Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[C:10]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[F:19][C:17]1[CH:18]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:15]([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C(O)c1ccc(F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(F)cc1Sc1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a solution of 3.28 g. (0.0256 mol) of p-fluorothiophenol and 6.8 g. (0.0256 mol) of 2-iodo-4-fluorobenzoic acid in 40 ml. of pyridine is added 3.54 g. (0.0256 mol) of potassium carbonate at room temperature with stirring. Additional pyridine is added to dissolve the precipitate and then 1.54 g. of cuprous chloride is added. The mixture is refluxed overnight, cooled, poured into ice-water, stirred and filtered. The aqueous solution is acidified, filtered and the solid dissolved in 5% sodium bicarbonate solution, then extracted with ether. The aqueous solution is acidified, extracted with ether, and the dried extract is concentrated to give 4-fluoro-2-(4-fluorophenylthio)benzoic acid, m.p. 209°-218° C. The latter (3.0 g., 0.0113 mol) is cyclized by heating for one hour with 45 g. of concentrated sulfuric acid to obtain 2,6-difluorothioxanthone, m.p. 205°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[C-:10]#[N:11].[K+]>C(O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Cl)nc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (5.0 g, 0.031 mol) in ethanol (38 mL) and water (19 mL) was added potassium cyanide (2.41 g, 0.0370 mol) at RT under nitrogen atmosphere. The reaction mixture was stirred at 50° C. overnight. The reaction was diluted with water and extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate. The solution was filtered and the filtrate was concentrated to afford the desired compound (4.2 g, 89%). Analytical LCMS: (M+H)+=153.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]([Cl:71])=[C:50]([C:52]2[C:67](=[O:68])[N:66]([O:69][CH3:70])[C:55]3[N:56]=[C:57]([NH:60][CH2:61][CH2:62][N:63]([CH3:65])[CH3:64])[N:58]=[CH:59][C:54]=3[CH:53]=2)[CH:51]=1>C1COCC1.C(Cl)Cl.CO.CN(C=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[N:10]=1)[C:5]([NH:45][C:46]1[CH:47]=[CH:48][C:49]([Cl:71])=[C:50]([C:52]2[C:67](=[O:68])[N:66]([O:69][CH3:70])[C:55]3[N:56]=[C:57]([NH:60][CH2:61][CH2:62][N:63]([CH3:65])[CH3:64])[N:58]=[CH:59][C:54]=3[CH:53]=2)[CH:51]=1)=[O:7]
Reactant: COn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COn1c(=O)c(-c2cc(NC(=O)c3cc(Cl)nc(Cl)c3)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (0.37 g) in 10 ml THF was added diisopropylethylamine (0.449 ml) followed by HATU (0.733 g). After 10 min 1 ml DCM and 2 ml DMF were added. Then 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one (0.5 g) was added as solution in THF (10 ml) with 1 ml DCM and 2 ml DMF. The reaction was stirred at r.t. for 1 h. The reaction mixture was diluted with 10 ml DCM, treated with 5 ml methanol and evaporated on 15 g alox (neutral).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1>C(O)C.[C].[Pd]>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(=O)[nH]c2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(n1)NC(=O)CC2
Temperature: 45 °C
Reaction time: 17 h
Yield: 45.4 %

Procedure:
A solution of 2.0 g of 7-methyl-1,8-naphthyridin-2(1H)-one in 150 mL of ethanol, 1.0 g of 5% palladium-carbon was added, and the mixture was stirred at 40 to 50° C. for 17 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble substance was filtered off, and the filtration residue was washed with methanol. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 0.92 g of 7-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[C:9]2[CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[Li].Cl.Cl.[NH2:22][CH2:23][CH:24]([OH:40])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[Cl:39])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:22][CH2:23][CH:24]([OH:40])[CH2:25][N:26]3[CH2:27][CH2:28][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=4[Cl:39])[CH2:30][CH2:31]3)=[O:15])[N:10]=[C:9]2[CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1
