Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:9]=[N:8][NH:7][C:6]=1[NH2:10])([O-:4])=[O:3].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[N+:2]([C:5]1[CH:9]=[N:8][N:7]2[C:11]([OH:16])=[CH:12][C:13]([CH3:15])=[N:10][C:6]=12)([O-:4])=[O:3]
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(O)n2ncc([N+](=O)[O-])c2n1
Yield: 84.5 %

Procedure:
50 g of 4-nitro-2H-pyrazol-3-ylamine hydrochloride (prepared in accordance with H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707, 141, 1967) and 60 g of ethyl acetoacetate in 160 cc of acetic acid were introduced into a 500 cc three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer and a condenser. The reaction medium was refluxed for 12 hours. The precipitate which formed was filtered off at about 90° C. It was washed with diisopropyl ether and dried under vacuum over phosphoric anhydride. This gave 50 g of 3-nitro-5-methylpyrazolo[1,5-a]pyrimidin-7-ol in the form of yellow crystals (yield=84.5%; melting point=290° C. with decomposition), whose elemental analysis, calculated for C7H6N4O3 (MW=194.15 g), was as follows:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COCC1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC1CN(c2ccc(C3CCN(Cc4ccccc4)CC3)cc2)C(=O)O1
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
290.4 mg (1.0 mmol) of (RS)-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine were dissolved in 5 ml of abs. dimethylformamide and treated with 171.0 mg(1.0 mmol) of benzyl bromide in the presence of 404.8 mg (4.0 mmol) of triethylamine. The reaction mixture was stirred at 600 for 90 minutes. Thereafter, it was evaporated, the residue was partitioned in ethyl acetate and 3N ammonia solution and the organic phase was washed with water, dried over sodium sulfate, filtered and evaporated. The base was dissolved in ethanol, made acid with ethereal hydrochloric acid and distilled repeatedly with toluene. After recrystallization from ethanol/ether there were obtained 291.2 mg of (RS)-1-benzyl-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine.HCl. M.p.: 175°-177°.
Reaction SMILES: C[O-].[Na+].CN(C)[CH:6]=[O:7].Cl[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[CH:11]=1.O>CO>[CH3:6][O:7][C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[CH:11]=1
Reactant: Cc1cc(Cl)cc(C)n1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C)nc(C)c1
Yield: 72 %

Procedure:
Sodium methoxide (2 eq.) was dissolved in methanol (1.5 volumes) and dry dimethylformamide (2 volumes). The solution was heated to (95-100ℑ C.)and while stirring under a stream of nitrogen, 4-chlorolutidine (1 eq.) was added dropwise. At the end of the reaction (about 2 hours), the mixture was cooled in an ice bath and cold water (10 volumes) was added. The product was extracted with dichloromethane (3×2 volumes). The combined organic extracts were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. Light yellow oil was obtained in 72% yield.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][C:21]([CH3:25])([CH3:24])[CH2:22][NH2:23].CCN(C(C)C)C(C)C>>[OH:20][C:21]([CH3:25])([CH3:24])[CH2:22][NH:23][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CC(C)(O)CN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Then similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-hydroxy-2-methyl-propylamine and DIEA to give 2-(2-hydroxy-2-methyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 328 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13][N:30]3[CH:25]4[CH2:26][CH2:27][CH:28]3[CH2:29][CH:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24]4)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2cc(F)ccc21
Yield: 30 %

