19]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:18]1=[O:32]
Reactant: NC(=O)CCc1cccc(N)c1
Reactant: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)c4ccc(C)cc4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2c(=O)c3c(Nc4cccc(CCC(N)=O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Temperature: 130 °C
Yield: 85.9 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (xxx) (2 gm, 2.79 mmol) in DMA (5 ml) was added 2,6-lutidine (0.597 g, 5.57 mmol) and 3-(3-aminophenyl)propanamide (intermediate xxvi) (0.915 gm, 5.57 mmole). The reaction mixture was heated at 130° C. for 16 h. The reaction mixture was cooled to room temperature and added water until a solid precipitate was obtained. The solid was filtered, washed with water and small amount of MeOH. The solid was purified by silica gel column chromatography, eluting with DCM:Methanol (9:1), to yield the titled compound (1b) (1.7 g) [m/z=710.20 (M+1)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:7][C:6]([C:20]2[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][C:4]=1[C:27]1([CH3:30])[CH2:29][CH2:28]1>CO.CCOC(C)=O.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:20]3[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=3)[CH:5]=[C:4]([C:27]3([CH3:30])[CH2:29][CH2:28]3)[C:3]=2[O:2][CH3:1])=[CH:12][CH:13]=1
Reactant: COc1c(/C=C/c2ccc([N+](=O)[O-])cc2)cc(-c2ccc[nH]c2=O)cc1C1(C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(CCc2ccc(N)cc2)cc(-c2ccc[nH]c2=O)cc1C1(C)CC1
Yield: 72.5 %

Procedure:
To a suspension of 136 (0.14 g, 0.35 mmol) in MeOH-EtOAc (2:1, 7.5 mL) was added 10% Pd/C (0.014 g), and the reaction mixture was stirred under a hydrogen atmosphere maintained by a balloon for 16 h. The reaction mixture was filtered through diatomaceous earth and the pad was rinsed successively with EtOAc, MeOH and DCM. The combined filtrates were concentrated under reduced pressure, and the crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.095 g (76%) of 3-[3-[2-(4-amino-phenyl)-ethyl]-4-methoxy-5-(1-methylcyclopropyl)phenyl]-1H-pyridin-2-one (I-99) as a light yellow powder.
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C(OC)(=O)CC(C)=O.C[O-].[Na+].Cl[C:22]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:23]>C1(C)C=CC=CC=1>[O:23]=[C:22]([CH:3]([C:2]([O:8][CH3:9])=[O:7])[C:4](=[O:5])[CH3:6])[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C(C)C(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)C(=O)C(C(C)=O)C(=O)OC

Procedure:
Methyl acetoacetate sodium salt (1.24 g; 9 mmole) prepared from methyl acetoacetate and sodium methoxide was suspended in dry toluene (10 ml), and a solution of ethyl 2-chloroformylpropanoate (1.12 g; 6.8 mmole) in dry toluene (5 ml) was dropwise added thereto at room temperature. The resultant mixture was stirred at the same temperature for 1 hour, and insoluble materials were removed by filtration. The filtrate was concentrated at 40° C. under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 3,5-dioxo-4-methoxycarbonyl-2-methylhexanoate.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]([CH3:40])[CH2:18][CH2:19][CH:20]1[CH:26]=[CH:25][N:24]([C:27](=[O:35])[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[S:21]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:40][N:17]([CH3:16])[CH2:18][CH2:19][CH:20]1[CH:26]=[CH:25][N:24]([C:27](=[O:35])[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:30][CH:29]=2)[C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[S:21]1
Reactant: CN(C)CCC1C=CN(C(=O)c2ccc(N)cc2)c2ccccc2S1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Phenylbenzoyl chloride (0.36 g, 1.67 mM)(prepared from 2-biphenylcarboxylic acid as described in Example 3) was slowly added to a solution of Compound 12 as prepared in Example 7 (0.5 g, 1.4 mM) and triethylamine (0.38 ml, 3.3 mM)in methylene chloride (30 ml). The mixture was stirred at room temperature for 16 hours and water (80 ml) was added. The layers were separated. The methylene chloride layer was dried (MgSO4), filtered and evaporated in vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 30% EtOAc in CH2Cl2) yielded the desired product as a white solid. m/z (MH+) 536.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:20][C:19]3[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH3:16])[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1Cn1nnc2c(-c3ccco3)nc(N)nc21
