Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](Cl)=O.B(F)(F)F.CCOCC>O1CCOCC1>[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:10][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: NC(=NO)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1-c1nc(-c2ccccc2)no1

Procedure:
A solution of 13.6 g. (0.1 mole) benzamide oxime in 625 milliliters dioxane is treated dropwise with 19.8 g. (0.1 mole) 2-chloroformyl benzoic acid methyl ester in 200 milliliters dioxane. This mixture is then refluxed for one hour, cooled slightly and treated with 3.3 milliliters of boron trifluoride etherate. The reaction mixture is refluxed for 18 hours. The resulting residue is cooled and filtered to remove a small amount of solid. The filtrate is evaporated in vacuo and the resulting oil is dissolved in ether, washed with water, 10 percent sodium carbonate, water and then brine. The ether solution is dried over anhydrous magnesium sulfate decolorized with charcoal filtered to remove the charcoal and the filtrate evaporated in vacuo to give o-(3-phenyl-1,2,4-oxadiazol-5-yl)-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].[Cl:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[C:39](=[N:41][OH:42])[NH2:40])[CH2:25][N:26]([CH3:35])[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29]>>[ClH:21].[Cl:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[C:39]1[N:40]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:18])([F:19])[F:20])=[C:2]([CH3:1])[CH:7]=2)[O:42][N:41]=1)[CH2:25][N:26]([CH3:35])[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)c(Cl)c1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Product: Cc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)cc3Cl)no2)ccc1-c1ccccc1C(F)(F)F
Product: Cl

Procedure:
The title compound was prepared according the procedure described in Example 105, but using Intermediate 50 and Intermediate 65. It was obtained as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (1H, d, J=1.7 Hz), 8.16 (1H, d, J=8.0 Hz), 8.11 (1H, dd, J=8.0, 1.8 Hz), 7.95 (2H, d, J=8.1 Hz), 7.83 (1H, t, J=7.6 Hz), 7.78-7.69 (2H, m), 7.46 (2H, m), 4.44 (2H, br s), 4.11 (2H, br s), 2.83 (3H, br s), 2.15 (3H, br s). LC/MS (Method A): 516 (M+H)+. HPLC (Method F) Rt 3.25 min (Purity: 97.5%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](C=O)=[CH:2]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:17]1(C)C=CC=CC=1>>[N:12]1([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[CH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: Cc1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: C=C1Nc2ccccc2C1N1CCCC1
Temperature: 25 °C
Yield: 87 %

Procedure:
In a round bottom flask equipped with a Dean-Starck condenser, 1H-indole-3-carbaldehyde (40 g, 0.275 mmol) and pyrrolidine (27 ml, 0.330 mmol) were suspended in toluene (480 ml) and kept heating at reflux overnight. After cooling to rt, the solid was filtered off, washed with toluene and recrystallized from THF (100 ml) affording subtitle compound (47.7 g) as a reddish solid in 87% yield.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].S(=O)(=O)(O)O.[Br:23]N1C(=O)CCC1=O>>[Br:23][C:14]1[CH:15]=[C:16]([Cl:17])[C:9]([Cl:8])=[C:10]([CH:13]=1)[CH:11]=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cc(Br)cc(Cl)c1Cl
Reaction time: 3 h

Procedure:
To a TFA solution (0.38 M) of 2,3-dichlorobenzaldehyde (1 eq.) was added sulfuric acid (5 eq.). Over a period of 3 h, N-bromosuccinimide (1.5 eq.) was added portionwise at RT to afford, in the end, a yellow-orange solution. After 72 h, the crude reaction mixture was diluted with 9:1 (v/v) hexanes:ether and then washed sequentially with water, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([NH2:16])=[S:15].[I:17][CH3:18]>CC(C)=O>[IH:17].[CH3:18][S:15][C:14](=[NH:16])[CH2:13][CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: CI
Reactant: NC(=S)CCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)=O
Product: CSC(=N)CCN1C(=O)c2ccccc2C1=O
Product: I
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.2 %

Procedure:
To a suspension of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiopropionamide (2.13 g, 9.09 mmol) in acetone (30 mL) was added iodomethane (3.87 g, 1.71 mL, 27.3 mmol) at r. t. under a nitrogen atmosphere. The reaction mixture was stirred at RT for 48 h and the obtained suspension was filtered, washed with diethyl ether and dried in vacuo to give the product as light yellow solid (2.3 g, 6.11 mmol, 67.2%). MS: M=249.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:8]3([NH:12][CH2:11][CH2:10][NH:9]3)[C:6]=2[CH:7]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:16]=1[CH2:17]Cl>CO>[ClH:1].[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:16]=1[CH2:17][S:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]1[NH:12][CH2:11][CH2:10][N:9]=1
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: Clc1ccc2c(c1)C1(NCCN1)S2
Solvent: CO
Product: Cl
Product: Clc1ccc(Cl)c(CSc2ccc(Cl)cc2C2=NCCN2)c1

