Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].O.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:23][CH3:24])=[O:19]
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccccc1
Reactant: CCI
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Reaction time: 2 h
Yield: 4.7 %

Procedure:
A solution of 3.12 g (0.1 mole) of 2-amino-3-benzoyl-5-chlorobenzeneacetic acid, sodium salt.1/2 H2O in 250 ml of dry dimethylformamide was treated with 44 g of ethyl iodide (0.3 mole) under nitrogen and stirred for 2 hours. The resulting solution was then added to one liter of water and extracted several times with ethyl ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered and stripped to yield a solid yellow residue. This residue was recrystallized from ethyl alcohol, yielding 1.5 g of the title compound as yellow needles, m.p. 80°-82° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CO>[CH2:4]([O:3][C:1]([NH:11][CH:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])=[CH:18][CH:19]=1)[C:21]([OH:23])=[O:22])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC(Cc1ccc(OCCCCCBr)cc1)C(=O)O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
N-CBZ-L-tyrosine (2.06 g, 5.86 mmole) was treated with NaH (0.58 g, 12.08 mmole) and 1,5-dibromopentane (0.8 ml, 5.87 mmole) as described for 1-1 in Example 1. The crude product was dissolved in methanol and after stirring with silica gel for 0.5 hour, the solvent was removed. This was dry packed and eluted on a flash column with CHCl3 and then with 97:3:0.3 CHCl3 /CH3OH/HOAc to give pure 1-10.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26](ON=C(C(OCC)=O)C(OCC)=O)=[O:27])=[CH:22][CH:21]=1>O.C(O)(C)(C)C>[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(=NOC(=O)OCc1ccc(OC)cc1)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(COC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
L-Phenylalanine (330 mg.) and sodium bicarbonate (202 mg.) were dissolved in water (10 ml.) under heating and allowed to stand. A solution of diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (1.0 g.) in tert-butyl alcohol (10 ml.) was added to the solution with stirring at room temperature and water (10 ml.) was added thereto. The mixture was then stirred for 2 hours at room temperature. The reaction mixture was brought to pH 9 by adding water (20 ml.) and a saturated sodium bicarbonate aqueous solution (10 ml.), and water (10 ml.) was added thereto. The resulting mixture was then washed twice with ethyl acetate (20 ml.). The aqueous layer was adjusted to pH 7 with a 10% citric acid aqueous solution, washed twice with ethyl acetate (30 ml.), adjusted to pH 3.5 with a 10% citric acid aqueous solution and extracted three times with ethyl acetate (30 ml.). The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give N-(4-methoxybenzyloxycarbonyl)-L-phenylalanine (410 mg.), oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[Cl:10].[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH2:36][OH:37])[C:25]([C:38](NCC2C=CC(F)=CC=2)=[O:39])=[CH:24][N:23]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH2:36][OH:37])[C:25]([C:38]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([Cl:10])[CH:4]=2)=[O:39])=[CH:24][N:23]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)c(Cl)c1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Yield: 38.7 %

Procedure:
4-Fluoro-3-Chloro benzylamine (0.060 g, 1.29 mmol, 2 eq) and N,7-bis(benzyloxy)-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (0.050 g, 0.141 mmol, 1 eq) (compound 1c of example 1) were heated in DMF at 90° C. for 120 min. The crude product was purified by silica gel (100% ethyl acetate) yielding 0.03 g of N2,3-bis(benzyloxy)-N5-(3-chloro-4-fluorobenzyl)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide as a white solid; MS-ESI m/z 573 [MH]−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH2:9][O:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4].[N:16]([O-:18])=[O:17].[Na+].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[CH2:9][O:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(F)c2c1C=CCO2
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 50 °C
Yield: 55 %