Reactant: NCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: CCCc1nc(C(=O)O)cn1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)NCC(O)CN2CCN(c3cccc(Cl)c3Cl)CC2)cn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
To a mixture of lithium 1-(4-chlorophenyl)-2-propyl-1H-imidazole-4-carboxylic acid (compound 6, 150 mg, 0.57 mmol), 1-amino-3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propan-2-ol dihydrochloride (compound 41, 260 mg, 0.68 mmol), EDCI (165 mg, 0.85 mmol) and HOBt (154 mg, 1.14 mmol) in anhydrous DMF (7 mL) was added NMM (190 μl, 1.71 mmol). The reaction mixture was stirred at room temperature for 15 hrs. The mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (purification system, Gilson) to provide the title compound (74 mg, 24%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:48][CH2:49][CH2:50][OH:51]>>[OH:51][CH2:50][CH2:49][NH:48][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCCO)C(C)(C)C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (0.925 g, 4.0 mmol), HATU (1.597 g, 4.20 mmol) and triethylamine (0.810 g, 8.00 mmol) was added 2-aminoethanol (0.257 g, 4.20 mmol) at room temperature. The reaction was stirred overnight and concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.05 g) as a yellow oil. LCMS m/z=275.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:19][O:20][C:21]1[CH:61]=[CH:60][C:24]([CH2:25][N:26]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[C:27]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]3[C:35]([NH:42][C:43]4[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=4)=[N:36][CH:37]=[C:38]([CH:41]=3)[CH:39]=[O:40])[N:28]=2)=[CH:23][CH:22]=1>C1COCC1>[CH3:59][O:58][C:55]1[CH:54]=[CH:53][C:52]([CH2:51][N:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:61][CH:60]=2)[C:27]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]3[CH:41]=[C:38]([CH:39]([OH:40])[C:6]4[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=4[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:37]=[N:36][C:35]=3[NH:42][C:43]3[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=3)[N:28]=2)=[CH:57][CH:56]=1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4cc(Br)ccc4S(=O)(=O)N(C)C)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
A solution of 4-bromo-N,N-dimethylbenzenesulfonamide (Aldrich; 152 mg, 0.575 mmol) in THF (1.0 mL) was cooled to −78° C. and treated dropwise with n-butyllithium (1.60 M solution in hexanes) (359 μL, 0.575 mmol). The resulting pale solution was allowed to slowly warm to 0° C. over 30 min to give a dark brown solution which was then added dropwise to a suspension of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (110.7 mg, 0.192 mmol) in THF (2.0 mL) cooled to −78° C. The mixture was stirred for 2 h, slowly allowing to warm to 0° C., and the resulting yellow suspension was quenched (water) and extracted into DCM from saturated aqueous NaHCO3. The extracts were dried (MgSO4), concentrated and purified by flash chromatography (0 to 10 to 20 to 30 to 40% EtOAc in DCM) to give recovered 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (54.6 mg, 49%, eluting off with 20% EtOAc/DCM) followed by 2-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-4-bromo-N,N-dimethylbenzenesulfonamide (30.0 mg, 0.036 mmol, 18.60% yield) (eluting off with 30% EtOAc/DCM) followed by 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-N,N-dimethylbenzenesulfonamide (38.3 mg, 0.050 mmol, 26.2% yield) (eluting off with 40% EtOAc/DCM).