Procedure:
The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.208 g, 0.59 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane (0.106 g, 0.58 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF30) (0.070 g, 29%). 1H NMR (CDCl3) δ 7.23-7.19 (m, 1H), 6.66-6.60 (m, 2H), 4.60-4.46 (m, 2H), 4.05-3.99 (m, 1H), 3.95-3.90 (m, 1H), 3.06-3.03 (m, 1H), 2.99-2.96 (m, 1H), 2.24-2.19 (m, 1H), 2.07-1.94 (m, 3H), 1.90-1.73 (m, 3H), 1.60-1.45 (m, 3H), 1.33-1.25 (m, 2H), 1.24-1.12 (m, 8H), 0.83-0.78 (m, 6H); 13C NMR (CDCl3) δ 164.1, 158.8 (d, J=243.3 Hz), 146.4 (d, J=11.5 Hz), 125.1 (d, J=3.1 Hz), 116.6 (d, J=9.3 Hz), 108.9 (d, J=22.8 Hz), 105.0 (d, J=25.7 Hz), 67.7, 60.9, 58.8, 58.1, 45.4, 38.3, 36.8, 36.6, 32.1, 31.6, 28.5, 28.4, 28.1, 27.0, 22.8, 17.0, 14.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][O:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:7][O:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: COC(=O)C(C)(C)CO
Reactant: Ic1cn[nH]c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cn1cc(I)cn1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of 4-iodo-1H-pyrazole (194 mg, 1 mmol), 3-hydroxy-2,2-dimethylpropionic acid methyl ester (200 mg, 1.5 mmol) and triphenylphosphine (393 mg, 1.5 mmol) in THF (5 mL) was treated with DIAD (0.3 mL, 1.5 mmol) at room temperature. After 2 h, the reaction mixture was concentrated and the crude residue was purified by column chromatography (SiO2, 10% ethyl acetate/hexanes) to give 249 mg (81%) of desired product as an oil. 1H NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 7.46 (s, 1H), 3.69 (s, 2H), 3.55 (s, 3H), 1.18 (s, 6H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:20]=1>O>[C:1]([NH:15][C:13]1[CH:14]=[C:9]([Cl:8])[C:10]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:20]=2)=[C:11]([Cl:16])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)Nc2c(Cl)cc(N)cc2Cl)cc1OC1CCCC1
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cc(NC(C)=O)cc2Cl)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
Acetic anhydride (10 mL) is treated with N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8 g; that is prepared as described in Example 11), and the reaction mixture is stirred for 2 hours and left to stand overnight. It is then poured into water (100 mL), and extracted with ethyl acetate (100 mL) and then with dichloromethane (100 mL). The organic extracts are combined, dried over magnesium sulfate, and evaporated, to give N-(4-acetylamino-2,6-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.4 g), m.p. 250°-252° C. [Elemental analysis: C,57.6; H,5.05; N,6.3; Cl,16.1%; calculated: C,57.5; H,5.1; N,6.4; Cl,16.2%].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1)=O)(C)(C)C.O>COCCO>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:31][C:29]4[CH:30]=[N:26][NH:27][CH:28]=4)[N:3]=[CH:4][C:5]=3[N:10]=[N:9]2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Solvent: O
Solvent: COCCO
Product: COc1ccc(-n2nnc3cnc(Nc4cn[nH]c4)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 262 mg (1.00 mmol) 5-chloro-3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 183 mg (1.00 mmol) 4-amino-pyrazole-1-carboxylic acid tert-butyl ester in 2.5 ml 2-methoxy-ethanol is stirred for 3 hours at 100° C. The reaction mixture is cooled to room temperature and water is added. The resulting precipitate is filtered off, washed with water and dried. The crude product is recrystallized from isopropanol giving “A3” as brown crystals; HPLC/MS (A): 1.6 min, [M+H] 309;
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].N1C=CC=CC=1.[C:15]([O:19][C:20]([C@H:22]([C@@H:32]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:33]([NH:35][NH2:36])=[O:34])[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([O:19][C:20]([C@H:22]([C@@H:32]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:33]([NH:35][NH:36][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[O:34])[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NNS(=O)(=O)CCCCl)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
1.85 g of 3-chloropropylsulphonyl chloride and 0.85 g of pyridine were added to a solution of 3.0 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide in 40 ml of dichloromethane. After stirring at room temperature for 2 hours the solvent was evaporated and the residue was triturated with diethyl ether. The mixture was filtered and the solvent was evaporated to give 1.92 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-2′-(3-chloropropylsulphonyl)-4-methylvalerohydrazide in the form of a pale yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:3])[CH3:2].O[N:19]=[C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)[NH2:21]>C1COCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[N:19]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:2])[CH3:3]
Reactant: NC(=NO)c1ccc(CO)cc1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a solution of 4-isopropoxy-3-(trifluoromethyl)benzoic acid (CAS 213598-16-4)(1.04 g, 4.19 mmol) in THF (20 mL) was added CU (748 mg, 4.61 mmol). After stirring at rt for 2 h, N′-hydroxy-4-(hydroxymethyl)benzenecarboximidamide (CAS 1233243-49-6) (766 mg, 4.61 mmol) was added to the mixture and resulting solution was stirred at 50° C. for 3 h. The reaction mixture was submitted to the microwave at 150° C. for 20 min. The reaction mixture was quenched with water, extracted with EtOAc and washed with K2CO3, brine, dried over magnesium sulfate and concentrated. The crude material was purified by MPLC (1:1 ethyl acetate in hexanes) to give rise to 874 mg of the title compound as a colorless solid.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C([O-])(=O)C.[Na+].[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>O.C(#N)C>[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Oc1cc(O)nc(S)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Oc1cc(O)nc(SCc2cccc(F)c2F)n1
Temperature: 40 °C

