Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36](Br)=[CH:37][CH:38]=1)(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[N:4]=[CH:5][N:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32]
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.18) (130 mg, 0.37 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (115 mg, 0.37 mmol) according to general procedure II. Obtained as a red solid (150 mg, 70%). MS (ISN) 586.0 [(M−H)−]; mp 178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]([F:15])([F:14])[CH2:12]I.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:12][C:11]([F:15])([F:14])[F:10])[CH:4]=1
Reactant: FC(F)(F)CI
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OCC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A suspension of 5.00 g of 3-methoxy phenol, 10.0 g of 2,2,2-trifluoroethyl iodide and 20.0 g of cesium carbonate in DMF (15 ml) was stirred at 80° C. for two hours. The solution was added with water and extracted with Et2O; the organic layer was washed in saturated brine, then, was dried in MgSO4, the drying agent was separated by filtration and solvent was evaporated under reduced pressure obtained 6.60 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29](C)C=O>CN.CO>[CH3:28][NH:29][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)c2cc(-c3ccccc3)n(-c3ccc(Cl)nc3)n2)CC1
Reactant: CN(C)C=O
Agent: CN
Solvent: CO
Product: CNc1ccc(-n2nc(C(=O)N3CCN(C)CC3)cc2-c2ccccc2)cn1
Reaction time: 72 h
Yield: 4 %

Procedure:
To a solution of 1-[1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (300 mg) obtained in Example 110 in N,N-dimethylformamide (1.5 mL), 40% methylamine-methanol solution (0.6 mL) was added. The mixture was stirred at 85>C for 3 days in a sealed tube, and then cooled in air. The reaction mixture was partitioned between 1N aqueous sodium hydroxide (30 mL) and ethyl acetate. The organic layer was sequentially washed with water, saturated aqueous sodium hydrogencarbonate, and water, and then dried over magnesium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (1 mL). The solution was purified through preparative high-performance liquid chromatography (eluent: water acetonitrile), followed by recrystallization from ether-hexane, to thereby give the title compound (11.7 mg, 4%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:14])[CH2:12]Br>>[CH3:9][O:10][C:11](=[O:14])[CH2:12][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1c[nH]cn1
Product: COC(=O)Cn1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was alkylated with bromo-acetic acid methyl ester to provide the title compound: 1H NMR (400 MHz) 3.82 (s, 1H), 4.80, (s, 2H), 7.47 (d, 1H, J=1.7 Hz), 7.84 (d, 1H, J=1.7 Hz); gc/ms m/z 185 (M).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[Si:7]([CH2:14][CH2:15][SH:16])([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].[OH-].[K+]>O>[Si:7]([CH2:14][CH2:15][S:16][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9]
Reactant: C=CC(=O)OC
Reactant: CO[Si](CCS)(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)CCSCC[Si](OC)(OC)OC
Temperature: 60 °C
Yield: 87 %

Procedure:
A mixture of 26 gms of methyl acrylate (0.3 mols) and 36.4 gms of (CH3O)3SiCH2CH2SH was catalyzed by adding 1 ml. of N/2 alcoholic KOH into a 250 ml., round bottomed glass flask, with stirring. An exothermic reaction raised the temperature to 60° C. The mixture was refluxed for 30 minutes and then distilled under vacuum to recover 46 gms of water-white product with a boiling point at 0.7 mm Hg pressure of 115°-125° C. for an 87 percent yield of (CH3O)3Si(CH2)2S(CH2)2COOCH3. d420 =1.115, ND25 =1.4546. One tenth gram mol (26.8 gms) of this product was saponified by refluxing for one hour with 4 grams of NaOH (0.1 mol) in 80 gms of H2O. Methanol and other volatiles were taken off until the temperature, with auxiliary heating, reached 100° C. The residue was diluted to 100 gms with water to give a 1 molal solution of (Na)O1.5 Si(CH2)2S(CH2)2COONa.
Reaction SMILES: [O:1]([C:8]1[CH:19]=[CH:18][C:11]([O:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][N:15]1[CH2:16][CH2:17][C@@H:13]([O:12][C:11]2[CH:18]=[CH:19][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:14]1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(Oc2ccc(O[C@@H]3CCNC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)C1
Temperature: 60 °C
Yield: 59.2 %

