Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=[O:7].[C:13](Cl)(=[O:15])[CH3:14]>>[C:13]([O:9][CH:5]([C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=1)[C:6]([OH:8])=[O:7])(=[O:15])[CH3:14]
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Reactant: CC(=O)Cl
Product: CC(=O)OC(C(=O)O)c1cccc(Cl)c1

Procedure:
1 g of racemic 3-chloromandelic acid is mixed with 2 ml of acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]([C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:8])O[CH:7]=1.[CH3:14][C:15]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:16]=1[NH2:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:23]([C:19]1[CH:18]=[C:16]([N:17]2[CH:7]=[C:2]([Cl:1])[C:3](=[O:13])[C:4]([C:9]([O:11][CH3:12])=[O:10])=[C:5]2[CH3:8])[C:15]([CH3:14])=[CH:21][C:20]=1[CH3:22])([O-:25])=[O:24]
Reactant: COC(=O)c1c(C)occ(Cl)c1=O
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)n(-c2cc([N+](=O)[O-])c(C)cc2C)cc(Cl)c1=O

Procedure:
A solution of 10.1 g (0.05 mol) 5-chloro-3-methoxycarbonyl-2-methyl-4-pyranone, 8.5 g 2,4-dimethyl-5-nitroaniline and 0.1 g p-toluenesulfonic acid monohydrate in 100 ml of toluene are refluxed for 8 h in a water separator apparatus. The mixture is allowed to cool and the precipitating product is filtered off, washed with a small amount of ethylacetate/petrolether and dried. Yield: 15.0 g (85.5%) 1-(3'-nitro-4',6'-dimethylphenyl)-5-chloro-3-methoxycarbonyl-2-methyl-4-pyridone, mp. 266° C.
Reaction SMILES: [CH:1]1([S:4]([O-:6])=[O:5])[CH2:3][CH2:2]1.[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1>C(#N)C.O>[CH:1]1([S:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S([O-])C1CC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc(CS(=O)(=O)C2CC2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
Sodium cyclopropanesulfinate (1.04 g; 8.1 mmol) was added to a solution of 1-(bromomethyl)-3-nitrobenzene (1.17 g; 5.4 mmol) in acetonitrile (50 mL) at room temperature. The batch was stirred at 90° C. for 4 hours. After cooling, the batch was diluted with water and extracted with DCM (2×). The combined organic phases were filtered using a Whatman filter and concentrated to give the desired product (1.26 g; 5.2 mmol) that was used without further purifications.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:19]1
Reactant: Cn1cc(Br)cc(Nc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(Br)cc(Nc2ccc(OC3CNC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 251c (1.14 g, 3.10 mmol), methylene chloride (10 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2 h. After this time, the mixture was concentrated under reduced pressure. The resulting residue was diluted with methylene chloride (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with methylene chloride (2×50 mL) and the combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford a 92% yield (1.10 g) of 251d as a colorless oil. This compound was used directly for the next step without any purification: 1H NMR (500 MHz, DMSO-d6) d 8.65 (s, 1H), 8.55 (d, 1H, J=2.5 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.48 (d, 1H, J=2.5 Hz), 7.30 (d, 1H, J=9.0 Hz), 7.21 (m, 1H), 4.95 (t, 1H, J=6.0 Hz), 3.76 (m, 1H), 3.48 (m, 5H); MS (ESI+) m/z 353.0 (M+H).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]([C:15]#[N:16])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl>[CH2:1]([N:4]([CH:5]1[CH2:6][CH2:7][C:8]2[C:13](=[CH:12][C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)[CH2:14]1)[C:18](=[O:17])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=CCNC1CCc2ccc(C#N)cc2C1
Solvent: ClCCl
Product: C=CCN(C(=O)OC(C)(C)C)C1CCc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-(Allylamino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (300 mg, 1.4 mmol) in 20 mL of DCM was added TEA (430 mg, 4.26 mmol) and BOC2O (460 mg, 2.1 mmol), and the mixture was stirred at room temperature overnight. The reaction was completed, and DCM was added. Then the mixture was washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound. MS m/z: 313 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH:19]=O)[CH:13]=1.S(=O)(=O)(O)O.C([BH3-])#N.[Na+]>O1CCCC1.O>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH2:19][NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:13]=1
Reactant: Cc1cc(C)nc(C=O)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)nc(CNc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
p-Nitroaniline (0.51 g, 3.7 mmol) was added to a solution of 4,6-dimethyl-pyridine-2-carbaldehyde (0.5 g, 3.7 mmol) in tetrahydrofuran (20 mL) at 0° C., followed by sulfuric acid and water (1 mL:1 mL). After stirring at 0° C. for 30 min. sodium cyanoborohydride (0.47 g, 7.4 mmol) was added portionwise at 0° C. The mixture stirred at room temperature for 1 h then concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic phase was washed with sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by column chromatography on silica gel (60-120 mesh) using 18% ethyl acetate/hexane as eluent to afford (4,6-dimethyl-pyridin-2-ylmethyl)-(4-nitro-phenyl)-amine (0.35 g, 37%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:29])[CH2:27][N:16]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:19])[O:3][C:2]([CH3:20])([CH3:1])[C:7]=3[CH:8]=2)=[CH:13][CH:14]=[C:15]1[C:17]#[N:18])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile (5.4 g, 20 mmol) and tert-butylbromoacetate (4.64 g, 22 mmol) were reacted, according to General Method A, to afford the title compound, m.p. 188-190° C. (3 g, 40%); 1H-NMR (DMSO-d6): δ 1.35 (s, 9H), 1.62 (s, 6H), 4.8 (s, 2H), 6.35 (d, J=4.3 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.09 (d, J=4.3 Hz, 1H), 7.26 (m, 2H), 10.42 (s, 1H), MS (APCI (−)) m/z 380 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:19]([NH2:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:11][C:12]([NH:21][CH2:19][CH3:20])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1Cl
Reactant: CCN
Product: CCNC(=O)CN(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3-chloro-4-cyanophenyl)-N-(cyclopropylmethyl)glycine and ethylamine: MS (ES) m/z 292 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11]Cl>>[CH3:9][O:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Product: COCOc1ccc(Br)cc1
Yield: 104.2 %

