Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][NH2:11].O1CCOCC1>ClCCl>[NH:10]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[N:11]1
Reactant: NN
Reactant: O=Cc1cccnc1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cnc2[nH]ncc2c1
Temperature: 150 °C

Procedure:
2-Chloro-3-formylpyridine (15.02 g, 106 Mmol, 1 equiv), hydrazine (10 mL, excess), and dioxane (90 mL) were combined in a sealed tube and heated at 150° C. for 16 hr. After cooling to room temperature, the solvent was evaporated in vacuo to provide a crude residue which was diluted with dichloromethane (600 mL). The organic solution was washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to provide 1H-pyrazolo[3,4-b]pyridine as a yellow powder which was used without further purification: LCMS (ES) M+H 120.3, Rf 0.20 min (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C., 1 mL/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:19](OC=C)(=[O:21])[CH3:20]>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1.[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]([O:18][C:19](=[O:21])[CH3:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C=COC(C)=O
Agent: CCOC(=O)CC(O)c1cc(OC)cc(OC)c1
Product: CCOC(=O)CC(OC(C)=O)c1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
The mixture of 5.0 g (20 mmol) of ethyl 3-(3,5-dimethoxyphenyl)-3-hydroxypropionate, 1.4 g (16 mmol) of vinyl acetate and 2.0 g of lipase PS was stirred at room temperature for 8 days. After the lipase was removed by filtration, the filtrate was eluted by column chromatography (eluting solution; 9/1 of toluene/ethyl acetate) to obtain 2.2 g (50%ee) of (-)-ethyl 3-(3,5-dimethoxyphenyl)-3-hydroxypropionate and 2.7 g of (+)-ethyl 3-(3,5-di-methoxyphenyl)-3-acetoxypropionate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([O:24][CH2:25][CH2:26][C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:8]=1.[OH-].[Na+]>CO.O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[CH:8]=[C:7]([CH:6]([O:24][CH2:25][CH2:26][C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C(OCCc2cncn2C)c2nccs2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cncc1CCOC(c1ccc(C(=O)O)c(-c2ccc(F)cc2)c1)c1nccs1
Temperature: 25 °C

Procedure:
A mixture of methyl 4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]-2-(4-fluorophenyl)benzoate (1.45 g, 3.21 mmol) and sodium hydroxide (0.64 g, 16.05 mmol) in methanol (75 ml) and water (7 ml) was stirred under a nitrogen atmosphere at reflux for 18 hours, cooled to ambient temperature and the methanol evaporated off. The residue was treated with aqueous citric acid (1M, 5 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to dryness to give 2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid as a white foam, (0.877 g, 63%).
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[CH:18][N+:19]([O-])=O)[CH2:9][C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](O)[CH3:24]>[Ni].O1CCCC1>[CH3:23][C:24]1[N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8](=[O:22])[CH2:9][C:10]2=[CH:18][N:19]=1
Reactant: CCO
Reactant: O=C1CC(=C[N+](=O)[O-])Nc2ccccc2N1c1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ncc2n1-c1ccccc1N(c1ccccc1)C(=O)C2
Reaction time: 20 h

Procedure:
Raney nickel, 11 g, was added to a solution of 3.5 g. (0.0118 m) of 5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1,5-benzodiazepin-4-one in 50 ml of tetrahydrofuran, and 150 ml of ethanol. The mixture was then hydrogenated at atmospheric pressure for a period of 20 hours. The catalyst was filtered off and washed with tetrahydrofuran and methylene chloride. The filtrate was evaporated and the remaining oil (3.1 g.) was dissolved in 250 ml of xylene and 6.2 ml of triethylorthoacetate. After heating to reflux with stirring for 30 min, the reaction mixture was evaporated. The residue was dissolved in 200 ml of toluene and 19 g of activated manganese dioxide was added to the solution. The mixture was stirred and refluxed for 30 min. The manganese dioxide was filtered off and washed well with tetrahydrofuran and methylene chloride. The filtrate was evaporated, and the residue was crystallized from ethyl acetate to yield crystals with mp 217°-220°. For analysis, the material was recrystallized from methylene chloride/ethyl acetate to give colorless crystals with mp 221°-223°.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH2:24][C:25]([CH3:36])=[CH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)=[O:28].C(O)(=O)C>CC(O)C>[CH3:23][C:16]1[NH:24][C:25]([CH3:36])=[C:26]([C:27](=[O:28])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(N)=CC(=O)c1ccc(C)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(C)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 69 mg (0.53 mmol) of ethyl 3-oxobutanoate, 93 mg (0.53 mmol) of 3-amino-1-(4-methylphenyl)but-2-en-1-one and 3 μl (0.05 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 180 mg (74% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1>O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:34][O:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH2:32][CH2:31][C:30]([NH:29][C:25]1[CH:24]=[C:23]([C:9]2[S:10][C:11]([C:12]3[NH:16][CH:15]=[N:14][N:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:28]=[CH:27][N:26]=1)=[O:33]
Reactant: C=CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Reactant: COC[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H]1CCCN1CCC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of N-(4-(4-phenyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl)pyridin-2-yl)prop-2-enamide (92 mg, 0.2 mmol) prepared in Example 4-B (iii) in tetrahydrofuran (2.0 mL) was added (2S)-2-(methoxymethyl)pyrrolidine (120 mg, 1.0 mmol), and the mixture was heated under reflux for 14 hr. The reaction solution was cooled to room temperature, and diluted with ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated, extracted with ethyl acetate (40 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was dissolved in trifluoroacetic acid (4.0 mL), and the mixture was stirred at room temperature for 3 hr. Trifluoroacetic acid was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→50/50) to give the title compound (60 mg, 62%) as a pale-yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)[CH:34]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].O[Li].O.Cl>O1CCCC1.O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)[CH:34]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(-c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)c(C(=O)O)n1)CC2
Reaction time: 8 h