Procedure:
32 Parts of 4-chlorobenzothietane-2-spiro-2'-imidazolidine is reacted as described in Example 11 with 29.5 parts of 2,5-dichlorobenzyl chloride in 300 parts of methanol. The yield is 53 parts (86% of theory) and the melting point is 260° C. with decomposition.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:13])[N:7]2[N:6]=1)=[O:4].CC(O[CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O.B(F)(F)F.CCOCC.ClCCl>S1(CCCC1)(=O)=O.ClCCl>[NH2:28][C@@H:25]1[C:26](=[O:27])[N:23]2[C@@H:24]1[S:29][CH2:30][C:21]([CH2:20][S:13][C:12]1[N:7]3[N:6]=[C:5]([C:3](=[O:4])[NH:2][OH:1])[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=1)=[C:22]2[C:31]([OH:33])=[O:32]
Reactant: Cc1cc(S)n2nc(C(=O)NO)nc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
N-Hydroxy-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide and 3.4 g (12.5 mmol) of 7-aminocephalosporanic acid (3.1 g) (13.9 mmol) are suspended in 75 ml of sulpholane/dichloromethane (1:1 v/v). 7.5 ml of boron trifluoride etherate are added dropwise thereto at 0° C. and the mixture is stirred at 0° C. for 2.5 hours and at room temperature for 15 hours. 200 ml of dichloromethane are now added. After stirring for 30 minutes the mixture is suction filtered. The filter material is dissolved in 100 ml of water. The product is precipitated with saturated sodium hydrogen carbonate solution (pH~5), filtered off and washed with water, ethanol and ether. There are obtained 3.5 g of (6R,7R)-7-amino-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C[O-].[Na+].CO.C(O)(=O)C>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:11])=[CH:10][C:14](=[O:15])[C:13]([F:20])([F:19])[F:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: O=C(C=C(O)c1ccc(F)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 40.0 g (0.256 moles) 2',4'-difluoroacetophenone (commercially available) in 400 mL diethyl ether at 0° C. was added 40 mL (0.405 moles) ethyl trifluoroacetate. At 5° C., 80 mL of a 25% wt. sodium methoxide in methanol (0.37 moles) were added over 15 minutes. The reaction mixture was stirred overnight at 25° C. The mixture was poured over 300 mL ice water and 21.3 mL (0.37 moles) acetic acid were added. The organic layer was washed two times with water, dried over anhydrous MgSO4, and concentrated in vacuo to give 62.85 g (97%) 4-(2,4-difluorophenyl)-1,1,1-trifluoro-4-hydroxy-3-buten-2-one as a yellow oil; 1HNMR (CDCl3) ppm: 6.61 (s,1H), 6.87 (m,1H), 6.97 (m,1H), 7.97 (m,1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(isopropyl-methyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example C34) (2.98 g, 7.90 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a orange oil (2.42 g, 88%).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1)=[O:4].[CH3:12]N1C=C(C(O)=O)C=N1.N1CCC1>>[N:2]1([C:3]([C:5]2[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=2)=[O:4])[CH2:11][CH2:12][CH2:1]1
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CN(C)C(=O)c1cnn(C)c1
Agent: C1CNC1
Product: Cn1cc(C(=O)N2CCC2)cn1

Procedure:
This compound was prepared in analogy to 1-methyl-1H-pyrazole-4-carboxylic acid dimethylamide (Example 97, step a) from 1-methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) and azetidine (475 mg, 8.33 mmol). Yield: 1.31 g (92%); light yellow solid; MS: m/z=166.1 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:10]/[C:11](/[NH:23][C:24]1[C:25]([CH3:41])=[N:26][CH:27]=[C:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:29]=1)=[N:12]\C(=O)OCC1C=CC=CC=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:37]([O:36][C:34](=[O:35])[NH:33][CH2:32][CH2:31][CH2:30][C:28]1[CH:27]=[N:26][C:25]([CH3:41])=[C:24]([NH:23][C:11]([NH2:12])=[NH:10])[CH:29]=1)([CH3:39])([CH3:40])[CH3:38]
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1NC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of dibenzyl{(Z)[(5-{3-[(tert-butoxycarbonyl)amino]propyl}-2-methylpyridin-3-yl)amino]methylylidene}biscarbamate (3.34 g, 5.80 mmol) in MeOH (100 mL) was added palladium hydroxide on carbon (0.41 g). The reaction vessel was flushed with hydrogen gas and then allowed to stir at rt under an atmosphere of hydrogen gas overnight. The reaction mixture was filtered over a pad of Celite® and the filtrate was concentrated to give tert-butyl[3-(5-{[amino(imino)methyl]amino}-6-methylpyridin-3-yl)propyl]carbamate (1.77 g, 5.76 mmol, 99%) as a white solid. LCMS (FA): Rt=0.76 min, m/z=308.0 (M+H).
Reaction SMILES: [C:1]([NH2:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)[C:11](Cl)=[O:12]>C(Cl)CCl>[CH2:1]([N:9]=[C:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cccnc1
Solvent: ClCCCl
Product: O=C=NCc1cccnc1
Temperature: 25 °C