Procedure:
In a manner similar to that of Example 7(a), by reaction of 48.84 g (282.3 mmol) of 4-bromophenol with 25.0 ml (310.5 mmol) of chloromethyl methyl ether, 63.85 g (100%) of the expected product are obtained in the form of a beige-coloured oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=1)#[N:2].[Cl:30]N1C(=O)CCC1=O>O1CCCC1>[Cl:30][C:20]1[S:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]=3[C:1]#[N:2])=[CH:17][CH:16]=2)=[C:22]([NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[CH:21]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1cc(Cl)sc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Reaction time: 72 h
Yield: 17.6 %

Procedure:
Dissolve 2-cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.021 g) in dry tetrahydrofuran (0.5 mL) at 0° C. and add N-chlorosuccinimide (0.007 g). Allow the reaction mixture to reach RT and stir for 72 h. Add diethyl ether, concentrate in vacuo and purify by Strata® silica gel cartridges, eluting with dichloromethane-methanol gradient. Purify by reverse phase HPLC to give 0.004 g of the title compound as a white solid. MS (ES−) (m/z): 459 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:12]O>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccccc1O
Agent: Cl
Product: COC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxybenzoic acid (110 g, 796 mmol) in MeOH (400 mL) was bubbled HCl (gas) for 1 h. The resulting mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude methyl 2-hydroxybenzoate that was used directly without further purification.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([N:19]([CH3:20])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:17][CH:16]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with 4-chloro-N-methylaniline (963 mg, 6.80 mmol) using method A to give 4-(N-(4-chlorophenyl)-N-methylsulfamoyl)benzoic acid as a white solid. Yield: 406 mg (55%). 1H-NMR: 8.11 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 3.15 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1.Cl.O1CCOCC1>CC(O)C>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cc(C)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1cc(C)ccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Temperature: 130 °C
Yield: 59.1 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (76 mg, 0.34 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-5,N-dimethyl-benzamide (120 mg, 0.38 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (95 μL, 0.38 mmol, 1.1 eq) was added and the reaction was heated at 130° C. in a microwave for 20 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5,N-dimethyl-benzamide as a yellow solid (99.4 mg, 59%). m.p.=210-212° C.; LCMS (m/e) 495 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.87 (s, 1H), 8.51 (d, 1H, J=8.5 Hz), 8.05 (d, 1H, J=1.0 Hz), 7.35 (s, 1H), 7.30-7.15 (m, 3H), 7.01 (d, 1H, J=8.1 Hz), 6.86 (s, 1H), 6.23-6.10 (m, 1H), 3.54 (t, 2H, J=5.4 Hz), 3.37 (s, 3H), 3.02 (d, 3H, J=5.0 Hz), 2.96-2.84 (m, 5H), 2.80-2.66 (m, 6H), 2.36 (s, 3H).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5]2)[CH2:3][O:2]1.[CH2:20]1[O:22][CH2:21]1>CO>[OH:22][CH2:21][CH2:20][N:12]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]2([CH2:3][O:2][CH2:1]2)[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCOCC2(COCCOCCN1)COC2
Reactant: C1CO1
Solvent: CO
Product: OCCN1CCOCCOCC2(COCCOCC1)COC2
Yield: 86.4 %