Procedure:
Into a reactor, equipped with mechanic stirrer and reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid methyl ester (6.6 g; 30 mmoles), sodium nitrite (6.2 g; 90 mmoles) and ethyl acetate (60 ml) were added at room temperature and under inert gas. The mixture was heated under stirring at 50° C., then iodine (2:6 g; 10 mmoles) and, slowly in 4 hours, Oxistrong 15® (7.4 ml) were added. At the end of the addition the reaction mixture was kept under stirring for a further hour, then cooled at 0° C. A 20% solution of sodium metabisulphite (about 25 ml) was added and the mixture was kept under stirring for 1 hour. After filtration the solid was washed with water (2×10 ml). The mother liquors were separated and, the previously filtered solid was added to the organic phase. The solvent was removed under reduced pressure and the semisolid residue was taken up with methanol (about 10 ml) and kept under stirring at 0° C. for 1 hour. After filtration and wash of the panel with methanol pre-cooled at 0° C. (3 ml), the resultant solid was dried in oven under vacuum at 40° C. overnight obtaining 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid methyl ester (4.6 g; titre 92%; 55% yield). The mother liquors were evaporated to dryness obtaining an oil (2.7 g) containing 55% of 8-fluoro-3-nitro-2H-chromene-5-arboxylic acid methyl ester. Overall yield 75%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[NH:29][C:10]2=[N:11][C:12]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[N:29]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:10]2=[N:11][C:12]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC(=O)OCCc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCn1c(CCOC(C)=O)cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,3-Dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate (step 3)(12 mg, 0.031 mmol) was dissolved in dry DMF (1 ml) at RT and treated with K2CO3 (12.91 mg, 0.093 mmol) and ethyl 7-bromoheptanoate (0.012 ml, 0.062 mmol). The resulting brown suspension was stirred at RT for 16 hours. The mixture was then heated at 60° C. for 5 hours and after cooling to RT, stirred overnight. The mixture was added to water (30 ml) and extracted with DCM (×3). The combined organic extracts were passed through a phase separating column and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[Cl:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(C#N)(C)=O>[Cl:19][C:20]1[N:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)Cc1cccc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)c1
Temperature: 70 °C

Procedure:
2-[3-(4-Chloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (136.5 mg, 0.5177 mmol) is combined with 2-chlorobenzimidazole (86.9 mg, 0.5177 mmol) and potassium carbonate (93 mg, 0.673 mmol) in AcCN (5 ml) and heated at 65-75° C. for 2 to 20 hours. The reaction mix is cooled to RT and the inorganic salts are filtered off. The AcCN solution is concentrated down under reduced pressure. The crude is purified on a silica gel column with an EtOAc/hexane to MeOH/CH2Cl2 elution gradient, giving 2-{3-[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}acetamide.
Reaction SMILES: Cl.[OH:2][CH:3]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:2][CH:3]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:8]1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 2-hydroxy-2-(piperidin-3-yl)acetic acid hydrochloride (1.956 g; 10 mmoles) in 2.7 (w/w) % aqueous sodium hydroxide solution is added 1.72 ml (1.2 equivalents) of benzyloxycarbonylchloride. After 2 hours, the reaction mixture is washed twice with ether, adjusted to pH 1 to 2 with 10% hydrochloric acid, and extracted thrice with methylene chloride. The extract is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to yield 2.650 g of oily 2-hydroxy-2-(1-benzyloxycarbonylpiperidin-3-yl) acetic acid in 90.4% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]1(=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]1=[O:32].C(N(CC)CC)C>ClCCl>[O:32]=[C:23]1[C:22](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:24]1
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C=C(N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
To a solution of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (2.3 g, 7.64 mmol) in dichloromethane (200 mL) was added naphthalene-1,2-dione (1.2 g, 7.64 mmol) followed by triethylamine (1.05 mL, 8.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The residue was dissolved in minimal tetrahydrofuran and then precipitated with EtOAc. The precipitate was collected by vacuum filtration. The filtrate was then suspended in tetrahydrofuran:EtOAc (1:1, 100 mL). The suspension was stirred, sonicated, and the solid collected by vacuum filtration. The tituration was once more repeated and the resulting reddish brown powder was recrystallized from dichloromethane/methanol (1:1) to afford the product (0.5 g) as the pure reddish brown solid. M.p.=250-260° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89-7.93 (m, 3H), 7.71-7.81 (m. 3H), 7.55-7.65 (m, 2H), 6.10 (s, 1H), 3.67-3.75 (m, 2H), 3.45-3.53 (m, 2H), 3.19 (s, 2H), 2.20 (m, 2H), 1.25 (m, 1H), 1.01 (m, 1H). LCMS: 458 [M+H].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(C(C)C)CC)(C)C.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24][NH:25][CH2:26][CH2:27][CH3:28])[CH:17]=[CH:16]1>C(Cl)Cl>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24][N:25]([CH2:26][CH2:27][CH3:28])[C:3](=[O:4])[CH2:2][Cl:1])[CH:17]=[CH:16]1
Reactant: O=C(Cl)CCl
Reactant: CCCNCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(Cc1cccc2cc[nH]c12)C(=O)CCl
Reaction time: 2 h
Yield: 100 %