Reaction time: 1 h
Yield: 25.3 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (606 mg, 3 mmol) in DMF (5 mL) at 0° C., was treated with CsCO3 (977 mg, 3 mmol), stirred for 1 h, treated with 2-methoxy-5-nitrobenzyl bromide (738 mg, 3 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (10 mL), filtered and the resulting solid purified by chromatography [SiO2; EtOAc:Heptane (2:1)] to give the title compound (279 mg, 25%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:2]=1.[C:14]([NH:21][CH2:22][C:23](O)=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14](=[O:15])[NH:21][CH2:22][C:23](=[O:24])[N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][CH2:10]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1cncc(CN2CCNCC2)c1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(Cc2cccnc2)CC1

Procedure:
The title compound is synthesized by condensation of 1-Pyridin-3-ylmethyl-piperazine and N-Boc-glycine analogously to the preparation of Example 2 as a colorless solid; ES-MS: M+H=335.3; HPLC: AtRet=3.93 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][S:20][C:12]=3[N:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=2)[CH2:6][CH2:5]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]3[C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][S:20][C:12]=3[N:13]=[C:14]([CH2:16][C:17]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:18])[N:15]=2)[CH2:6][CH2:5]1
Reactant: C1CCNC1
Reactant: COCC1CCN(c2nc(CC(=O)O)nc3scc(-c4ccccc4)c23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC1CCN(c2nc(CC(=O)N3CCCC3)nc3scc(-c4ccccc4)c23)CC1
Yield: 11.1 %

Procedure:
2-[4-[4-(Methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]acetic acid (24 mg, 0.06 mmol), pyrrolidine (5 mg, 0.067 mmol), HATU (26 mg) and triethylamine (0.025 mL) were stirred in acetonitrile (2 mL) at 50° C. for 20 hrs. The reaction was partitioned between water and DCM. The organics were separated and concentrated in vacuo. The residue was purified by preparative TLC, eluting 10% methanol in DCM. The isolated band was repurified by preparative TLC, eluting ethyl acetate to give 2-[4-[4-(methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]-1-pyrrolidin-1-yl-ethanone (3 mg). LCMS RT=4.61 min. M+1=451.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: Cn1cncc1CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1cncc1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) was added 5-[(aminooxy)methyl]-1-methyl-1H-imidazole 100 (0.172 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 101 (0.40 g, quantitative yield) as a white foam.
Reaction SMILES: [Cl-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[S:9][CH2:10][C:11](=[O:14])[CH2:12][Cl:13].[CH3:15][N:16]1[CH:20]([CH3:21])[CH:19]([CH3:22])[N:18]([CH3:23])[C:17]1=[S:24]>C(O)C>[Cl-:13].[Cl-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[S:9][CH2:10][C:11](=[O:14])[CH2:12][S:24][CH:17]1[N:18]([CH3:23])[C:19]([CH3:22])=[C:20]([CH3:21])[NH+:16]1[CH3:15]
Reactant: CC1C(C)N(C)C(=S)N1C
Reactant: CN1C=C[NH+](C)C1SCC(=O)CCl
Agent: [Cl-]
Solvent: CCO
Product: CC1=C(C)[NH+](C)C(SCC(=O)CSC2N(C)C=C[NH+]2C)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.255 g (0.001 mole) of 1,3-dimethyl-2-[(3-chloro-2-oxopropyl)thio]-1H-imidazolium chloride was added a solution of 0.156 g (0.001 mol) of 1,3,4,5-tetramethylimidazoline-2-thione in 5 mL of ethanol and the reaction mixture was stirred for 3 hours at ambient temperature. At the end of this period, the solvent was evaporated and the residue was crystallized from isopropyl alcohol-acetonehexane to obtain the desired 2-{(3-[(1,3-dimethyl-1H-imidazolium-2-yl)thio]-2-oxopropyl)thio}- 1,3,4,5-tetramethyl-1H-imidazolium dichloride compound as a hygroscopic solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4].[N-:30]=[N+:31]=[N-:32].[Na+]>C(#N)C.C(OCC)(=O)C>[N:30]([CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CCl)c2c1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CN=[N+]=[N-])c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 2-chloro-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide (120 mg, 0.28 mmol) in acetonitrile (3 mL) was added sodium azide (72 mg, 1.1 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 mL), washed with water (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% ethyl acetate in petroleum ether) to give 110 mg of the product as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:23][C:24]=1[C:25](O)([CH3:27])[CH3:26].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:25]([CH3:27])([C:24]2[S:23][C:22]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:21][C:20]=2[CH3:19])[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)(C)O