Procedure:
To an ambient solution of EXAMPLE 104B (75 mg) in tetrahydrofuran (1.5 mL) and water (0.5 mL) was added LiOH H2O (13 mg). The reaction was stirred overnight, diluted with 2 mL water and 2 mL ethyl acetate, and acidified to pH ˜3 with 10% aqueous HCl solution. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×8 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.85 (s, 1H), 8.26 (m, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (d, 1H), 7.43 (m, 5H), 7.26 (d, 1H), 7.14 (m, 4H), 7.00 (d, 1H), 4.99 (s, 2H), 3.91 (t, 2H), 3.01 (t, 2H).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([NH:7][C:8]([C:10]1[C:18]2[S:17][C:16]([NH:19][C:20](=[O:24])[NH:21][CH2:22][CH3:23])=[N:15][C:14]=2[CH:13]=[C:12]([O:25]C)[CH:11]=1)=[O:9])[CH3:6]>C(Cl)Cl.CCOC(C)=O>[CH2:5]([NH:7][C:8]([C:10]1[C:18]2[S:17][C:16]([NH:19][C:20](=[O:24])[NH:21][CH2:22][CH3:23])=[N:15][C:14]=2[CH:13]=[C:12]([OH:25])[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)Nc1nc2cc(OC)cc(C(=O)NCC)c2s1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)cc(C(=O)NCC)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Boron tribromide (8.72 mL, 8.72 mmol, 4M solution in DCM was added to a suspension of N-ethyl-2-(ethylcarbamoylamino)-5-methoxy-1,3-benzothiazole-7-carboxamide in dichloromethane (10 mL). The reaction was stirred at ambient temperature overnight then diluted with EtOAc, washed with saturated aqueous sodium hydrogen carbonate and brine and the organic layer dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using DCM:MeOH 95:5. The product was obtained as a white solid, 212 mg, 31% yield.
Reaction SMILES: C(OC)(C)(C)C.[F:7][C:8]1[CH:16]=[C:15]([CH3:17])[C:14]2[N:13]3[C@H:18]([CH3:23])[CH2:19][NH:20][C:21](=O)[C:12]3=[CH:11][C:10]=2[CH:9]=1.[ClH:24]>ClCCl.C(OCC)C>[ClH:24].[F:7][C:8]1[CH:16]=[C:15]([CH3:17])[C:14]2[N:13]3[C@H:18]([CH3:23])[CH2:19][NH:20][CH2:21][C:12]3=[CH:11][C:10]=2[CH:9]=1
Reactant: Cc1cc(F)cc2cc3n(c12)[C@H](C)CNC3=O
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Cc1cc(F)cc2cc3n(c12)[C@H](C)CNC3

