Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[CH3:17][C:18]1[CH:19]=[C:20]2[N:25]([C:26]=1[CH3:27])[CH:24]=[CH:23][CH:22]=[C:21]2[CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.[Al]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:28][C:21]2[C:20]3[N:25]([C:26]([CH3:27])=[C:18]([CH3:17])[CH:19]=3)[CH:24]=[CH:23][CH:22]=2)[C:7]1=[O:15]
Reactant: Cc1cc2c(CO)cccn2c1C
Reactant: COC(=O)CCn1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCn1c(=O)n(Cc2cccn3c(C)c(C)cc23)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a stirred solution of the 3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (100 mg, 0.45 mmol) and (2,3-Dimethyl-indolizin-8-yl)-methanol (88 mg, 0.50 mmol) in THF (8 ml) was added triphenylphosphine (143 mg, 0.54 mmol) followed by DIAD (0.11 ml, 0.54 mmol, dropwise) at ambient temperature. After five minutes the reaction became dark brown and was consequently wrapped in aluminum foil. After stirring over night the reaction was treated with silica gel and concentrated. The remaining solid was purified via column chromatography (silica gel, 5-40% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give the product which was used without further purification.
Reaction SMILES: [CH:1]1([CH:4]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][C:7]=2[O:14][CH3:15])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][C:34]([I:40])=[CH:33][N:32]=1>C(#N)C>[CH:1]1([CH:4]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:31]3[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][C:34]([I:40])=[CH:33][N:32]=3)=[CH:8][C:7]=2[O:14][CH3:15])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: COc1ccc(C(Oc2ccc(CN)cc2OC)C2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(Oc2ccc(CNc3ncc(I)cc3[N+](=O)[O-])cc2OC)C2CC2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a stirred solution of (4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine (2.50 g, 7.95 mmol) and potassium carbonate (1.41 g, 10.20 mmol) in acetonitrile (10 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.90 g, 10.20 mmol). The resulting mixture was heated to 80° C. After 2 h, the mixture was filtered, and the filtrate was concentrated. Chromatographic purification of the residue (silica gel, 20% ethyl acetate in petroleum ether elute) afforded 2.60 g (58%) of N-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodo-3-nitropyridin-2-amine as a yellow oil.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.[F:10][C:11]1[CH:20]=[C:19]([CH3:21])[C:18]([N:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[OH:38])[CH2:31][CH2:30]3)[C:23]2=[O:39])=[CH:17][C:12]=1[C:13](OC)=[O:14].Cl>C1COCC1.O>[CH:6]1([NH:9][C:13](=[O:14])[C:12]2[CH:17]=[C:18]([N:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[OH:38])[CH2:31][CH2:30]4)[C:23]3=[O:39])[C:19]([CH3:21])=[CH:20][C:11]=2[F:10])[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c(C)cc1F
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Temperature: 25 °C

Procedure:
Isopropylmagnesium chloride (5.19 mL of a 2.0 M solution in THF) was added over 20 min of a solution of cyclopropylamine (1.830 mL) and methyl 2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate (Example 318f, 1.063 g) in THF (20 mL) stirring at room temperature under nitrogen. The reaction mixture was stirred for 1 h. Water and 2 M HCl were cautiously added and the volatiles removed in vacuo. The residue was basified with saturated aqueous sodium bicarbonate solution and extracted into DCM. The organics were combined, dried (MgSO4) and evaporated to give the subtitle compound (1.189 g).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:23]([O:33][CH3:34])=[C:24]([CH:27]=[CH:28][C:29]=1[CH:30]1[CH2:32][O:31]1)[C:25]#[N:26]>>[OH:31][CH:30]([C:29]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([O:33][CH3:34])[C:22]=1[CH3:21])[CH2:32][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[C:11]=2[CH3:20])[CH2:5][CH2:6]1
Reactant: COc1c(C#N)ccc(C2CO2)c1C
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Product: COc1c(C#N)ccc(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)c1C