Procedure:
(R)-3-(4-Phenoxy-phenoxy)-pyrrolidine (1.24 g, 4.25 mmol) was taken into anhydrous DMF (10 mL) in a nitrogen flushed 100 mL, 1-neck round bottom flask. Methyl-4-bromobutyrate (846 mg, 4.68 mmol) was added to the mixture followed by potassium carbonate (1.18 g, 8.5 mmol). The reaction was heated at 60° C. for 24 h. The mixture was then cooled to room temperature and partitioned between ethyl acetate and water. The water layer was washed with ethyl acetate (3×). The combined ethyl acetate layers were then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was then purified by silica gel flash chromatography (20:1 silica ratio, eluted with 1:1 ethyl acetate and hexane) to obtain the title product (894.4 mg, 59%) LCMS; m/z 356 (M+1); 1H NMR (400 MHz, DMSO) δ 1.65-1.78 (m, 3H), 2.21-2.26 (m, 1H), 2.32-2.35 (m, 2H), 2.37-2.42 (m, 3H), 2.58-2.61 (m, 1H), 2.63-2.69 (m, 1H), 2.80-2.84 (m, 1H), 3.58 (s, 3H), 4.80 (s, 1H), 6.89-6.98 (m, 6H), 7.07-7.09 (m, 1H), 7.32-7.36 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S:11]([CH2:13][C:14]3[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1.[Na].C(=O)([O-])[O-].[Na+].[Na+].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>ClCCl>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:8]2[C:7]3[CH:24]=[CH:25][C:4]([O:3][CH:2]([F:1])[F:26])=[CH:5][C:6]=3[N:10]=[C:9]2[S:11]([CH2:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=2)=[O:12])(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3n2S(=O)(=O)c2ccc(Cl)cc2)c1OC
Temperature: 4 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole, sodium salt sesquihydrate (432 mg, 1 mmole) was suspended in 30 ml of dichloromethane in the presence of anhydrous sodium carbonate (100 mg). 4-Chlorobenzenesulfonyl chloride (211 mg, 1 mmole) was added to the suspension and stirred at 4° C. overnight. The organic layer was separated by filtration and concentrated under reduced pressure. The residual solid was crystallized from dichloromethane-ethyl ether-heptane. 417 mg of 1-(4-chlorobenzenesulfonyl)-5-difluoromethoxy-2- [(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole was obtained. Yield 74.5%.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.Cl[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])=[C:21]([O:39][CH3:40])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:40][O:39][C:21]1[CH:20]=[C:19]([CH:38]=[CH:37][C:22]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30])[CH2:18][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: COC(=O)c1cc(O)nn1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
A mixture of methyl 3-hydroxy-1-phenyl-1H-pyrazole-5-carboxylate (3.36 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole (5.30 g), potassium carbonate (4.25 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give methyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carboxylate (7.53 g, yield 93%). The crystals were recrystallized from acetone-isopropyl ether. melting point: 143-144° C.
Reaction SMILES: [OH-:1].[Na+:2].[S:3](=[O:5])=[O:4]>>[S:3]([O-:1])([O-:5])=[O:4].[Na+:2].[Na+:2].[S:3](=[O:1])([OH:5])[O-:4].[Na+:2]
Reactant: [OH-]
Reactant: O=S=O
Agent: [Na+]
Product: O=S([O-])O
Product: O=S([O-])[O-]

Procedure:
In the upper section 3, caustic soda in solution will react with sulphur dioxide to form sodium sulphite and sodium bi-sulphite, whilst in the bottom section 5 a new balance will be favoured to produce sodium sulphate by reaction with sulphuric acid. Sufficient alkali will consequently be injected through stream 16 essentially to neutralise the sulphuric acid present in the bottom section 5. Also, sufficient water is introduced into the upper section 3 via the stream 16, or via some other source (not shown) to compensate for water flashed-off in the flash pan 9.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.ClC1N=CC(CN2C(=O)C3=CC=CC=C3C2=O)=CC=1>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)nc1
Agent: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Product: NCc1ccc(Br)nc1

Procedure:
The reaction procedure of Reference Example 3 was repeated except that N-(6-bromo-3-pyridylmethyl)phthalimide was used in lieu of N-(6-chloro-3-pyridylmethyl)phthalimide, to give the title compound as sale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=1.C([Li])(C)(C)C.CCCCCC.CN(C)[CH:28]=[O:29]>O1CCCC1>[CH:4]1[C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[C:2]([CH:28]=[O:29])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)oc1ccccc12
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)oc1ccccc12
Temperature: -78 °C