Procedure:
The tide compound (ISP-MS: m/e 219.3 ([M+H]+)) was produced in accordance with the general method of example 1a), using tert-butyl-methyl ether instead of tetrahydrofuran as solvent, from (R)-8-fluoro-4,6-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one. The product (20 mg) was dissolved in dichloromethane and treated with a solution of HCl in diethyl ether to precipitate the hydrochloride salt Yield: 18 mg.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.C([O-])(C)(C)C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH2:25][O:26][CH3:27].Cl>CN1CCCC1=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH2:25][O:26][CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: COCc1cc([N+](=O)[O-])ccc1F
Reactant: O=c1[nH]cccc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 44.2 g (85% purity, 216 mmol) of 3-bromopyridone in 450 ml of N-methylpyrrolidone were introduced as initial charge, and 29.1 g of potassium tert-butanolate (259 mmol) were added in portions such that the temperature remained below 30° C. The mixture was stirred for 1 h and then 40 g (216 mmol) of 1-fluoro-2-(methoxymethyl)-4-nitrobenzene were added. The reaction mixture was stirred for 4 h at 80° C., cooled to RT and stirred into an ice/water mixture. The pH was adjusted to pH=4 with semi-concentrated hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The residue was dissolved in 2 l of dichloromethane, absorbed on five times the amount of silica gel and chromatographically purified on silica gel with ethyl acetate:dichloromethane 3:97 and 5:95. The product fractions were evaporated to dryness on a rotary evaporator and the residue was dried in vacuo. This gave 55 g (73%) of the desired product.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=[O:8])C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:18]#[N:19])=[CH:13][CH:12]=1.[OH-].[NH4+]>CCCCCC>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:18]([NH2:19])=[O:8])=[CH:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#CC(c1ccc(F)cc1)(c1ccc(F)cc1)c1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Product: NC(=O)C(c1ccc(F)cc1)(c1ccc(F)cc1)c1cccc(F)c1
Temperature: 130 °C

Procedure:
A solution of concentrated sulfuric acid (10 mL) and glacial acetic acid (10 mL) was added to bis(4-fluorophenyl)-3-fluorophenylacetonitrile (3.18 mmol) at rt. The resulting orange solution was stirred and heated at 130° C. for 3 h. The reaction was cooled to 0° C., poured into ice water (50 mL) and neutralized with ammonium hydroxide. The organics were extracted with chloroform (3×50 mL). The organics fractions were combined washed with brine (2×20 mL), dried (Na2SO4) and concentrated under reduced pressure to afford a yellow-orange solid. The solid was stirred with hot hexane (50 ml) for 30 mins and filtered. Crystallization from dichloromethane/hexane gave the desired product bis(4-fluorophenyl)-3-fluorophenylacetamide 16 as a white crystalline solid (147 mg, 0.43 mmol, 11%, 4 steps).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(C(C)C)CC)(C)C.[CH2:25]([O:28][C:29](Cl)=[O:30])[CH:26]=[CH2:27].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:6][C:29]([O:28][CH2:25][CH:26]=[CH2:27])=[O:30])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of L-Tyrosine methyl ester hydrochloride (25 g, 107.9 mmol, 1.0 equiv) in THF (500 mL) and CH2Cl2 (250 mL) at room temperature was added diisopropyl ethylamine (56.5 ml, 322.5 mmol, 3.0 equiv). The solution was cooled to 0° C. and allylchoroformate (11.5 ml, 107.9 mmol, 1.0 equiv) was added dropwise. The reaction was stirred at 0° C. for 1.5 hours, after which time saturated ammonium chloride (100 mL) was added and the THF and CH2Cl2 were removed under reduced pressure. The aqueous suspension was extracted with ether (4×300 mL). The organics were combined, washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (15→60% EtOAc/hexane) afforded 18 (30 g, 96%) as a white solid. Rf=0.43 (50% EtOAc/hexane); FTIR (neat, cm−1) 3297, 2959, 1734, 1688, 1566, 1518, 1441, 1229; 1H NMR (400 MHz, CDCl3) δ6.95 (d, J=7.9 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 5.85 (m, 1H), 5.24 (m, 3H), 4.6 (m, 1H), 4.53 (d, J=5.2, 2H), 3.71 (s, 3H), 3.01 (m, 2H); 13C NMR (100 MHz, CDCl3) δ172.3, 155.8, 155.2, 132.3, 130.3, 127.0, 118.0, 115.5, 66.0, 54.9, 52.9, 52.4, 37.4; HRMS (ES+) calculated for C14H17NO5 (M+H)+: 280.1107, found: 280.1195.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].[CH2:15]([S:19]Cl)[CH2:16][CH2:17][CH3:18].C1C=CC=CC=1>N1C=CC=CC=1>[CH3:1][N:2]([S:19][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4]
Reactant: CCCCSCl
Reactant: CNC(=O)Nc1cc(C(C)(C)C)no1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCSN(C)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
To a solution of 1-methyl-3-(3-t-butyl-5-isoxazolyl)-urea (0.99 g) in pyridine (8 ml), butylsulfenyl chloride (0.67 g) is added dropwise at -30° to -40° C., and the resultant mixture is stirred at the same temperature for 6 hours. The reaction mixture is allowed to stand at room temperature overnight, poured into ice water and shaken with benzene. The organic layer is washed with 3% hydrochloric acid, 5% aqueous sodium bicarbonate solution and water in that order, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The residue is chromatographed on a column of silica gel, whereby 1-methyl-1-butylthio-3-(3-t-butyl-5-isoxazolyl)urea (0.031 g) is obtained as an oil. IR: 1712, 1617 cm-1 (CC14).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=O.[CH3:12][C:13]([OH:15])=[O:14]>CC(OC(C)=O)=O>[C:13]([O:15][CH:1]1[C:2]2[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:4]=[C:5]1[CH3:6])(=[O:14])[CH3:12]
Reactant: CC(=O)O
Reactant: Cc1ccccc1C=CC=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1C(C)=Cc2ccccc21
Yield: 70 %

