Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[C:6]1([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:9]1[CH:8]=[CH:7][C:6]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(O)CC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A flask charged with concentrated H2SO4 (400 mL) was cooled to 0° C. and treated with 50.0 g (240 mmol) of 3-phenyl-pentanedioic acid portionwise over 20 min and with fuming HNO3 (10 mL) dropwise over 20 min. The mixture was stirred at RT for 3 h, poured over ice (amount equivalent to 1000 mL), and the precipitate was filtered, washed with cold water, air-dried, and dried in a vacuum dessicator. The solid was triturated with a minimum amount of CH3CN, filtered, and air-dried. The filtrate was concentrated and triturated again with a minimum amount of CH3CN, filtered, and air-dried to afford a second batch. The two batches were combined to afford 56.9 g (94%) of the title compound as an off-white solid: 1H-NMR (DMSO-d6; 400 MHz): δ 8.15 (d, 2H, J=8.8 Hz), 7.58 (d, 2H, J=8.8 Hz), 3.62-3.50 (m, 1H), 2.79-2.57 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]=[CH2:17])[C:11]([CH2:18][C:19]#[C:20][CH3:21])=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH:2]=[CH2:3].[N:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:1]([O:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]=[CH2:17])[C:11]([CH2:18][C:19]#[C:20][CH3:21])=[CH:10][C:6]=1[C:7]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:34][CH:33]=1)=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OCC=C)c(C(=O)O)cc1CC#CC
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCC=C)c(C(=O)Nc2ccc(CN3CCOCC3)cc2)cc1CC#CC
Reaction time: 4 h
Yield: 86.8 %

Procedure:
2,4-bis-allyloxy-5 (but-2-ynyl)-benzoic acid (Example 1-4, IM07-c: 287 mg, 1 mmol) and 4-(morpholin-4-ylmethyl)-phenylamine (IM08-02: 193 mg, 1 mmol) were dissolved in dimethylformamide (4 mL) and mixed with 1-hydroxybenzotriazole monohydrate (176 mg, 1.3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg, 1.3 mmol) at 0° C., and the resulting mixture was stirred for 4 hours under ice cold conditions. The reaction mixture was mixed with water (40 mL) and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and then were concentrated. The residue was purified by silica gel column chromatography (hexane-ethylacetate=1:2-1:5) to obtain the title compound (F470-IM09: 0.40 g, yield 82%).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)[CH2:4][CH3:5])[CH3:2].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:22])[CH3:2]
Reactant: Nc1ccccc1N
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Solvent: CCO
Product: CCN(CC)c1ccc(C=Nc2ccccc2N)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.479 g (17.64 mmol) 4-(N,N-Diethylamino)-salicylaldehyde are added at 5° C. in portions to a solution of 1.927 g (17.64 mmol) 1,2-phenylenediamine in 18 ml ethanol, the temperature being kept below 10° C. The resultant dark red suspension is stirred for 8 hours at room temperature and and concentrated to dryness in vacuo. The crude product (6,34 g) is resolved by column chromatography (n-hexane/ethyl acetate 65:35). Yield: 1,27 g (26%), golden yellow crystalls.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]([OH:19])=O)[S:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)([CH3:49])[CH3:48].CCN(CC)CC>C(Cl)Cl>[CH:47]([N:50]1[CH2:55][CH2:54][N:53]([C:17]([C:4]2[S:5][C:6]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9][CH:8]=3)=[C:2]([CH3:1])[N:3]=2)=[O:19])[CH2:52][CH2:51]1)([CH3:49])[CH3:48]
Reactant: Cc1nc(C(=O)O)sc1-c1cccc2ccccc12
Reactant: CC(C)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCN(C(C)C)CC2)sc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methyl-5-naphthalen-1-yl-thiazole-2-carboxylic acid in methylene chloride (2 ml) is added BOP (44 mg, 0.10 mmol), isopropylpiperazine (13 mg, 0.10 mmol) and Et3N (20 mg, 0.20 mmol). The reaction mixture is stirred at rt for 2 hr. Solvent is removed and the resulting mixture is purified by PTLC to give the title compound. LC-MS M+1 380.03. 1H NMR δ (CDCl3) 7.90-7.96 (m, 2H), 7.68-7.72 (m, 1H), 7.46-7.56 (m, 4H), 4.51 (brs, 2H), 3.85 (brs, 2H), 2.77 (m, 1H), 2.67 (brs, 4H), 2.25 (s, 3H), 1.10 (d, 6H). LC-MS (M+1) 380.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].N.O1CCOCC1.[Li+].C[Si]([N-:39][Si](C)(C)C)(C)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH2:39])=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Agent: N
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(N)=O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoate (280 mg, 0.746 mmol) was dissolved in tetrahydrofuran (THF) (5 mL) and to this solution was added ammonia in dioxane (0.5 M) (4.47 mL, 2.237 mmol), followed by LiHMDS in THF (1 M, 0.895 mL, 0.895 mmol). The reaction was left to stir overnight at room temperature, under nitrogen. The reaction was quenched with water (1 mL) then combined with a previous identical trial reaction on a smaller (0.075 mmol) scale, for workup. The crude was concentrated in vacuo, then the product was extracted to the organic phase of an aqueous work up between ethyl acetate (15 mL) and brine (10 mL). The organic phase was passed through a hydrophobic frit and concentrated in vacuo to give the crude product, 263 mg. No further purification was undertaken. LCMS [LCMS1] Rt 1.14 min, m/z (ES+) 361 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.Cl>C(O)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1