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:15]3=[N:14][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:15]3=[N:14][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (700 mg, 2.0 mmol) and a 1.0 M solution of hydrogen chloride in diethyl ether (5 ml, 5.0 mmol) in methanol (100 ml) was stirred at room temperature overnight. After concentrating under reduced pressure, the residual solid was treated with ethyl acetate (20 ml) and stirred at room temperature for 2 hours. Filtration provided (R)-7,8-dihydro-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-13430) (400 mg, 65% yield) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:12]([S:17]([CH3:20])(=[O:19])=[O:18])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1)#[N:2]>CO.CCOC(C)=O.[Pd]>[NH2:9][C:7]1[CH:6]=[C:5]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[S:17]([CH3:20])(=[O:18])=[O:19])[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: CS(=O)(=O)N(c1cc(C#N)cc([N+](=O)[O-])c1)S(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)N(c1cc(N)cc(C#N)c1)S(C)(=O)=O
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
A suspension of Intermediate 76A (240 mg, 0.752 mmol) and 10% Pd/C (105 mg, 0.099 mmol) in MeOH (30 mL) and EtOAc (15 mL) was degassed and then stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The catalyst was filtered off, and the filtrate was concentrated to give Intermediate 76 (215 mg, 99%). HPLC: Rt=0.847 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (1H, s), 8.82 (1H, d, J=1.76 Hz), 7.43 (1H, t, J=1.63 Hz), 7.23 (1H, s), 7.14 (1H, t, J=2.01 Hz), 3.55 (6H, s). Intermediate 76 was used in the synthesis of Example 179.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16]O)=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:32]([CH2:16][C:13]1[S:12][S:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][CH:14]=1)=[N+:33]=[N-:34]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OCC1=CC=C(CN=[N+]=[N-])SS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred solution of 3.4 g (11.7 mmol) of 3-[(tert-butyldimethylsilyloxy)methyl]-6-hydroxymethyl-1,2-dithiin (10) in 12 mL of toluene was added diphenylphosphoryl azide (3.02 mL; 3.86 g, 14.0 mmol) in 8 mL of toluene and the solution was cooled to 0° C. To the cold solution was added dropwise 2.09 mL (2.13 g; 14.0 mmol) of DBU. The reaction mixture became dark. In 2 hours at 0° C., the reaction mixture was allowed to warm up to room temperature. After 14 hours the reaction mixture was purified on a silica gel column using 5% ethyl acetate in hexane to give 2.75 g (74.5%) of azide 15. 1H NMR (CDCl3) δ6.38 (m, 2H, C=CH), 4.30 (s, 2H, CH2O), 3.98 (s, 2H, CH2O), 0.92 (s, 9H, CCH3), 0.10 (s, 6H, SiCH3). 13C NMR (CDCl3) δ136.898 128.007, 123.471, 64.726, 55,145, 25.780, 25.735, 18.278, -5.443; MS (EI) m/z=315.1 (100%; M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH2:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20].[CH2:21]([Li])CCC.C(OC)=O.Cl>O1CCCC1>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]2[CH:21]=[C:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[S:11][C:3]=2[C:2]=1[Cl:1]
Reactant: COc1ccc(SCc2c(F)cccc2F)c(Cl)c1Cl
Reactant: [Li]CCCC
Agent: Cl
Solvent: COC=O
Solvent: C1CCOC1