Procedure:
Using the same experimental procedure as under a), 2-methylcinnamaldehyde (21 g, 0.14 mol) in AcOH (27 g), FeCl3·6H2O (6 ml of a 0.25 M solution in Ac2O, 1.5 mmol) in Ac2O (53 g) were reacted together. After a further 2 hours at reflux the cooled mixture was treated to the same workup and purification as before to provide the title compound
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>CCCCO>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=2)[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: O
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Mechanically stir mixture of 6-chloro-2-methyl-3-nitro-pyridine (Asymchem, 25.00 g, 144.9 mmol), tert-butyl 1-piperazinecarboxylate (29.68 g, 159.4 mmol), and triethylamine (23.2 mL, 167 mmol) in n-BuOH (250 mL) at 50° C. under nitrogen for 4 hours, at 65° C. for 2 hours, then at room temperature overnight. Add additional tert-butyl 1-piperazinecarboxylate (1.5 g), and heat the reaction at 65° C. for 4 hours. Cool the resulting slurry to 30° C. then add hexanes (75 mL). Cool the slurry to room temperature over 1 hour, then add water (150 mL). Allow the slurry to stand for 45 min then filter. Wash the cake with water (4×100 mL) then hexanes (100 mL) and air-dry overnight to yield 4-(6-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester as bright yellow crystals (46.30 g, 99% yield, MS(ES): m/z=267 [M+H—C4H8]).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2F)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[O:9][C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: Oc1cc(F)c(Br)cc1N=Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(c1)Oc1cc(F)c(Br)cc1N=C2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-[(2,4-difluorobenzylidene)amino]-5-fluorophenol (15 g, 45.4 mmol) in 60 mL of DMF, Cs2CO3 (22 g, 67.5 mmol) was added. The resulting mixture was stirred at 50° C. for 3 h and then allowed to cool to ambient temperature. Water was added and the product was collected by filtration, washed with water, and dried under reduced pressure to yield the title compound which was used without further purification (14.1 g, 100%). 1H-NMR (400 MHz, CDCl3) 6.82-6.99 (m, 3H), 7.33 (m, 1H), 7.55 (d, J=7.8, 1H), 8.38 (s, 1H).
Reaction SMILES: Cl.Cl.[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=1.[N:16]#[C:17]Br.[OH-].[Na+]>O>[N:6]1[NH:5][N:4]=[N:3][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:17]([NH2:16])=[N:15][C:10]=2[CH:9]=1
Reactant: N#CBr
Reactant: Nc1ccc(-c2nn[nH]n2)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc(-c3nn[nH]n3)ccc2[nH]1
Temperature: 4 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To 4-(2H-tetrazol-5-yl)-benzene-1,2-diamine dihydrochloride (8.56 g, 34 mmol) in water (45 ml) was adjusted to pH 6.0. Cyanogen bromide (3.91 g, 37 mmol) was added and the mixture stirred for 4 hours. The reaction mixture was analyzed by HPLC. The pH of the reaction mixture was adjusted to pH 4.0 with 40% (v/v) sodium hydroxide. The mixture was cooled to 4° C. and the brown solid filtered and washed with water. The material was dried to yield a brown solid 5-(2H-tetrazol-5-yl)-1H-benzimidazol-2y-amine (4.10 g) with a purity of 88%, Rt=7.3 mins. To a suspension of crude 5-(2H-tetrazol-5-yl)-1H-benzimidazol-2-ylamine (4.10 g) in water (40 ml), the pH was adjusted to 1.2 with 50% (v/v) hydrochloric acid. Activated carbon was then added (0.2 g) and the mixture stirred for 18 hours. The mixture was filtered and the pH of the filtrate adjusted to pH 3.7 to yield a tan colored solid. The material was dried (3.01 g) and had a purity of >97% by HPLC. 1H NMR (d6-DMSO, 400 MHz) 13.04 ppm (0.3H, s), 12.99 ppm (0.3H, s), 8.85 ppm (1H, s), 8.074 ppm (1H, s), 7.96 ppm (dd, 8.4 Hz, 1.2 Hz), 7.55 ppm (d, 8.4 Hz). MS: (Electrospray+) 201.8 m/z (M+), 223.7 m/z (M+Na).