Procedure:
A solution of 4-chloro-7-trifluoromethylquinoline (400 mg, 0.0018 M), 1-methyl-4-[(4-aminophenyl)methyl]piperazine (400 mg, 0.0019 M) and 1.4 ml of ethanolic hydrogen chloride in 10 ml of ethanol is heated to reflux, under nitrogen for 15 minutes. The reaction mixture is quenched with ice, neutralized with aqueous 10% sodium hydroxide and extracted with methylene chloride. The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to a white solid. This solid, after recrystallization from ethyl acetate, gives 250 mg (32%) of white crystalline 4-[[4-[(4-methyl-1-piperazinyl)methyl]phenyl]amino]-7-(trifluoromethyl)quioline of melting point 218°-220° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17]2)(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(tert-butoxycarbonylamino)-5-hydroxyindan (100 mg, 0.40 mmol) synthesized in Predagation Example 1 was dissolved in dry methylene chloride (2 ml), to which pyridine (0.19 ml, 2.3 mmol) and acetic anhydride (0.11 ml, 1.2 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture then was concentrated under reduced pressure, to which diethylether was added. The organic layer was washed with, in the order of, an aqueous solution of saturated potassium hydrogen sulfate, brine, an aqueous solution of saturated sodium hydrogen carbonate, and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5-acetoxy-2-(tert-butoxycarbonylamino)indan (120 mg, 0.40 mmol) having the following physical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=O)[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.Cl.[NH2:44][OH:45]>N1C=CC=CC=1.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[N:44][OH:45])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[N:22]=[C:23]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:29][CH2:30]3)[C:11]=2[N:10]=1
Reactant: NO
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=NO)ccc3c21
Temperature: 25 °C
Reaction time: 64 h
Yield: 85.1 %

Procedure:
A 100 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 211 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde in 8.5 ml of pyridine, 36 mg of hydroxylamine hydrochloride are added, and the mixture is stirred at RT for 64 h. It is concentrated under RP and the solid obtained is taken up in AcOEt, washed with a 1M aqueous solution of potassium phosphate and then with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under RP. Purification is carried out by flash chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and AcOEt (75/25 by vol.), to give 184 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime (yellow solid). MS (E/I): m/z=630 (M+); 1H NMR: 0.04 (s, 9H); 0.89 (m, 2H); 1.61 (m, 2H); 2.11 (m, 2H); 2.74 (m, 2H); 2.85 (s, 3H); 3.58 (m, 2H); 3.67 (m, 2H); 4.46 (m, 1H); 5.65 (s, 2H); 6.50 (d, J=8.3 Hz, 1H); 7.33 (broad t, J=8.1 Hz, 2H); 7.65 (m, 1H); 7.72 (broad s, 1H); 8.01 (dd, J=8.4, 17 Hz, 1H); 8.27 (s, 1H); 8.35 (d, J=8.4 Hz, 1H); 11.39 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[C:6]3[S:11][CH:10]=[CH:9][C:7]=3[S:8][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1>>[Br:19][C:10]1[S:11][C:6]2[C:5]3[S:1][CH:2]=[CH:3][C:4]=3[S:8][C:7]=2[CH:9]=1
Reactant: c1cc2sc3ccsc3c2s1
Reactant: O=C1CCC(=O)N1Br
Product: Brc1cc2sc3ccsc3c2s1

