Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>CN1CCCC1=O>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:21]1[CH:22]=[C:17]([Cl:16])[C:18]([N+:27]([O-:29])=[O:28])=[CH:19][C:20]=1[N+:24]([O-:26])=[O:25])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH3:9]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 1.60 mmol) was added to a mixture of tert-butyl ethyl malonate (300 mg) in 1-methyl-2-pyrrolidinone (3 mL) and was followed by 1,5-dichloro-2,4-dinitrobenzene (0.45 g). The reaction mixture was stirred for 15 minutes and was then quenched by addition of a diluted aqueous solution of hydrochloric acid. The resulting mixture was extracted with ethyl acetate; the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexane, 5/95 to 15/85) to give 0.4 g of 2-(5-chloro-2,4-dinitro-phenyl)-malonic acid tert-butyl ester ethyl ester.
Reaction SMILES: [C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl.CCOC(C)=O>[C:1]12([C:6]([O:8][CH3:9])=[O:7])[O:18][CH:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1=CCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C12CCCC1O2
Reaction time: 2 h
Yield: 142 %

Procedure:
Methyl cyclopent-1-ene-1-carboxylate (30.0 g, 237.8 mmol) was dissolved in 20 mL of dichloromethane and 3-chloroperbenzoic acid (64.4 g, 373.3 mmol) was added. The reaction was allowed to stir vigorously for 2 hours. The reaction mixture was diluted with EtOAc and washed with 0.5 N NaOH. The organic layer was dried over sodium sulfate, filtered and concentrated to give 48.0 grams of methyl 6-oxabicyclo[3.1.0]hexane-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH3:57])[C@H:3]([N:43]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[N:50]=2)[C:44]1=[O:56])[C:4]([NH:6][C@@H:7]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:8]([OH:35])[CH2:9][C@@H:10]([NH:24]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>CO.O1CCOCC1.[Pd]>[NH2:24][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[CH2:9][C@H:8]([OH:35])[C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:43]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[N:50]=2)[C:44]1=[O:56])[C:2]([CH3:57])([CH3:1])[CH3:58])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@H](Cc3ccc(-c4ccccn4)cc3)NC(=O)OCc3ccccc3)C(C)(C)C)C2=O)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccc(-c4ccccn4)cc3)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 130B (0.067 g, 0.086 mmol) in methanol (3 mL) was treated with a solution of HCl in dioxane (0.025 mL, 4 M) and Pd on carbon (0.007 g, 10% Pd by wt.), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt (0.053 g), which was used without further purification.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:35]=[CH:34][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][Si](C)(C)C)=[CH2:20])=[C:15]([O:26][Si](C)(C)C)[C:14]=2[CH2:31][CH2:32][CH3:33])=[CH:9][CH:8]=1.[CH:36]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][N:45]=1)[C:41]#[N:42])=[O:37].Cl>O1CCCC1.O>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:34]=[CH:35][C:7]([CH:36]([OH:37])[C:38]3[CH:39]=[C:40]([CH:43]=[CH:44][N:45]=3)[C:41]#[N:42])=[CH:8][CH:9]=2)=[C:14]([CH2:31][CH2:32][CH3:33])[C:15]=1[OH:26])(=[O:21])[CH3:20]
Reactant: N#Cc1ccnc(C=O)c1
Reactant: C=C(O[Si](C)(C)C)c1ccc(OCc2ccc(I)cc2)c(CCC)c1O[Si](C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(O)c3cc(C#N)ccn3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 2.98 mL, 5.95 mmol) to a solution of 1-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene (3.00 g, 5.41 mmol) in tetrahydrofuran (0.1M) cooled to 0° C. After 15 minutes, warm reaction to room temperature. After 1 hour, cool the reaction to −78° C. Add a solution of 2-formyl-isonicotinonitrile (612 mg, 5.95 mmol) in tetrahydrofuran (10 mL) via syringe. After 1 hour, warm the reaction to room temperature. Add 10% hydrochloric acid (30 mL). After 5 minutes, pour the reaction into water and extract with ethyl acetate. Combine organics, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with methanol:dichloromethane followed by trituration with acetonitrile to yield the title product as a white solid (1.71 g, 76%): 1H NMR (CDCl3) δ 0.95 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 4.50 (d, 1H), 5.16 (s, 2H), 5.84 (d, 1H), 6.46 (d, 1H), 7.41 (m, 4H), 7.51 (s, 1H), 7.55 (d, 1H), 8.76 (d, 1H), 12.74 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:32])=[N:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.C(OCC)C>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:32])=[N:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCNCC4)o3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[5-(2-amino-5-p-tolyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.574 mmol) in DCM (20 mL) was added 2M HCl in diethyl ether (20 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature, and was stirred for 2 h. After completion of the reaction, reaction mixture was filtered and washed with diethyl ether (2×30 mL), which afforded the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)c1sc(NS(=O)(=O)c2ccc(Cl)cc2)nc1-c1ccccc1