Procedure:
A mixture of 27.5 g (0.10 mol) of 2,6,9,15,18-pentaoxa-12-azaspiro[3,15]nonadecane, 10 g (0.21 mol) of ethylene oxide and 200 ml of methanol was heated in a bomb tube at 100° for 6 hours under autogenous pressure. Solvent was evaporated, and the product was volatilized in a very short path still at 190° (~20 μ), giving 27.6 g (87%) of N-hydroxyethyl-2,6,9,15,18-pentaoxa-12-azaspiro[3.15]nonadecane as a nearly colorless oil. Ir: 2.90 (OH), 8.7-9.5 (COC, COH), 10.23 and 10.80 μ oxetane). Nmr ((CD3)2CO): 4.29 (singlet, 4, oxetane CH2), 3.74 (singlet, 4, C-CH2O), 3.6-3.3 (multiplet, 15, OCH2CH2O + OH + OCH2CH2N), 2.85-2.5 ppm (multiplet, 6, CH2N).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].C([Li])CCC.[CH:19]([O:21][CH2:22]Cl)=[O:20]>O1CCCC1>[CH3:22][O:21][C:19]([C:5]1[S:1][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[CH:3][CH:4]=1)=[O:20]
Reactant: COc1ccccc1-c1cccs1
Reactant: O=COCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2OC)s1
Temperature: 25 °C
Yield: 60 %

Procedure:
2-Thienyl-1-methoxybenzene (10 g, 53 mmol) is cooled to −78° C. in dry tetrahydrofuran (265 ml) under nitrogen while stirring. n-Butyl lithium in hexanes (1.6M, 37 ml, 59 mmol, 1.1 eq.) is added slowly and the resulting mixture is stirred cold for an hour. Chloromethyl formate (4.1 ml, 53 mmol, 1.0 equivalent) is added and the reaction is stirred cold for another hour. The mixture is allowed to warm to room temperature before quenching with saturated bicarbonate solution and ethyl acetate. The layers are separated and the organic phase is washed with brine, dried over sodium sulfate and concentrated. The residue is purified via flash chromatography in 5% ethyl acetate/hexanes to afford 7.9 g of 2-(5-methoxycarbonylthien-2-yl)-1-methoxybenzene (61%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:33][C:34]([OH:36])=[O:35])=[C:18]([CH3:32])[C:19]2=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[CH:25][CH:24]=2)=[CH:15][C:14]=1[O:37][CH3:38]>CC(C)=O>[F:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:33][C:34]([OH:36])=[O:35])=[C:18]([CH3:32])[C:19]2=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:31])(=[O:9])=[O:30])=[CH:25][CH:24]=2)=[CH:15][C:14]=1[O:37][CH3:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2c(cc1F)C(=Cc1ccc(S(C)=O)cc1)C(C)=C2CC(=O)O
Solvent: CC(C)=O
Product: COc1cc2c(cc1F)C(=Cc1ccc(S(C)(=O)=O)cc1)C(C)=C2CC(=O)O