Procedure:
Compound 2 was synthesized as shown in Scheme 2. Under acid condition, dithieno[3,2-b:2′,3′-d]thiophene (Organic Syntheses, Vol. 83, p. 209 (2006)) was reacted with NBS affording 2-bromodithieno[3,2-b:2′,3′-d]thiophene 7, which underwent Suzuki cross-coupling reaction with boronic acid R1—B(OH)2 (J. Mater. Chem., 2010, 20, 2182-2189) to afford intermediate 8 in 71% yields. Finally 8 was converted to PhN-OFFT-TCN by reacting with n-BuLi and tetracyanoethylene at low temperature in 85% yield.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[C:15]([NH:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>C1COCC1>[C:15]([NH:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2](=[S:3])[NH:1][C:4]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]3)=[CH:6][CH:5]=2)=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: O=C1CCc2ccc(N=C=S)cc2N1
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=S)Nc2ccc3c(c2)NC(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution containing 0.8 g of 7-isothiocyanato-3,4-dihydro-2(1H)quinolone and 0.59 g of 4-acetamidoaniline in 10 ml of THF was stirred for 5 h at room temperature. The product was filtered, dried and used as such to the next step. Yield 0.45 g (32%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[OH-].[NH4+:26]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)[N:10]=2)=[CH:4][C:5]([NH2:26])=[N:6][CH:7]=1
Reactant: C[C@@H]1CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)C[C@H](C)O1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@@H]1CC(CNc2cccc(-c3cc(N)ncc3Cl)n2)C[C@H](C)O1
Temperature: 130 °C

Procedure:
A mixture of 5′-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2′-fluoro-2,4′-bipyridin-6-amine (60 mg, 0.17 mmol), and 3.0 ml 28% ammonium hydroxide aqueous solution was heated at about 130° C. in an oil bath for 17 hours. Formation of compound M was Reaction confirmed by LCMS/LC data. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, and brine, dried over sodium sulfate and concentrated to yield 50 mg of the desired product. LCMS (m/z): 347 (MH+), retention time=0.53 min.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[OH:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])[NH:9][C:8]=2[CH:7]=1>>[CH:2]([O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:20](=[O:25])(=[O:24])[N:21]([CH3:22])[CH3:23])[NH:9][C:8]=2[CH:7]=1)([CH3:4])[CH3:3]
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Reactant: CC(C)I
Product: CC(C)Oc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 94.6 %

Procedure:
2-Isopropoxy-6-dimethylsulphamoylphenothiazine (42.8 g.) is prepared by reacting 2-iodopropane (33.8 g.) with 2-hydroxy-6-dimethylsulphamoylphenothiazine (40.0 g.) prepared as indicated in Example 1.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23](=[O:34])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([OH:33])=O)[CH:26]=2)[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:42][CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=1)=[O:45].CN1CCOCC1>ClCCl.CN(C)C=O>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([C:23](=[O:34])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([NH:42][CH2:43][C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=3)=[O:45])=[O:33])[CH:26]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)Nc2cccc(C(=O)O)c2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: NCC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C(=O)Nc2cccc(C(=O)NCC(=O)OCc3ccc([N+](=O)[O-])cc3)c2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 55.6 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxyphenylcarbamoyl)pyrrolidine (0.49 g, 1 mM) in dichloromethane (10 ml) was added oxalyl chloride (0.20 ml. 1.1 mM) and dimethylformamide (2-3 drops). After 1 hour a further amount of oxalyl chloride (0.20 ml, 1.1 mM) and DMF (2-3 drops) were added and the mixture stirred for a further hour. The solution was evaporated to leave a yellow gum. The gum was dissolved in dichloromethane (10 ml) and added to a suspension of 4-nitrobenzyl 2-aminoethanoate hydrochloride salt (0.30 g, 1.2 mM) and N-methylmorpholine (0.27 ml, 2.4 mM) in dichloromethane (10 ml). After 17 hours the mixture was diluted with dichloromethane (80 ml), washed with water (20 ml), brine (20 ml) and dried (MgSO4). Purification by flash chromatography through silica using a gradient of dichloromethane to ethyl acetate as eluent gave (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-(4-nitrobenzyloxycarbonylmethylaminocarbonyl)phenylcarbamoyl)-pyrrolidine (380 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].[P:14]([Cl:19])(Cl)(Cl)(Cl)[Cl:15].Cl.C(O)=[O:22]>C(Cl)(Cl)(Cl)Cl>[Cl:15][P:14]([Cl:19])([NH:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)=[O:22]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=CO
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A suspension of 15 g (0.08 mole) of 3-trifluoromethylbenzamide, 16.5 g (0.08 mole) of phosphorus pentachloride and 150 ml of AR carbon tetrachloride was heated at 65°-70° until the HCl gas evolution nearly stops, ca. 30 min. The solution was cooled to 30° and 3.8 g (0.08 mole) of 97% formic acid added dropwise. Stirring was continued for 30 min., then the precipitate was collected, washed with AR carbon tetrachloride and air-dried to give 14 g, m.p. softens 112°, melts 114°-116°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[O:11]=[C:12]1[NH:20][CH:19]=[N:18][C:17]2[N:16]([CH2:21][CH2:22][C:23](OCC)=[O:24])[CH:15]=[N:14][C:13]1=2>C(#N)C>[O:11]=[C:12]1[NH:20][CH:19]=[N:18][C:17]2[N:16]([CH2:21][CH2:22][C:23]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:24])[CH:15]=[N:14][C:13]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCCN1CCOCC1
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
475 mg (3.29 mmol) of 4-(3-aminopropyl)morpholine was added to a 10 ml round bottom flask equipped with a magnetic stirring bar. The flask was heated to 100°-120° C. and 250 mg (1,06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester AIT-0027 was added to the stirring flask. Heating was continued for two hours. The solution was allowed to cool to room temperature and was then treated with 8 ml acetonitrile with stirring. A white precipitate formed and the solution was filtered after 20 minutes of stirring in acetonitrile. The filtrate was washed with acetonitrile and then with ether. This yielded 130 mg of a white solid. The mother liquor was allowed to stand overnight in a fume hood and was filtered the next day to yield another 100 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[3-(4-morpholinyl)propyl]propanamide (AIT-0043). Yield: 65%. m.p. 145°-148° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>CC#N>[CH:27]1([NH:26][C:24](=[O:25])[CH2:23][N:8]2[C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[S:4][C:5]=3[N:6]=[CH:7]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(CCl)NC1CCCCC1
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2ncn(CC(=O)NC3CCCCC3)c(=O)c2c1C