Procedure:
Combine 3-bromodibenzofuran (0.5 g, 2.0 mmol) and tetrahydrofuran (30 ml). Cool to about −78° C. Add a solution of t-butyllithium, 1.6 M solution in hexane (2.2 ml, 3.0 mmol), then warm to about 0° C. for 10 min. Cool to about −78° C. and add dimethylformamide (0.5 ml, 5.9 mmol). Warm to room temperature, quench with water, and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 8:2 hexane:EtOAc to give the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[NH:14]2)=[CH:6][CH:5]=1.[CH3:17]S(Cl)(=O)=O.CN([CH:25]=[O:26])C>>[C:25]([C:12]1[C:13]2[NH:14][C:15]3[C:7](=[CH:6][CH:5]=[C:4]([Br:3])[CH:16]=3)[C:8]=2[CH:9]=[CH:10][N:11]=1)(=[O:26])[CH3:17]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)[nH]c1cnccc12
Agent: [H-]
Agent: [Na+]
Product: CC(=O)c1nccc2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (95%, 14 mg, 0.60 mmol) in DMF (1.0 ml) at 5° C. to 10° C. was added the product from example 1 (74 mg, 0.30 mmol). The resulting mixture was stirred for 15 min at 5° C. to 10° C., before adding methanesulfonylchloride (0.030 ml, 0.38 mmol). The reaction was allowed to warm to RT and stirred for 2 h before partitioning into saturated aqueous NaHCO3 and EtOAc. After stirring the mixture overnight, the organic layer was washed with water, dried (brine; MgSO4), and concentrated. The residue was purified by chromatography (1:1 hexane-ethyl acetate) on silica gel to give 23 mg of 1-acetyl-7-bromo-β-carboline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][OH:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[CH2:33][OH:34])[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1
Reactant: OC[C@@H]1CCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCC[C@H]2CO)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 32.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (S)-pyrrolidin-2-ylmethanol hydrochloride (0.21 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.25 g, 32%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.[Cu][C:14]#[N:15].CN1CCCC1=O.C(N)CN>O>[OH:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:14]#[N:15])=[CH:12][C:6]=2[CH:7]=1
Reactant: OCc1cc2cc(Br)ccc2o1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: N#Cc1ccc2oc(CO)cc2c1
Temperature: 200 °C
Reaction time: 3.5 h
Yield: 73.9 %

Procedure:
A solution of 5-bromo-2-benzofuranylmethanol (1.19 g, 5.24 mmol), copper (I) cyanide (0.470 g, 5.25 mmol) and N-methylpyrrolidinone (15 ml) was left under stirring at 200° C. for 3.5 h, then was poured onto a solution of ethylenediamine (6 g) in water (80 ml) and extracted with ethyl acetate (3×75 ml). The organic phase was dried and the solvents were evaporated off under reduced pressure. The resulting crude was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate mixtures of increasing polarity, thereby obtaining 0.671 g of title product as a yellow solid with melting point 113-114° C. (74% yield).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH2:54])[CH3:50]>CN(C=O)C.O>[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:12]([C:11]1[CH:10]=[N:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1)=[O:14])[CH3:50]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(Nc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)nc1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 6-phenylamino-nicotinic acid (0.1 g, 0.00047 mol) in DMF (2 mL), was added DIPEA (0.181 g, 0.001401 mol), HOBt (0.0756 g, 0.00056 mol) and EDCI.HCl (0.107 g, 0.00056 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.0782 g, 0.00056 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.135 g (97%) of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 299.13 (M+1)+, 99%. To a stirred solution of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid ethyl ester (0.135 g, 0.00045 mol) in a mixture of THF (5 mL), methanol (7 mL) and H2O (2 mL) was added LiOH.H2O (0.0568 g, 0.00135 mol) at ambient temperature and the resulting mixture was stirred for 2 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.078 g (64%) of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].[OH-].[Na+]>C(O)(=O)C>[OH:12][C:10]1[C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17](=[O:19])[CH:18]=1
Reactant: O=C(O)c1ccccc1Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1cc(O)c2ccccc2n1-c1ccccc1
Temperature: 0 °C