Procedure:
To a slurry of 2-mercaptopyrimidine-4,6-diol (55.6 g) in water (735 ml) was added sodium acetate (47.4 g) with stirring forming a complete solution over 20 minutes. A solution of 2,3-difluorobenzyl bromide (80 g) in acetonitrile (73.5 ml) was then added dropwise over 15 minutes and the resulting mixture heated at 40° C. with stirring for 18 h. After cooling to ambient temperature the resulting precipitate was then filtered and washed with H2O (1 L) before drying in vacuo at 100° C. to afford the subtitle compound as a cream solid.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([NH2:10])[CH2:16][CH2:15]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Reaction time: 3 h

Procedure:
Combine trans-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-carbamic acid benzyl ester (23.0 g, 0.06 mol), palladium, 10% wt. on activated carbon (0.5 g), in EtOAc (100 mL) and charge the flask with hydrogen (50 psi). After 3 hours, filter the reaction mixture through a pad of Celite® and evaporate the solvent to obtain trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine as a dark oil (14.4 g, 99%): MS (EI) m/z=229 (M+).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C=O.[BH3-][C:45]#N.[Na+]>CC#N.O>[C:1]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][S:22][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:18])[CH3:45])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NCCNCCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(CCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Boc-NH—(CH2)2—NH—(CH2)5—CONH—(CH2)2-STrt (189 mg, 0.27 mmol) and HCHO (35% aqueous, 113 μl) were dissolved in MeCN (1.5 ml) and NaCNBH3 (34 mg, 0.54 mmol) was added. The reaction mixture was stirred for 5 h at RT. After completion of the reaction (MS) the solution was diluted with H2O (5 ml) and extracted with CH2Cl2 (3×5 ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by RP-HPLC to get Boc-NH—(CH2)2—N(CH3)—(CH2)5—CONH—(CH2)2-STrt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH2:18]O)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH2:18][Cl:22])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1cn2cccc(OCc3ccccc3)c2n1
Product: ClCc1cn2cccc(OCc3ccccc3)c2n1

Procedure:
A mixture of 8-benzyloxy-2-hydroxymethylimidazo[1,2-a]pyridine (2 g) and phosphorylchloride (10 ml) was heated on a steam bath for 1 hr. Excess phosphoryl chloride was distilled off in vacuo, the solid residue triturated with acetonitrile and the mixture filtered to give the title product as the hydrochloride salt.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:25]([CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28])[C:15]2=[O:17]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2cc3ccccc3o2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cc5ccccc5o4)c3C2=O)C(=O)N1
Yield: 65 %

Procedure:
A mixture of 3-(benzofuran-2-ylmethoxy)-phthalic acid (0.55 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.30 g, 1.8 mmol) in pyridine (10 mL) was heated to reflux for 16 h. The mixture was cooled and evaporated under vacuum. The residue was dissolved in CH2Cl2 (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL) and was evaporated. The residue was chromatographed using a CH2Cl2-methanol gradient, eluting the title compound at 95:5 CH2Cl2-methanol, 0.46 g, in 65% yield; mp 234-236° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.16 (98.58%); 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H), 2.43-2.61 (m, 2H), 2.81-2.95 (m, 1H), 5.08 (dd. J=12.7 Hz, J=5.3 Hz, 1H), 5.55 (s, 2H), 7.14 (s, 1H), 7.23-7.37 (m, 2H), 7.50 (d, J=7.0 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 11.11 (s, 1H); 13C NMR (DMSO-d6) δ 23.9, 30.9, 48.8, 63.1, 107.4, 111.3, 115.9, 116.7, 120.2, 121.6, 123.1, 125.0, 127.5, 133.3, 137.0, 152.0, 154.6, 155.0, 165.2, 166.7, 169.9, 172.7; Anal. Calcd for C22H16N2O6.0.15H2O: C, 64.91; H, 4.04; N, 6.88. Found: C, 64.89; H, 3.99; N, 6.84.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[S:11])[NH:13][CH2:14][C:15]([NH2:17])=[O:16]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: NCC(N)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=S)NCC(N)=O
Yield: 77.2 %