Procedure:
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 3-methyl-2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1[S:27][CH:28]=[C:29]([CH:31]([NH2:33])[CH3:32])[N:30]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([NH:33][CH:31]([C:29]3[N:30]=[C:26]([CH3:25])[S:27][CH:28]=3)[CH3:32])=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(C)N)cs1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3csc(C)n3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (30 mg, 0.097 mmol), 1-(2-Methylthiazol-4-yl)-ethylamine hydrochloride (22 mg, 0.12 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (92 mg, 0.24 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol), and N,N-dimethylformamide (1.0 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to get the product as a light peach colored solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]([C:10]3[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=3)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>C(O)C>[CH:30]1([NH:33][CH:24]=[C:18]([C:17](=[O:28])[C:13]2[CH:14]=[C:15]([F:16])[C:10]([CH:7]3[CH2:8][CH2:9][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6]3)=[CH:11][C:12]=2[F:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:32][CH2:31]1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F
Reaction time: 1.5 h
Yield: 83 %

Procedure:
A solution of 20.5 g (50 mmol) of 4-(1,4-dioxaspiro[4.4]non-7-yl)-α-(ethoxymethylene)-2,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester in 200 ml of ethanol was cooled to 10° and treated dropwise with 3.4 g (60 mmol) of cyclopropylamine maintaining the temperature below 15° with an ice bath. After the addition was complete, the reaction was stirred at 5°-15° for 1.5 hours and then at room temperature for 1 hour. The resulting suspension was chilled to 5° and the solid removed by filtration, washed with ethanol, then hexane. The combined filtrate and washings were evaporated in vacuo and the residue was recrystallized from hexane to give 17.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:5].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:23]=[O:25])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Oc1ccc(N=C=O)cc1
Temperature: 75 °C
Reaction time: 26 h
Yield: 143.8 %

Procedure:
To a mixture of 2-(4-Aminophenoxy)propionic acid methyl ester 18 (15 grams, 76.9 mmol) and triethylamine (15.6 g, 154.16 mmol) in toluene (210 ml) under nitrogen atm. was added triphosgene (8.4 g, 28.3 mmol) in one lot. Later the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temp. for 26 hours. The reaction mixture was cooled to room temperature, the solids were filtered off, and the toluene was distilled off under vacuum to get crude 32, which was vacuum distilled to get pure 32 (9 g, 52.9%) as a light yellow syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].C([Na])#N.N[C:26]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:27]=1[CH:28]([OH:44])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:30]=1>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][C:26]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:27]=1[CH:28]([OH:44])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2Cc2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
In methanol (15 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol produced in Example 1-(2) (0.6 g) and 3-benzyloxybenzaldehyde (0.38 g). To the solution was added acetic acid (0.12 g). To the mixture was added dropwise, while stirring at room temperature, cyano sodium borohydride (0.13 g). The reaction mixture was stirred for one hour at 60° C., to which was then added water (50 ml), followed by extraction with ethyl acetate (80 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(3-benzyloxybenzyl)-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.9 g) as a colorless oily product.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23][CH:24]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:27][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:23][CH:24]=2)[CH:19]=[N:18]1)[CH3:16]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1ncc2cc(CN)ccc21
Product: CCn1ncc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-ethyl-1H-indazol-5-yl)methanamine (step-3 of Example 14).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].C(Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
2.37 G. 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide under nitrogen is treated with 0.38 g. sodium borohydride at 20°-25° C. After one hour 2.4 ml. benzylbromide is added, the mixture left for 2 hours, then diluted with water, filtered, washed with cyclohexane, recrystallized from methanol yielding 1-acetamido-2-nitro-4-benzylthiobenzene.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(Cl)Cl>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][N:13]2[CH2:12][CH2:11][CH:10]([O:9][C:8]3[CH:16]=[CH:17][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=3)[CH2:15][CH2:14]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OCCN2CCC(Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 90 °C
Yield: 75.7 %