Procedure:
To a suspension of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (2.24 g, 10 mmol) in CH3CN (25 mL) was added K2CO3 (1.38 g, 10 mmol), KI (1.61 g, 10 mmol), and 2-chloro-N-cyclohexylacetamide (1.75 g, 10 mmol). The reaction mixture was refluxed overnight and quenched with H2O (120 mL). The resulting precipitate was filtered and dried to afford methyl 3-(2-(cyclohexylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, as a solid (yield: quantitative).
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:14]1([S:24](Cl)(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(C)=O.CCOCC.C1(C)C=CC=CC=1>[C:14]1([S:24]([NH:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=2)(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NCc1ccc(C(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(CNS(=O)(=O)c2cccc3ccccc23)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
4 N NaOH solution (30 ml) is added to a suspension of 4-(aminomethyl)benzoic acid (5.01 g, 31.82 mmol) in acetone (100 ml). Toluene (100 ml) is added and the reaction is heated at 40° C. to obtain dissolution. The solution is cooled to 0° C. and treated with 1-naphthalene sulfonyl chloride (12 g, 51.35 mmol) in acetone (100 ml) and the resulting reaction mixture is stirred for 3 hours. The reaction is acidified using citric acid and concentrated in vacuo. The residue is taken up in EtOAc and washed with water. The aqueous layer is back extracted with EtOAc and the combined organic layers are washed with water, brine, dried (Na2SO4) and the solvent removed in vacuo to yield a light brown solid. Trituration with Et2O yields the title compound.
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(OCC)(=O)C>CO>[CH3:1][NH:2][C:5](=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: CN
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Monomethylamine (22.43 kg, 722.15 mol, 6 eq.) was added over a 7-hour period to a solution of methyl-4-hydroxyphenylacetate (20.0 kg, 120.35 mol, 1.0 eq.) in methanol (31.7 gal) and stirred overnight at room temperature. Methanol was then displaced under vacuum with ethyl acetate. The resulting slurry (ca. 20 gal) was stirred at +10° C. for 1 hour, then filtered and dried under vacuum at 45° C. to yield of the title compound(18.68 kg, 94% of theory). mp 124-125° C. NMR (300 MHz, d6-DMSO): δ=9.26 (s, 1H), 8.00-7.65 (br s, 1H), 7.21-6.90 (m, 2H), 6.86-6.55 (m, 2H), 3.26 (s, 2H), 2.75-2.45 (m, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C>CCOCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCCc2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Oc1ccc(CCCCCCc2ccc(O)cc2)cc1
Yield: 77.3 %

Procedure:
A mixture 40.0 g of 1,6-bis(4-methoxyphenyl)hexane of Example 2, 150 ml of HBr (48%) and 150 ml of glacial acetic acid was refluxed for 5 hours. It was concentrated by evaporation to give a dark brown semi-solid. This was dissolved in ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 28.0 g of dark brown semi-solid.