Procedure:
To a mixture of nicotinamide (24.4 g., 0.20 mole) and dry ethylene dichloride (2500 ml.) is added oxalyl chloride (38.1 g., 0.30 mole). The mixture is then heated to reflux for 4.5 hours and then cooled to room temperature. It is filtered to give a clear pale orange solution of nicotinyl isocyanate which is used directly in the next step.
Reaction SMILES: [Na:1].CC1C(C[S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])=NC=CC=1OCC1(C)OCC2(OCCO2)CO1.[CH3:34][C:35]1([CH3:53])[O:40][CH2:39][CH:38]([CH2:41][O:42][C:43]2[C:48]([CH3:49])=[CH:47][N:46]=[C:45]([CH2:50]O)[C:44]=2[CH3:52])[CH2:37][O:36]1.O.CC1(C)OCC(COC2C(C)=CN=C(CO)C=2C)CO1.N1C2C=[C:81]3[O:87]CC[O:84][C:82]3=CC=2N=C1S>C1(C)C=CC=CC=1>[Na:1].[CH3:34][C:35]1([CH3:53])[O:40][CH2:39][CH:38]([CH2:41][O:42][C:43]2[C:48]([CH3:49])=[CH:47][N:46]=[C:45]([CH2:50][S:23]([C:25]3[NH:26][C:27]4[CH:33]=[C:32]5[O:87][CH2:81][CH2:82][O:84][C:31]5=[CH:30][C:28]=4[N:29]=3)=[O:24])[C:44]=2[CH3:52])[CH2:37][O:36]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Sc1nc2cc3c(cc2[nH]1)OCCO3
Reactant: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(CS(=O)c2nc3cc4c(cc3[nH]2)OCCO4)c(C)c1OCC1COC(C)(C)OC1
Yield: 61.7 %

Procedure:
The same procedure as in the steps (5f) to (5h) was repeated using the (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol, which was obtained by subjecting (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol monohydrate obtained in the same manner as in Example 96 (5) to azeotropic distillation with toluene, and 6,7-dihydro-1H-[1,4]dioxino[2′,3′:4,5]benzo[d]imidazole-2-thiol, to obtain the title compound (395 mg, total 61.7% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:14]([CH3:16])[CH3:15])[C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[C:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH:14]([C:5]1[C:6](=[O:13])[NH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([O:1][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH:11]=[CH:10][C:9]=2[CH3:12])([CH3:16])[CH3:15]
Reactant: CC(C)=CCBr
Reactant: Cc1ccc(O)c2cc(C(C)C)c(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Temperature: 70 °C
Reaction time: 7 h
Yield: 93.8 %

Procedure:
5-HYdroxy-3-isopropyl-8-methylcarbostyril (1.50 g, 6.91 mmol) was dissolved in dimethylformamide (30 ml). To the solution, potassium carbonate (3.00 g, 21.7 mmol) and prenyl bromide (0.90 ml, 7.67 mmol) were added, and the mixture was stirred at 70° C. for 7 hours. The reaction mixture was condensed under reduced pressure, and the resultant residue was extracted from chloroform-water. The organic phase was washed with saturated aqueous NaCl solution, dried, and condensed under reduced pressure. The residue was recrystallized from chloroform-ethyl acetate to obtain 1.85 g of the title compound as pale yellow needles (97.9%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.O1CCOCC1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1C=CC=CC=1>[CH3:22][S:23]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])(=[O:25])=[O:24]
Reactant: O=C1CCC(=O)N1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)ON1C(=O)CCC1=O
Reaction time: 8 h