Procedure:
A mixture of 4-(4-nitrophenoxy)piperidine hydrochloride (1.15 g, 5.80 mmol), 1-bromo-2-(4-nitrophenoxy)ethane (1.43 g, 5.80 mmol), K2CO3 (1.60 g, 11.80 mmol), and DMF (15 mL) was heated at 90° C. for 6 hours. The mixture was cooled, diluted with CH2Cl2, and washed with water. The organic phase was dried (MgSO4) and concentrated to give 1.70 g (80%) of N-2-(4-nitrophenoxy)ethyl-4-(4-nitrophenoxy)piperidine as a yellow solid. 1H NMR (DMSO-d6): δ 8.10 (m, 4H), 7.05 (d, 4H), 4.60 (m, 1H), 4.15 (t, 2H), 2.78 (m, 4H), 2.40 (t, 2H), 1.95 (m, 2H), 1.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]([CH2:66][C:67]([NH2:69])=[O:68])[C:60]2=[O:65]>>[NH2:69][C:67](=[O:68])[CH2:66][N:59]1[CH:58]=[CH:57][C:56]2[C:61](=[CH:62][CH:63]=[CH:64][C:55]=2[NH:54][C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=2)[C:60]1=[O:65]
Reactant: NC(=O)Cn1ccc2c(N)cccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cn1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (170 mg, 0.00072 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (400 mg, 0.001 mol), N,N-diisopropylethylamine (0.2 mL, 0.001 mol), N,N-dimethylformamide (2 mL, 0.03 mol) and 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)acetamide (120 mg, 0.00055 mol). The reaction was stirred for 16 h at room temperature and the solvent was removed and the residue purified by preparative HPLC (reverse phase) to yield the product as a white powder. MS m/z=437.8 (M+1). 1H NMR (400 MHz; DMSO-d6) δ 10.09 (s, 1H), 8.04 (d, J=8.07 Hz, 1H), 7.89 (bs, 1H), 7.83 (d, J=8.07 Hz, 1H), 7.73-7.70 (m, 2H), 7.63 (bs, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.42 (d, J=7.76 Hz, 1H) 7.19 (bs, 1H), 6.64 (d, J=7.70 Hz, 1H), 4.56 (s, 2H), 3.92 (s, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](N)=[N:21][C:20]=2[CH:31]=1.C1(C)C=CC=CC=1>CS(C)=O>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:22]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[NH:25][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:31][C:20]=3[N:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1=Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Clc1ccc2c(c1)N=C(N1CCN[C@@H](Cc3ccccc3)C1)c1ccccc1N2
Yield: 52.3 %

Procedure:
Combine 3-(S)-benzyl-piperazine (800 mg, 4.5 mmol), 8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (424 mg, 1.5 mmol), toluene (8 mL), dimethylsulfoxide (2 mL) and reflux for 3 days. Concentrate and pour into water (50 mL), filtrate the resulting solid, redissolve in dichloromethane (200 mL), wash with water and dry over magnesium sulfate. After concentration, purify by flash chromatography (dichloromethane then gradient of methanol 3–10%) to give (316 mg, 53%) of the title compound as a yellow foam: mp 79–92° C.; 1H NMR (CDCl3): δ 2.59 (dd, 1H), 2.90–2.66 (m, 3H), 3.09–2.94 (m, 3H), 3.85 (bm, 1H), 4.03 (bm, 1H), 4.88 (s, 1H), 6.61 (dd, 1H), 6.79–6.84 (m, 2H), 6.97 (t, 1H), 7.06 (t, 1H), 7.35–7.19 (m, 7H); MS (APCI) m/z (rel intensity) 403.4 (100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][CH2:10][C:11](=[O:14])[N:12]([CH3:26])[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NN(C)C(=O)CS3)c(F)c2)C(=O)O1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A mixture of N-{3-[3-fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-acetamide (0.100 g, 0.273 mmol), potassium carbonate (0.075 g, 0.546 mmol), and iodomethane (0.0187 ml, 0.300 mmol) in DMF (3 ml) is heated at 80° C. overnight. The reaction mixture is filtered and evaporated to dryness. The residue is purified by PTLC (10% MeOH/DCM) to give product as a white solid (0.104 g, 90%); 1HNMR (300 MHz, DMSO-d6) δ 1.82 (s, 3H), 3.39 (s, 3H), 3.42 (t, J=5.5, 2H), 3.66 (s, 2H), 3.76 (dd, J=6.6, 9.3 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.71-4.80 (m, 1H), 7.43 (dd, J=2.2, 8.8 Hz, 1H), 7.59 (dd, J=1.9, 14 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 8.25 (t, J=5.8 Hz, 1H); mp 179-80; MS (m/z): [M+H]+=381.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1>>[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH:25][C:1](=[O:11])[CH:2]=[CH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)C=Cc1ccccc1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C=Cc2ccccc2)cn1
Yield: 4 %