Procedure:
A mixture of 2,6-dimethylphenyl-isothiocyanate (16.3 g), glycinamide hydrochloride (11.05 g), triethyl amine (12.0 g), and chloroform (250 mL) was heated at reflux for 3 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with 1N HCl (300 mL) then with water (300 mL). The organic phase was evaporated to dryness, then the residue was stirred with diethyl ether. The solid was collected by filtration and dried to afford 2-[3-(2,6-dimethylphenyl)-thioureido]-acetamide as a solid (18.3 g). Mass spectrum (EI, M.+) m/z 237. This compound was used without further purification in the preparation of the title compound.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=1[O:20][CH3:21])[CH3:3].C(O)(=O)C.[Br:27]Br>O1CCOCC1>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:13]([O:20][CH3:21])=[C:14]([OH:19])[CH:15]=[C:16]([Br:27])[C:17]=1[OH:18])[CH3:3]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(O)ccc(O)c1OC
Reactant: BrBr
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCN1CCC[C@H]1CNC(=O)c1c(O)c(Br)cc(O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3,6-dihydroxy-2-methoxybenzamide hydrochloride (90 mg, 0.27 mmol), 0.5 ml dioxane and 0.1 ml acetic acid was added a solution of 18 μl bromine (0.35 mmol) in 0.5 ml dioxane. After stirring at room temperature for 1 h the solvent was evaporated.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:13])[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[Cl:15][C:16]1[C:21]([OH:22])=[C:20]([Cl:23])[C:19]([Cl:24])=[C:18]([OH:25])[C:17]=1[Cl:26]>>[C:8]([C:7]1[C:2]([F:1])=[C:3]([C:4]([F:13])=[C:5]([F:12])[C:6]=1[C:10]#[N:11])[O:22][C:21]1[C:16]([Cl:15])=[C:17]([Cl:26])[C:18]([O:25][C:3]2[C:4]([F:13])=[C:5]([F:12])[C:6]([C:10]#[N:11])=[C:7]([C:8]#[N:9])[C:2]=2[F:1])=[C:19]([Cl:24])[C:20]=1[Cl:23])#[N:9]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Reactant: Oc1c(Cl)c(Cl)c(O)c(Cl)c1Cl
Product: N#Cc1c(F)c(F)c(Oc2c(Cl)c(Cl)c(Oc3c(F)c(F)c(C#N)c(C#N)c3F)c(Cl)c2Cl)c(F)c1C#N

Procedure:
The objective 1,4-bis(3,4-dicarboxytrifluorophenoxy)tetrachlorobenzene dianhydride is produced as an embodiment by reacting tetrafluorophthalonitrile and tetrachlorohydroquinone (or its metal salts such as 2 Na salt; it is summarized as “tetrachlorohydroquinone”) in the presence of a base in a solvent at a temperature of −20° C. to 200° C. for 0.1 to 20 hours to form 1,4-bis(3,4-dicyanotrifluorophenoxy)tetrachlorobenzene (Step 1a); hydrolyzing the resulting 1,4-bis(3,4-dicyanotrifluorophenoxy)tetrachlorobenzene with an acid at a temperature of 50° C. to 300° C. for 0.5 to 20 hours to form 1,4-bis(3,4-dicarboxytrifluorophenoxy)tetrachlorobenzene (Step 1b); dissolving the reaction solution including 1,4-bis(3,4-dicarboxytrifluorophenoxy)tetrachlorobenzene in a medium containing an organic solvent once, purifying and separating the product therefrom (Step 1c); and then dehydrating the separated 1,4-bis(3,4-dicarboxytrifluorophenoxy)tetrachlorobenzene (Step 1d).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: CN1CCCN(c2nnc3ccc(F)cn23)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of Intermediate A (183 mg, 1.12 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 149 mg, 2.24 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 69a (400 mg, 1.12 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.5 h. The cooled mixture was diluted with water and extracted with DCM (3×20 mL) and DCM-MeOH (4:1, 2×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-25% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (179 mg, 41%). LCMS (Method 3): Rt 0.44 min, m/z 393 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[N+:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:24]1[CH:25]=[N:26][C:22]([N+:19]([O-:21])=[O:20])=[N:23]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Cn1c(Cn2cnc([N+](=O)[O-])n2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (3 mmol) and 3-nitro-[1,2,4]triazole (3 mmol) are dissolved in DMSO (20 ml). Potassium carbonate (6 mmol) is added to the solution. The mixture is allowed to stir at room temperature overnight. The reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:5) to give 7-(2,2-dimethyl-propyl)-6-(3-nitro-[1,2,4]triazol-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 41% yield.