Procedure:
N-Hydroxysuccinimide (11.5 g) and triethylamine (14.0 ml) are suspended into a mixture of benzene (100 ml) and dioxane (50 ml), and thereto is added dropwise a solution of methanesulfonyl chloride (7.8 ml) in benzene (20 ml) with stirring under ice-cooling and the mixture is stirred for 1 hour. After allowing to stand overnight, the solvent is distilled off. To the residue is added water and the resulting crystals are separated by filtration, washed with water and dried to give N-methanesulfonyloxysuccinimide (6.3 g), melting point: 148°-150° C. The product is recrystallized from ethyl acetate-petroleum ether to give crystals having a melting point of 150°-152° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:36]>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH2:36])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(N)=O)cc2)CC(C)(C)C1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a stirred suspension of (2E)-3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic acid (16) (0.18 g, 0.46 mmol) in CH2Cl2 (6 mL) at room temperature was added oxalyl chloride (0.15 mL, 0.218 g, 1.72 mmol, 3.7 eq) followed by several drops of DMF (Note: vigorous bubbling occurred upon addition of DMF). The reaction mixture was stirred under a nitrogen atmosphere for 1 h and concentrated in vacuo. Toluene was added to the crude acid chloride and the solvent was removed in vacuo. To the crude acid chloride was added ammonia (0.5 M in 1,4-dioxane) (6 mL) and the turbid reaction mixture stirred at room temperature under a nitrogen atmosphere for 3 h. Ammonia (0.5 M in 1,4-dioxane) (2 mL) was added to the reaction mixture and stirring was continued overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo. Ammonia (0.5 M in 1,4-dioxane) (8 mL) and CH2Cl2 (8 mL) were added to the residue. The flask was equipped with a rubber septum and the reaction mixture was stirred at room temperature for 2 d. The reaction mixture was transferred to a separatory funnel and partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous phase was extracted with CH2Cl2. The organic extracts were combined, washed with brine, dried (MgSO4) filtered, and the filtrate was concentrated to give the crude product as an amorphous solid. The crude product was purified by flash chromatography on silica gel with CH2Cl2:MeOH (100:0 to 19:1) as eluant to provide the product which was dried to give 0.026 g (15%) of compound 17 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (s, 6 H), 0.88 (s, 6 H), 1.25 (s, 2 H), 1.89 (s, 2 H), 1.92 (s, 2 H), 6.53 (d, J=15.8 Hz, 1 H), 6.66 (d, J=8.5 Hz, 2 H), 6.93 (d, J=8.5 Hz, 2 H), 7.06 (br s, 1), 7.14 (d, J=8.1 Hz, 2 H), 7.35 (d, J=15.9 Hz, 1 H), 7.45 (d, J=8.1 Hz, 2 H), 7.50 (br s, 1 H), 9.30 (s, 1). HRMS (ESI) Calcd for C26H32 NO2: 390.2433 (M+H)+. Found: 390.2427.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:16])=O.CN(C)C=O>COCCOC>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:16])=[O:9])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 50.0 ml of 1,2-dimethoxyethane (DME), 10.0 g of 2- (5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 8.4 g of phosphorus oxychloride at 5° C. to a mixture of 20 ml of DME and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 160 ml of ice water to precipitate crystals. The resulting crystals were collected by filtration, washed with 200 ml of ice water and then stirred for 30 minutes in 120 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.43 g (76.6%). Purity: 97.2%.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:7]=[CH:6][CH:5]=1)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl.[OH-].[Na+]>CN(C)C=O>[C:1]([C:4]1[N:9]=[C:8]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: NC(=O)c1cccc(C=CC(=O)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(C=CC(=O)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 3-(6-carbamoyl-2-pyridyl)-1-phenyl-2-propen-1-one (0.5 g) in N,N-dimethylformamide (5 ml) was added phosphorus oxychloride (0.46 g) under ice-cooling. After stirring for 30 minutes at same temperature, the solution was poured into a mixture of ice-water (50 ml) and chloroform (10 ml). The resultant solution was adjusted to pH 9 with 4N-sodium hydroxide. The organic layer was washed with water and brine and dried over magnesium sulfate. After evaporating the solvent to give 3-(6-cyano-2-pyridyl)-1-phenyl-2-propen-1-one (0.38 g).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])/[C:11](=[O:20])[NH:12]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])/[C:11](=[O:20])[NH:12]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (52.6 mg, 0.63 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (100 mg, 0.25 mmol) (Starting Material 4 supra) using (Ph3P)2PdCl2 (17.5 mg) and Cul (4.8 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 12 mg, 14%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:16]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
Neat i-Pr2NEt (0.21 mL, 1.19 mmol) was added to a DCM mixture (5 mL) of 3-bromo-5-chlorobenzoic acid (140 mg, 0.60 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (145 mg, 0.71 mmol), HOBt (92 mg, 0.60 mmol) and EDCI (114 mg, 0.60 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting precipitate was filtered off, washed with water and MeOH, and dried in vacuo to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=[N:35][C:30]2[CH:31]=[CH:32]C=N[C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C[O:48][CH2:47]C1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:35][CH:30]3[CH2:29][CH2:47][O:48][CH2:32][CH2:31]3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: NC1CCOC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NC1CCOCC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 4-aminotetrahydrofuran (27 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C16H22ClN5O3, 368.15. found 368.3.