Procedure:
Add chloroacetyl chloride (1.7 ml, 21.71 mmol) and diisopropylethylamine (10.38 ml, 62.04 mmol) to a solution of (1H-Indol-7-ylmethyl)propylamine (3.89 g, 20.68 mmol) in methylene chloride. Stir for 2 hours, quench with saturated aqueous ammonium chloride and extract into ethyl acetate. Wash the organic layers with saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure to yield N-(1H-indol-7-yl)methyl N-propyl 2-chloroacetamide (5.47 gm, 20.68 mMol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:56][CH2:57][C:58]1[CH:59]=[C:60]([OH:64])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([OH:64])[CH:59]=2)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: NCc1cccc(O)c1
Reactant: CCc1cc(C(=O)O)sc1C(=O)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.5 %

Procedure:
To a solution of 3-Ethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (250 mg, 1.17 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.50 mL, 3.51 mmol), HBTU (0.67 g, 1.76 mmol), HOBT (190 mg, 1.40 mmol), and 3-Aminomethyl phenol (160 mg, 1.29 mmol). The mixture was stirred at room temperature 2 d, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-50% EtOAc in hexane to afford the desired product (0.140 g, 38% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:12][C:13]2[CH:18]=[N:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Oc1ccc(Cl)nc1
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
A mixture of 2,5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen atmosphere. To this slurry were added copper (I) trifluoromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The resulting suspension was heated to 105° C. and stirred for 2 h before being cooled to RT. The toluene was decanted, and water (8 L) and EtOAc (8 L) were added. The resulting mixture was stirred until the solid was completely dissolved. The EtOAc layer was separated and the pH of the aqueous layer was adjusted to pH 2˜3 with 6N HCl. The aqueous layer was extracted with EtOAc (3×5 L). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 1.28 Kg of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid. This material was used in next step without further purification.
Reaction SMILES: F[C:2]1[N:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[NH4+:32]>>[NH2:32][C:2]1[N:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1cnc(F)c(C(=O)c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cnc(N)c(C(=O)c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Temperature: 110 °C
Yield: 18 %

Procedure:
A microwave vial was charged with tert-butyl 4-(6-(2-fluoro-5-methylnicotinoyl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (280 mg, 0.68 mmol) and a saturated aqueous solution of ammonium hydroxide (1.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 30 minutes. The mixture was cooled down to room temperature and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as an orange solid (49 mg, 18% yield).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.O>CC(C)=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(O)c(CC(C)C)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reaction time: 4 h
Yield: 88.5 %