Procedure:
The title compound was prepared from ethyl 2-amino-4-phenylthiazole-5-carboxylate and 4-chlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (61.7 mg) with purity >90%. LCMS (pos) m/z 423.0.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CO>[N:26]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1c(-c2ccc(OCCBr)cc2)c(C#N)c2ccc(OC)cc21
Agent: [Na+]
Solvent: CO
Product: CCn1c(-c2ccc(OCCN=[N+]=[N-])cc2)c(C#N)c2ccc(OC)cc21
Temperature: 75 °C
Yield: 79.6 %

Procedure:
2-[4-(2-Bromoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (258 mg, 0.65 mmol), prepared in example 1BA, step A, is combined with NaN3 (144 mg, 2.2 mmol), and MeOH (3.2 mL). This is heated overnight at 75° C. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields 2-[4-(2-azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg, 80%), compound 266 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>C(O)C>[C:13]([C:15](=[CH:5][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[C:16]([NH2:18])=[O:17])#[N:14]
Reactant: N#CCC(N)=O
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])C(N)=O

Procedure:
A mixture of 3-fluoro-6-nitrobenzaldehyde (10.0 g., 0.0592 mole), 2-cyanoacetamide (5.24 g., 0.0622 mole), piperidine (0.37 g., 4.36 millimole) and ethanol (92 ml.) is heated to reflux on a steam bath for 2 hours. It is then cooled in an ice-bath whereupon the product precipitates and is recovered by filtration, washed with cold ethanol and dried. Yield = 9.1 g. (65%) of crude product. M.P. 162°-166° C.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][NH:17][C:9]1[C:8]2[C:7](=[O:23])[C:6]3[C:15](=[C:2]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)CCNc1cccc2c1C(=O)c1cccc(Cl)c1C2=O
Reactant: COCCN
Product: COCCNc1cccc2c1C(=O)c1cccc(NCCN(C)C)c1C2=O

Procedure:
This procedure was carried out as described previously in step (a) of Example 15, using Compound 17 (0.25 g, 0.76 mmol) and 2-methoxyethylamin (0.66 mL, 7.6 mmol). This product was used in the next step without any purification. The structure of Compound 23 is given below:
Reaction SMILES: [N:1]([C@H:4]1[C@H:9]2[CH2:10][C@H:6]([C@@H:7]([C:18]([O:20][CH3:21])=[O:19])[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C@H:4]1[C@H:9]2[CH2:10][C@H:6]([C@@H:7]([C:18]([O:20][CH3:21])=[O:19])[N:8]2[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:5]1
Reactant: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](N=[N+]=[N-])C2)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H]2C[C@@H](N)[C@@H](C2)N1C(=O)OC(C)(C)C
Yield: 99.9 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4S,6R)-6-azido-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-2 (170 mg) in methanol (4 mL), was added 10% palladium on carbon (30 mg). The mixture was stirred under 1 atm of hydrogen for 1.5 hrs at room temperature. The resulting mixture was filtered through celite and washed with methanol. The filtrate and washings were evaporated in vacuo to give the target compound (155 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].OS(O)(=O)=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(F)c(F)n1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)nc1F
Temperature: 60 °C
Yield: 50.5 %