Product: COc1cc2cc(-c3c(F)cccc3F)sc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 15 g of (2,3-dichloro-4-methoxyphenyl)-(2',6'-difluorobenzyl)sulfide in 140 ml of dry tetrahydrofuran at -75° is added dropwise 25 ml of 2.2M n-butyllithium over a period of 20 mins, maintaining the temperature below -65°. After stirring at this temperature for 1 hr, 10 ml of dried methyl formate is added dropwise, maintaining the temperature below -60°. The reaction mixture is poured onto 100 ml of 10N hydrochloric acid. The mixture is extracted with ethyl ether. The ether extract is dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil. The oil is heated to 120° and 240 g of warm polyphosphoric acid is added. The reaction mixture is warmed at 130° for 20 mins. The mixture is allowed to cool and to the mixture is added 400 ml of ice water. The aqueous solution is extracted with ethyl ether. The ether extract is washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil. Crystallization from hexane, followed by recrystallization from acetone-hexane, gives 7 g of 6,7-dichloro-2-(2',6'-difluorophenyl)-5-methoxybenzo[b]thiophene.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH:13]([O:21][C:22]1[C:23]2[N:24]([C:28]([CH2:32][C:33]#[CH:34])=[C:29]([CH3:31])[N:30]=2)[CH:25]=[CH:26][CH:27]=1)[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.Cl>C(O)C>[NH2:8][CH2:9][C:10]([NH:12][CH:13]([O:21][C:22]1[C:23]2[N:24]([C:28]([CH2:32][C:33]#[CH:34])=[C:29]([CH3:31])[N:30]=2)[CH:25]=[CH:26][CH:27]=1)[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: C#CCc1c(C)nc2c(OC(NC(=O)CNC(=O)OC(C)(C)C)c3ccccc3C)cccn12
Agent: Cl
Solvent: CCO
Product: C#CCc1c(C)nc2c(OC(NC(=O)CN)c3ccccc3C)cccn12
Reaction time: 3 h
Yield: 63.1 %

Procedure:
To a solution of 8-(2-t-butoxycarbonylamino-acetamido-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (435 mg) in ethanol (2 ml) was added 25% ethanolic hydrogen chloride (0.53 ml) with ice-cooling. After being stirred for 3 hours with ice-cooling, the solvent was evaporated under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydogen carbonate and the aqueous layer was extracted with chloroform. The extract was washed with a water and dried over magnesium sulfate. The solvent was distilled off and the residue was triturated with diethyl ether to give 8-(2-aminoacetamido- 6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (215 mg).
Reaction SMILES: [CH2:1]([C:3]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:17]([CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)#[N:18]>O1CCOCC1>[C:17]([CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:15][CH2:14][C:13]([NH:12][C:3]([CH2:4][CH3:5])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:1][CH3:2])=[O:16])[CH:24]=1)#[N:18]
Reactant: N#CCc1c[nH]cn1
Reactant: C=CC(=O)NC(CC)(CC)c1ccccc1
Solvent: C1COCCO1
Product: CCC(CC)(NC(=O)CCn1cnc(CC#N)c1)c1ccccc1

Procedure:
In a similar manner to Example 24, N-(1-ethyl-1-phenylpropyl)acrylamide (6.1 g) and 4-cyanomethylimidazole (3.0 g, Sigma Chemicals) were reacted in 1,4-dioxane (60 ml) in the presence of Triton B (0.8 ml) to give 3-[4-(cyanomethyl)imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propionamide, m.p. 121-122° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[CH2:42]1[O:45][CH:43]1[CH3:44]>>[OH:45][CH:43]([CH3:44])[CH2:42][NH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:31][C:32]([CH3:41])([CH3:40])[N:33]([O:38][CH3:39])[C:34]([CH3:37])([CH3:36])[CH2:35]2)[N:3]=1
Reactant: CC1CO1
Reactant: CON1C(C)(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)nc(NCC(C)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of the compound prepared in Example 20 with propylene oxide.