Procedure:
Ethyl 4-hydroxy-3-isobutylbenzoate (25.6 g), potassium carbonate (31.8 g), and 4-fluorobenzyl bromide (26.1 g) were refluxed in acetone (150 ml) with stirring for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum. The resulting residue, with water (50 ml), potassium hydroxide (12.9 g), and ethanol (100 ml) added thereto, was refluxed with stirring for 2 hours. The reaction mixture, with water added thereto, was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid and water successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained solid was recrystallized (from n-hexane/ethanol), thereby yielding 30.8 g of the aimed compound.
Reaction SMILES: N#N.[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1)(=[O:6])=[O:5].CCN(CC)CC.S([Cl:25])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][CH2:12][C:10]1[O:11][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(CO)o1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.5 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-methanesulfonyl-furan-2-yl)-methanol (692 mg, 3.93 mmol) in dry CH2Cl2 (7.0 mL) was treated at 0° C. with Et3N (0.71 mL, 5.11 mmol) followed by DMAP (50 mg, 0.39 mmol) and Ms-Cl (0.37 mL, 4.71 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 868 mg of crude 2-chloromethyl-5-methanesulfonyl-furan as a yellow oil. 150 mg of this crude material in acetone (2.0 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (87 mg, 0.77 mmol) in acetone (2.0 mL). K2CO3 (320 mg, 2.13 mmol) followed by TBA bromide (50 mg, 0.15 mmol) were added and the reaction mixture was stirred at rt overnight. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (40:60 hept-EA) gave the title compound as a yellow oil. TLC: rf (40:60 hept-EA)=0.27. LC-MS-conditions 02: tR=0.82 min.
Reaction SMILES: [CH3:1][C:2]1(Br)[CH2:4][CH2:3]1.[S:6]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O-:9])(=[O:8])=[S:7].[K+]>C(O)C>[CH:4]1([CH2:3][O:9][S:6]([C:10]2[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=2)(=[S:7])=[O:8])[CH2:2][CH2:1]1
Reactant: CC1(Br)CC1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCC2CC2)cc1
Temperature: 90 °C
Yield: 72.5 %

Procedure:
To a solution of methylcyclopropyl bromide (4.00 g, 29.6 mmol) in ethanol (20.0 mL) was added potassium thiotosylate (10.0 g, 44.4 mmol) and the mixture heated to 90° C. for 10 h. The mixture was then quenched into a 1:1 mixture of H2O (50.0 mL) and diethyl ether (50.0 mL). The layers were separated and the organic layer washed with brine (50.0 mL). The organic layer was then dried with MgSO4 and concentrated in vacuo to yield the title compound as a solid (5.2 g, m.p. 46°-48° C.). 'H NMR (400 MHz, CDCl3) δ 7.816 (d, 2H, J=8.8 Hz), 7.308 (d, 2H, J =8.8 Hz), 2.945 (d, 2H, J=7.6 Hz), 2.451 (s, 3H), 1.010-0.933 (m, 1H), 0.592-0.545 (m, 2H), 0.236-0.197 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(C1C(N)SC2=CC=CC=12)=O)C.S(Cl)(Cl)=O>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C1=C2C=CC=C2SC1N
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (5.0 g) was dissolved in methanol (150 ml). Thionyl chloride (9.5 ml) was added to the solution at 0° C., and the mixture was heated under reflux with stirring for 15 hr. After the completion of the reaction, distilled water was added thereto at 0° C., and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with distilled water and saturated brine, was dried over sodium sulfate, and was then concentrated to give 5-chloro-2-nitro-benzoic acid methyl ester as a useful intermediate (12.9 g, yield 92%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH2:16][C:15]2=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].Cl>CCOCC>[N+:23]([CH:16]1[C:15](=[O:22])[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:13]=2)[C:17]1=[O:21])([O-:25])=[O:24]
Reactant: O=C1CC(=O)c2cc(OCCCOc3ccccc3)ccc21
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CCOCC
Product: O=C1c2ccc(OCCCOc3ccccc3)cc2C(=O)C1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 5-(3-phenoxypropoxy)-indan-1,3-dione (0.296 gm, 0.001 mole) was suspended in dry ether (10 ml) and cooled to 0° C. The stirred mixture was treated with fuming nitric acid (1 ml) added dropwise over 15 mins and stirred in the ice bath for 1 hr. The mixture was then stirred at r.t. for a further 11/2 hrs. During this time all the solid dissolved leaving a deep yellow solution. Dilute hydrochloric acid (20 ml) was added and the ether evaporated in vacuo. A yellow gum formed which solidified on scratching to give 0.25 gm of yellow solid which had mp 77°-79° C.(d). (73%) (Found; C, 60.71; H, 4.58; N, 3.66; C18H15NO6.0.75H2O requires; C, 60.92; H, 4.69; N, 3.95%).