Procedure:
A solution of sodium periodate, 4.28 g (20 mol) in 40 ml of water is added dropwise to 6-fluoro-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid, 3.70 g (10 mmol) in 300 ml methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, and is cooled. Collected crystals are washed with water and methanol-water (1:1). The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° C. The crude product is recrystallized from methylene chloride-petroleum ether to give 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinyl-benzylidene)-3-indenylacetic acid (m.p. 190°-193°). 6-fluoro-5-methoxy -2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid is prepared according to the procedure of Example 1, part G by the addition of 1.0 mol of m-chloroperbenzoic acid per mol of 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl acetic acid in an acetone solution.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=3[N:10]=[CH:9]2)=[CH:3][CH:2]=1.[N:18]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[O:31][CH3:32])=[C:19]=[O:20]>CN(C)C=O.ClCCl>[CH3:32][O:31][C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=1[NH:18][C:19]([NH:17][C:16]1[C:11]2[N:10]=[CH:9][N:8]([CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:20]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Nc1cccc2c1ncn2Cc1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc2c1ncn2Cc1ccncc1

Procedure:
Compound 3d (75 mg, 0.334 mmol) is dissolved in dimethylformamide/dichloromethane (1:4, 5.0 mL) and 2-isocyanato-1-methoxy-4-trifluoromethyl-benzene (1.0 equiv., 73 mg, 0.334 mmol) is added at room temperature and allowed to react for 16 hours under nitrogen atmosphere. All solvent is then removed on a rotary evaporator and toluene (3×25 mL) is added and stripped off to remove residual dimethylformamide. The crude solid is then triturated using ethyl ether, and the resulting solid is then filtered and dried yielding title compound as a white solid.
Reaction SMILES: [ClH:1].Cl.Cl.O[N:5]([CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])[C:6]([NH2:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17].Cl.[CH3:30][O:31]N.C(=O)([O-])O.[K+]>O>[ClH:1].[ClH:1].[ClH:1].[CH3:30][O:31][NH:18][C:6]([NH:5][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17]
Reactant: CON
Reactant: Cc1nc[nH]c1CSCCN=C(N)N(O)CCSCc1[nH]cnc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CONC(=NCCSCc1[nH]cnc1C)NCCSCc1[nH]cnc1C
Yield: 34.3 %

Procedure:
A mixture of the isothiourea trihydrochloride from Example 2 (ii) (5.1 g), methoxyamine hydrochloride (2.5 g), potassium hydrogen carbonate (5.0 g) and water (30 ml) was refluxed for 24 hours. The products were partitioned between N sodium hydroxide and n-butanol. The n-butanol solution was then extracted with N hydrochloric acid, and the extracts concentrated and dissolved in isopropanol. After filtration from inorganic material, the filtrate gave the title compound (0.6 g). When a solution in aqueous ethanol of this compound was eluted from an ion exchange column of IRA-401 in nitrate form, the corresponding trinitrate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.9 %

Procedure:
To a solution of 4-(2-fluorophenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3 carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (62.5 mg, 53%).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH2:5]1[C:14](=[O:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH2:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][NH:1][C:14]1=[O:15]
Reactant: O=C1CCc2ccccc2C1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2CCN1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
While maintaining the temperature of the reaction mixture below 65° C., NaN3 (13.35 g; 205.2 mmol) is added in small portions to a solution, heated beforehand to 55° C., of β-tetralone (25 g; 171 mmol) in a mixture of 150 ml of glacial acetic acid and concentrated sulphuric acid (33.39 g; 342 mmol; 18.25 ml). Stirring is then carried out for 8 hours at 70° C. After returning to ambient temperature, the reaction mixture is poured onto ice and diluted with ethyl acetate. After extracting the organic phase, drying over magnesium sulphate and concentrating, the residue obtained is purified by chromatography on silica gel (eluant ethyl acetate) to yield the expected compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O>[N+](C1C=CC=CC=1)([O-])=O>[F:12][C:13]1[CH:14]=[C:15]([C:16]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]3[N:8]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1cnc2[nH]c(-c3ccc(F)c(F)c3)nc2c1
Yield: 27.9 %

Procedure:
1.00 g 2,3-diamino-5-nitro-pyridine and 0.95 g 3,4-difluorobenzaldehyde were stirred in 60 ml nitrobenzene at 160° C. for 26 hrs. The solvent was removed under vacuum and the residue dissolved in 40 ml pyridine at 60° C. The solution was cooled in an ice bath. Precipitated product was isolated by filtration and dried to yield 0.5 g of the title product.