Reaction SMILES: FC(F)(F)C(O)=O.NC[C@@H]1OC(=O)N(C2C=CC(C3SC(CCO)C(=O)NN=3)=C(F)C=2)C1.[C:33]([NH:36][CH2:37][C@@H:38]1[O:42][C:41](=[O:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[S:51][CH:52]([CH2:57][CH2:58][O:59]C(=O)C)[C:53](=[O:56])[NH:54][N:55]=3)=[C:46]([F:63])[CH:45]=2)[CH2:39]1)(=[O:35])[CH3:34]>>[F:63][C:46]1[CH:45]=[C:44]([N:40]2[CH2:39][C@H:38]([CH2:37][NH:36][C:33](=[O:35])[CH3:34])[O:42][C:41]2=[O:43])[CH:49]=[CH:48][C:47]=1[C:50]1[S:51][CH:52]([CH2:57][CH2:58][OH:59])[C:53](=[O:56])[NH:54][N:55]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)C(CCOC(C)=O)S3)c(F)c2)C(=O)O1
Agent: NC[C@H]1CN(c2ccc(C3=NNC(=O)C(CCO)S3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)C(CCO)S3)c(F)c2)C(=O)O1

Procedure:
Prepared from 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-6-(2-hydroxyethyl)-4H-[1,3,4]thiadiazin-5-one, trifluoroacetate salt according to the method of Example 2 (0.021 g, 31%). MS (m/z): [M+H]+=411. A second acetylation product is isolated and identified as acetic acid 2-(2-{4-[5(S)-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluorophenyl}-5-oxo-5,6-dihydro-4H[1,3,4]thiadiazin-6-yl)-ethyl ester (0.025 g, 37%); 1H NMR (300 MHz, DMSO-d6) δ 1.83-1.91 (m, 1H), 2.00 (s, 3H), 2.06-2.14 (m, 1H), 3.43 (t, J=5.4 Hz, 2H), 3.74-3.83 (m, 2H), 4.08-4.18 (m, 3H), 7.43 (dd, J=2.1, 8.7 Hz, 1H), 7.59 (dd, J=1.8, 13.5 Hz, 1H), 7.69 (t, J=8.7 Hz, 1H), 8.26 (t, J=5.7 Hz, 1H); mp 223-4; MS (m/z): [M+H]+=453.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=O.Cl.NC1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[N:13]1([C:10]2[CH:9]=[CH:8][C:7]([C:5]3[N:23]4[CH:24]=[N:25][C:26]([C:27]([NH2:29])=[O:28])=[C:19]4[N:2]=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CN(C)C=CC(=O)c1ccc(N2CCOCC2)cc1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1ncn2c(-c3ccc(N4CCOCC4)cc3)ccnc12
Yield: 78.3 %

Procedure:
A mixture of 15.0 g of 3-dimethylamino-4'-morpholinoacrylophenone (prepared as described in Example 13) and 7.26 g of 4-amino-5-imidazolecarboxamide hydrochloride in 250 ml of glacial acetic acid was stirred and heated at reflux for 5 hours. The solution was evaporated in vacuo to give a black oil that was then dissolved in dichloromethane and then saturated sodium bicarbonate solution was added. A precipitate was formed which was collected by filtration as a yellow crystalline solid. The solid was triturated with ether then filtered to give 11.3 g of the product of the example as yellow crystals, mp 274°-277° C.
Reaction SMILES: C([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)(=O)C.ClC1C=[C:21](C=CC=1)[C:22]([O:24]O)=[O:23]>C(Cl)Cl>[C:22]([O:24][C:4]1[CH:17]=[CH:16][C:15]2[C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)(=[O:23])[CH3:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(ccc3ccccc32)c1
Reaction time: 93 h
Yield: 64.3 %

Procedure:
A solution of 2.2 g (10 mmol) of 2-acetylphenanthrene in 50 mL of CH2Cl2 was stirred with 3.45 g (20 mmol) of m-chloro-peroxybenzoic acid for 3 h and allowed to stand for 93 h at room temperature. The solution was washed twice with 5% KOH solution and once with H2O, was dried and the solvent removed. From MeOH there was obtained 1.52 g of the title compound, m.p. 141°-142.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([CH3:50])([CH3:49])[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:39][C:38]1[CH:37]=[CH:36][C:35]([CH2:40][C:41]([CH3:50])([CH3:49])[C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[CH:34][C:33]=1[NH:32][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(N)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Nc1cc(CC(C)(C)C(=O)OC(C)(C)C)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.50 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 24 ml of dichloromethane, 320 mg (2.40 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 364 μl (4.5 mmol) of pyridine and 510 mg (1.80 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-2,2-dimethylpropanoate were then added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, and the crude product obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethylacetate 20:1). This gave 462 mg of the target compound (58% of theory).