Procedure:
Prepared as in Example 4-8 from cinnamic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 4%. MS M+H calculated 322.6, found 322.4.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[S:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Product: COC(=O)CSC(c1ccc(C)cc1)c1ccc(C)cc1
Yield: 73 %

Procedure:
Following the procedure of Example 4, 4,4'-dimethylbenzhydrol, synthesized in accordance with M. R. Pavia, et. al. in J. Med. Chem. 35, 4238 (1992), is reacted with methyl thioglycolate for 18 hours at room temperature. Chromatography on silica gel, eluting with 10% ethyl acetate in hexane, gives methyl [[bis-(4-methylphenyl)methyl]thio]acetate as a colorless oil in 73% yield.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].C(O)C[OH:14]>C1(C)C=CC=CC=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>[O:3]1[CH2:1][CH2:2][O:14][CH:4]1[CH2:5][C:6](=[O:11])[C:7]([F:9])([F:10])[F:8]
Reactant: OCCO
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CC1OCCO1)C(F)(F)F
Yield: 67.3 %

Procedure:
4-Methylbenzenesulfonic acid monohydrate (500.1 mg, 467.4 μL, 2.629 mmol) was added to a solution of 4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (200.97 g, 1.195 mol) and ethylene glycol (77.27 g, 69.42 mL, 1.245 mol) in toluene (502.5 mL). The reaction mixture was heated to reflux for 90 min (oil bath). Then, the reflux was continued with simultaneous distillation of ethanol/toluene. The Dean-Stark was removed and the flask was connected to a distillation apparatus. 3-(1,3-Dioxolan-2-yl)-1,1,1-trifluoro-propan-2-one was distilled using a KNF pump (Bp 81° C.) as a light yellow oil (148 g, 67% yield). 1H NMR (500 MHz, CDCl3) δ 5.38-5.40 (t, 1H), 4.02-4.05 (m, 2H), 3.93-3.95 (m, 2H), 3.10 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[C:36](=[C:51]([C:54]#[N:55])[C:52]#[N:53])[O:37][C:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:41]([F:44])([F:43])[F:42])[C:39]=1[CH3:40])#[N:34]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=[CH:40][C:39]2[C:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:41]([F:44])([F:42])[F:43])[O:37][C:36](=[C:51]([C:54]#[N:55])[C:52]#[N:53])[C:35]=2[C:33]#[N:34])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94.7 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 730 mg (1.63 mmol) of 5-[2-(2-benzyloxy-4-dibutylaminophenyl)vinyl]thiophene-2-carboaldehyde and 573 mg (1.82 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at room temperature for 21 hours and further stirred with heating at 50° C. for 3 hours. The solvent was evaporated off and the residue was washed with ethanol to give 1.15 g of a dark reddish brown crystal (yield: 94.7%; mp: 196-197° C.)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].Br[CH2:13][C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4][N:5]([CH2:13][C:14]([OH:16])=[O:15])[C:6]=1[CH3:7]
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Temperature: 55 °C
Yield: 84.1 %

Procedure:
To a solution of 4-chloro-5-methyl-3-(trifluoromethyl)pyrazole (15 g, 81.3 mmol) in DMF (82 mL) was added ethyl 2-bromoacetate (13.6 g, 81.3 mmol) and potassium carbonate (12.4 g, 89.4 mmol). The mixture was heated at 55° C. for 10 hours with stirring. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 0-30% ethyl acetate in hexanes) to afford the desired product (18.5 g, 68.4 mmol, 84%).