Procedure:
To neat 2,3,6-trifluoropyridine (12.0 g, 90 mmol) was slowly added fuming HNO3 (142 g, 2254 mmol) and H2SO4 (133 g, 1353 mmol) slow enough to keep the internal temperature below 40° C. Upon completion of the addition, the resulting solution was heated to 60° C. for 30 minutes, and then cooled to 0° C. Ice water (21) was added, and the reaction was extracted with hexanes (2×300 ml) and then DCM (1×300 ml). The combined organic fractions were dried over Na2SO4, filtered, and concentrated to give the title compound (8.1 g, 50%), which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][O:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][OH:22]>[Cl-].[Zn+2].[Cl-]>[OH:22][CH2:21][CH2:20][N:19]1[CH2:10][CH2:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:9]
Reactant: O=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: NCCO
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C1N(CCO)CCC1(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 3,3-diphenyldihydrofuran-2(3H)-one (0.5 g, 2.098 mmol), 2-aminoethanol (1282 mg, 20.98 mmol) and zinc chloride (0.23 g, 1.679 mmol) was heated neat at 100° C. for 16 hours. The reaction mixture was cooled and partitioned in H2O/ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated to yield the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (m, 8H), 7.23 (m, 2H), 3.81 (q, J=5.42 Hz, 2H), 3.52 (t, J=5.42 Hz, 2H), 3.45 (t, J=6.44 Hz, 2H), 2.85 (t, J=5.52 Hz, 1H), 2.79 (t, J=6.44 Hz, 2H); MS (ESI+) m/z 282 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[NH:25][C:24]2=[O:34])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:35](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[N:25]([CH3:35])[C:24]2=[O:34])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
To ethyl [2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate, are added N,N-dimethylformamide and potassium carbonate, then, methyl iodide is added to the reaction solution, and the mixture is stirred at room temperature. Diluted hydrochloric acid is added to the reaction solution and extracted with ethyl acetate. The organic layer is washed with water and then saturated saline, and dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain ethyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [compound 3-12 of the present invention].
Reaction SMILES: [Cl:1][CH:2]([C:10](=O)[CH3:11])[C:3](=[O:9])[C:4]([O:6]CC)=[O:5].Cl.[NH2:14]O.O.[OH-].[Na+]>CO>[CH3:11][C:10]1[C:2]([Cl:1])=[C:3]([C:4]([OH:6])=[O:5])[O:9][N:14]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)C(Cl)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
A solution of ethyl 3-chloro-2,4-dioxovalerate (3.0 g, 15.6 mmol) and hydroxylamine hydrochloride (1.08 g, 15.6 mmol) in a mixuture of 1.5 mL of H2O and 1 mL of CH3OH was heated to reflux. After four hours TLC analysis indicated that all of the starting material had been consumed. Sodium hydroxide (0.31 g, 7.8 mmol) was added to the hot solution. After four hours the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was taken up in a 1:1 mixture to ethyl acetate/H2O. The aqueous layer was made basic with 2N NaOH and separated. The aqueous layer was then acidified with 2M HCl and extracted with ethyl acetate (125 mL). The ethyl acetate extract was washed with H2O (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 600 mg (24% yield) of the desired product a gummy tan solid: 1H NMR (CDCl3) 67 8.8 (bs, 1H), 2.3 (s, 3H).
Reaction SMILES: OS(O)(=O)=O.[N-:6]=[N+]=[N-].[Na+].[F:10][C:11]([F:30])([F:29])[C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[CH2:20]2)[CH2:16][CH2:15]1)=[O:13].C([O-])(O)=O.[Na+]>O.C(Cl)(Cl)Cl>[F:10][C:11]([F:30])([F:29])[C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:6][C:21](=[O:28])[CH2:20]2)[CH2:16][CH2:15]1)=[O:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Concentrated H2SO4 (1.1 mL) was added slowly to sodium azide (2.49 g, 38.3 mmol) in water (2.7 mL) and chloroform (15 mL) keeping the temperature between 0-5° C. After 10 min the cold bath was removed and the reaction was stirred for 3 h at rt. Na2SO4 was added to the solution to dry it and the resulting chloroform solution (containing HN3) was then decanted into a solution of 19a (4.55 g, 15.3 mmol) in chloroform (16 mL). Concentrated H2SO4 (4.1 mL) was added and the reaction was stirred for 30 min. at rt. The mixture was heated to 50° C. for 45 min. and then stirred at rt for 2 h. The reaction was poured into sat. NaHCO3 solution and extracted with CH2Cl2 (3×) and with EtOAc (2×). The combined organics were dried (MgSO4), filtered and evaporated to give the crude product. The crude product was purified by flash chromatography on Biotage using EtOAc/CH2Cl2 (50-80%) to give 19b as lightly colored foam (2.6 g, 54%). (M+H)+=313. 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (s, 1H); 7.29 (d, J=7.8 Hz, 1H); 7.24 (t, J=7.8 Hz, 1H); 7.10 (t, J=7.6 Hz, 1H); 6.83 (d, J=7.8 Hz, 1H); 4.44 (d, J=13.9 Hz, 1H); 3.92 (d, J=14.1 Hz, 1H); 3.48 (t, J=13.2 Hz, 1H); 3.18 (t, J=11.9 Hz, 1H); 2.77 (m, 2H); 2.00 (m, 2H); 1.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=O)[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:17]([NH2:18])=[C:16]([O:22][CH3:23])[CH:15]=1>CN1CCCC1=O.ClCCl>[Br:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9]([NH:18][C:17]3[C:19]([CH3:21])=[CH:20][C:14]([Cl:13])=[CH:15][C:16]=3[O:22][CH3:23])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c2cccc(Br)c21
Reactant: COc1cc(Cl)cc(C)c1N
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1cc(Cl)cc(C)c1Nc1nc2cccc(Br)c2n1C
Temperature: 110 °C
Yield: 84.9 %