Procedure:
A solution of N-phenyl anthranilic acid (30.1g.; 0.146 mole) and acetic anhydride (74 ml.) in glacial acetic acid (74 ml.) was refluxed for 4 hrs. The resulting red solution was cooled, poured onto crushed ice-water (600 ml) and brought to pH 9 with dilute sodium hydroxide solution. After filtration the clear liquid was taken to pH 5 with hydrochloric acid and the white solid filtered off and dried, m.p. (AcOH) 298°-300° C. (Found: C, 75.40; H, 4.58; N, 5.70; C15H11NO2 requires; C, 75.94; H, 4.67; N, 5.90%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[C:33]([N:40]1[CH2:45][CH2:44][CH2:43][C@@H:42]([NH2:46])[CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CO>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([NH:46][C@@H:42]2[CH2:43][CH2:44][CH2:45][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:41]2)=[O:20])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)N2CCc3ccccc3C2c2ccc(C(F)(F)F)cc2)C1

Procedure:
A mixture of 4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (350 mg, 0.79 mmol, example 15) and (R)-1-Boc-3-amino-piperidine (1.6 mL, 7.91 mmol) was subjected to a microwave irradiation at 120° C. for 45 min. Then, MeOH (2 mL) was added to the mixture and the mixture was filtered. The solution mixture was purified by preparative HPLC (10%-100% of MeCN (0.1% TFA)/H2O (0.1% TFA). All fractions of the product were combined, saturated NaHCO3 (1 mL) was added and the solvents were removed. Then, an additional amount of saturated NaHCO3 (10 mL) was added and the aqueous mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a white solid. MS (ESI, positive ion) m/z: 504 (M+H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1.[NH2:17][NH2:18]>>[NH:17]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1)[NH2:18]
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Reactant: NN
Product: NNc1nc(N)c2ncn(COCCO)c2n1
Reaction time: 1 h

Procedure:
2-Chloro-9-(2-hydroxyethoxymethyl)adenine (0.83 g) was added with stirring to 95% hydrazine (11 ml) and the resulting solution stirred 1 hour under nitrogen. Excess hydrazine was removed by distillation in a rotary evaporator at a bath temperature of 30° C. followed by co-evaporation twice with ethyl acetate. The residue was thoroughly triturated with methanol to give a quantitative yield (0.8 g) of white to cream colored-2-hydrazino-9-(2-hydroxyethoxymethyl) adenine, m.p. 220°-222° C.
Reaction SMILES: FC1C=CC=C(F)C=1C1SC=C(C(O)=O)N=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=2)=[CH:19][CH:18]=1.[NH2:31][C:32]1[CH:33]=[N:34][S:35][C:36]=1[N:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[N:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:24][CH:25]=[C:26]([C:28]([NH:31][C:32]3[CH:33]=[N:34][S:35][C:36]=3[N:37]3[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]3)=[O:30])[N:27]=2)=[CH:21][CH:22]=1
Reactant: O=C(O)c1csc(-c2ccncc2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2sncc2N)CC1
Agent: O=C(O)c1csc(-c2c(F)cccc2F)n1
Product: CC(C)(C)OC(=O)N1CCN(c2sncc2NC(=O)c2csc(-c3ccncc3)n2)CC1
Yield: 89.3 %

Procedure:
Following the procedure described in Step (3) of Example 6, and substituting Compounds 2E and 6D8 with 2-(pyridin-4-yl)thiazole-4-carboxylic acid (19E) (58 mg, 0.28 mmol) and tert-butyl 4-(4-aminoisothiazol-5-yl)piperazine-1-carboxylate (31D3) (80 mg, 0.28 mmol) respectively, Compound 31A (120 mg, 0.25 mmol) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[N:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24](=[O:27])[CH2:25][SH:26]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([S:26][CH2:25][C:24]([O:23][CH3:22])=[O:27])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CSc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-5-nitro-nicotinic acid methyl ester (1.0 g) [prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590-2594 (1951)] in dichloromethane (10 mL) containing triethylamine (0.76 mL) was treated with mercapto-acetic acid methyl ester (0.44 mL) and the solution was stirred at room temperature for 1 hour and evaporated to dryness. Sodium bicarbonate solution was added and the mixture was extracted with dichloromethane, dried (anhydrous sodium sulfate) and evaporated to afford a solid (1.0 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH:16](OCC)O)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.[CH3:27][C:28]([NH2:37])([CH3:36])[CH2:29][CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1>>[CH3:36][C:28]([NH:37][CH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:11]=1)[OH:21])([CH3:27])[CH2:29][CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: CC(C)(N)CCn1cncn1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Product: CC(C)(CCn1cncn1)NCC(O)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
The target compound is prepared analogously to the methods described for Example 7 from 379 mg (1 mmol) N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 154 mg (1 mmol) 1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamine. Colourless solid.