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-2-ol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-2-ethoxy-3-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester as light yellow liquid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:17]([CH3:19])=[O:18])[CH:4]=1.N1C=CC=CC=1.[CH2:26]([O:29][C:30](Cl)=[O:31])[CH:27]=[CH2:28]>C1COCC1.C(Cl)Cl>[CH2:26]([O:29][C:30]([O:1][CH2:2][C:3]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:17]([CH3:19])=[O:18])[CH:4]=1)=[O:31])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)Cl
Reactant: CC(=O)c1cc(CO)c2c(c1)-c1ccccc1C2=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)OCc1cc(C(C)=O)cc2c1C(=O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Hydroxymethyl-3-methylcarbonyl-9-fluorenone (135 mg) was dissolved in THF (4 ml), cooled to 0° C. under N2. Pyridine (51 μl, 1.2 eq) was added followed by allyloxycarbonyl chloride (70 μl, 1.2 eq). The reaction mixture was allowed to stir overnight allowing it to come to room temperature. The reaction mixture was diluted with methylene chloride, washed with water, sat'd NaCl solution, dried and evaporated. The product was purified by preparative tlc (80 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:41][CH3:42])[C:9]([C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:39]=[CH:38][C:26]([O:27][CH2:28][CH2:29][C:30]([F:37])([F:36])[C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=3)=[O:22])[C@@H:13]([CH3:40])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Li+].CO.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:41][CH3:42])[C:9]([C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][C:30]([F:37])([F:36])[C:31]([OH:33])=[O:32])=[CH:38][CH:39]=3)=[O:22])[C@@H:13]([CH3:40])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)CCOc1ccc(C(=O)N2c3ccccc3[C@@H](C(=O)N(CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(F)(F)C(=O)O)cc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans-ethyl 4-(4-{[4-{[(4-chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-difluorobutanoate (190 mg, 0.32 mmol) in THF (4.4 mL) was added a solution of lithium hydroxide (15.2 mg, 0.63 mmol) in water (2 mL). To the resulting mixture was added methanol (2 mL) and the reaction stirred 18 hours at room temperature. The reaction mixture pH was adjusted to 2 via addition of 1N hydrochloric acid and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield (±)-trans-4-(4-{[4-{[(4-chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-difluorobutanoic acid. 1H-NMR (CDCl3) δ: 0.96 (d, 3H), 1.08 (t, 3H), 1.61-1.74 (m, 1H), 2.34-2.56 (m, 3H), 3.52-3.68 (m, 1H), 3.72-3.88 (m, 2H), 4.00-4.14 (m, 2H), 4.93-5.11 (m, 1H), 6.42-6.51 (m, 1H), 6.65-6.82 (m, 4H), 6.83-6.92 (m, 1H), 7.16-7.29 (m, 2H), 7.37-7.50 (m, 4H). MS m/z: 571 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24](Cl)[C:18]=2[S:17]1(=[O:27])=[O:26].O>CN(C)C=O>[CH3:15][N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([S:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:18]=2[S:17]1(=[O:26])=[O:27]
Reactant: CN1Cc2cccc(Cl)c2S1(=O)=O
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cccc(SCc3ccccc3)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 12 g of potassium-t-butoxide in 100 ml of dry dimethylformamide was added 12.9 mls of benzyl mercaptan at -5° to 0° C. under an inert atmosphere followed by 12.2 g of 2-methyl-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. The mixture was stirred at room temperature for 16 hours and poured into water to give a gummy solid. The water was decanted and extracted with ethyl acetate. The gummy solid was slurried in ethyl acetate and filtered to give 5.9 g of the title compound as a light orange solid, m.p. 119°-112° C. The combined ethyl acetate extract and filtrate were washed with water and brine, dried over MgSO4 and concentrated to a solid which was slurried in ether and filtered to give an additional 7.6 g of product, m.p. 121°-124° C. Total yield was 13.5 g.