Procedure:
To a mixture of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 2.32 g (9.69 mmol) and 4-chloro-2-methoxy-6-methylaniline 4.98 g (29.1 mmol) in 0.5 mL of N-methyl-2-pyrrolidone was heated at 110° C. for 2 days. The reaction was cooled to room temperature and diluted with dichloromethane. The mixture was washed with sodium bicarbonate and water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate/hexane (1:1) to give 3.13 g (8.23 mmol, 85%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[OH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:13][CH2:12]1
Reactant: OC1CCNCC1
Reactant: Cc1oncc1C(=O)Cl
Product: Cc1oncc1C(=O)N1CCC(O)CC1

Procedure:
of melting point 70.5° to 72.5° C., prepared from 5-methyl-4-isoxazolecarboxylic acid chloride and 4-hydroxypiperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O>[C:9]1([N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cnn(-c2ccccc2)c1
Reaction time: 3 h
Yield: 46.8 %

Procedure:
A mixture of 4-nitro-1-phenyl-1H-pyrazole (440 mg, 2.32 mmol) and SNCl2 dihydrate (2.18 g, 9.66 mmol) in EtOAc (15 mL) was stirred at 80 C for 3 h. Aqueous 1N NaOH was added to bring pH to 12. The mixture was filtered through celite. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 1-phenyl-1H-pyrazol-4-amine as a solid (173 mg).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].O.O.[Na].[S:12]1([C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[NH:15]1)(=[O:14])=[O:13]>CN(C)C=O.O>[O:17]=[C:16]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[S:12](=[O:14])(=[O:13])[N:15]1[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C)OC(=O)CCl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 120 °C
Yield: 86.4 %

Procedure:
23.3 kg (170.6 mol) of isopropyl chloroacetate are added to a solution at 50° C. of 40 kg (165.8 mol) of saccharin sodium dihydrate in 40 l of dimethylformamide. The mixture is heated to 120° C. and maintained for 3 hours at this temperature. The mixture is cooled and diluted with 240 l of water. Finally, the precipitate is centrifuged, washed with cold water and dried, 40.6 kg (86%) of a crystalline white solid, m.p. 112°-7° C. (118°-9° C. from isopropanol), being obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22].Cl>CN(C)C=O>[CH3:22][O:21][CH2:20][CH2:19][O:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: O=C1COc2cccc(O)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc2c1C(=O)CO2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A mixture of 4-hydroxy-benzofuran-3-one (CAS no: 19278-81-0) (4.9 g, 9 mmol), potassium carbonate (1.66 g, 12 mmol) and 2-bromoethyl methylether (1.13 mL, 12 mmol) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 1.5 h. Cooled to 23° C., poured into 1 N HCl, extracted four times with ethyl acetate, dried combined organic layer over Na2SO4. Removal of the solvent in vacuum left a yellow residue which was purified by silica gel column chromatography with heptane/ethyl acetate to give the title compound as a white solid (1.3 g, 63%); MS: m/e=177.2 (M−OMe+H+).
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([CH:10]2[C:15](=O)[CH2:14][CH2:13][O:12][CH2:11]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:31][C:32]([NH2:34])=[NH:33])[CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH:1]1([O:6][CH2:7][C:8]2[C:10]3[CH2:11][O:12][CH2:13][CH2:14][C:15]=3[N:34]=[C:32]([NH:31][C:21]3[CH:22]=[CH:23][C:24]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:19]([O:18][CH3:17])[CH:20]=3)[N:33]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: O=C1CCOCC1C(=O)COC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(COC4CCCC4)n2)COCC3)ccc1-n1cnc(C)c1
Yield: 16 %

Procedure:
3-(2-(Cyclopentyloxy)acetyl)dihydro-2H-pyran-4(3H)-one (280 mg, 1.24 mmol), 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (1 equiv.) and potassium carbonate (2 equiv.) were heated to 50° C. over night in EtOH (5 mL). The crude product was extracted into DCM, the organic phase collected and solvent evaporated. The crude product was purified by flash chromatography (0-100% EtOAc in Heptane). The purity was not satisfactory so further purification on prepHPLC was performed to afford the title compound (83 mg, 16% yield).