Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-:33].[K+].[K+].OO.O>CS(C)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:33])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C#N)C3)ccc1-2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C(N)=O)C3)ccc1-2
Temperature: 45 °C
Yield: 49.7 %

Procedure:
A solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.26 g, 0.6 mmol) in DMSO (5 mL) was treated with potassium carbonate (16 mg, 0.12 mmol) followed by hydrogen peroxide (30% aq., 0.33 mL) and the mixture was heated at 45° C. for 18 hours then at 50° C. for a few more hours. Further hydrogen peroxide (33 mL, 30% aq.) was added and the mixture heated at 50° C. for 18 hours. After cooling, water was added and the mixture was extracted with EtOAc (×5). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo and the residue purified by flash chromatography (SiO2, first time with 0-10% MeOH in EtOAc then second time with 0-5% MeOH in DCM). Further purification was by reverse-phase preparative HPLC (Gemini C18 column, gradient 30-40% MeOH in H2O+0.1% HCO2H). A solution of the product in a mixture of chloroform and DCM was treated with 0.2M HCl in ether (0.32 mL) and then concentrated in vacuo to give 446 (27 mg, 9%). LCMS: RT=7.41 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 10.79 (1 H, s), 8.34-8.28 (1 H, m), 8.06 (1 H, s), 7.82 (1 H, d, J=17.45 Hz), 7.65 (1 H, d, J=4.94 Hz), 7.27-7.16 (1 H, m), 7.07 (1 H, d, J=1.80 Hz), 5.80-5.72 (1 H, m), 4.47 (1 H, td, J=10.76, 4.67 Hz), 4.37-4.26 (3 H, m), 4.20-3.94 (3 H, m), 3.41 (2 H, q, J=4.96 Hz), 1.55-1.45 (12 H, m)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([C:21]=3[NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)[C:19]#[N:20])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(Cl)Cl.CN1C(=O)CCC1>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:21]3[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=3[C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:6]4[S:7][C:3]([CH2:1][N:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)=[CH:4][CH:5]=4)[CH:9]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: N#Cc1cncc(-c2cccc(-c3ccc(C=O)s3)c2)c1Nc1ccc2[nH]ccc2c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN1CCN(Cc2ccc(-c3cccc(-c4cncc(C#N)c4Nc4ccc5[nH]ccc5c4)c3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To 5-[3-(5-formyl-2-thienyl)phenyl]-4-(1H-indol-5-ylamino)nicotinonitrile 150 (100 mg, 0.238 mmol) in CH2Cl2 (5 mL) and NMP (0.5 mL), cooled with ice-water bath, was added Na(OAc)3BH (264 mg, 1.2 mmol) and N-methylpiperazine (133 μL, 1.2 mmol). The resulting mixture was stirred at r.t. overnight and partitioned between CH2Cl2 and aq. NaHCO3. The combined organics were dried over Na2SO4, concentrated and purified by preparative TLC eluting with 10% MeOH/CH2Cl2 to give 63 mg (53% yield) of the title compound as a light yellow solid. MS: 505.2 (M+H); melting range: 120-123° C.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[Cl:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O.O.[Sn](Cl)Cl>C(OC(=O)C)C>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[Cl:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc(Cc2c(Cl)cc(N)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In 11 ml of ethylacetate were dissolved 1.1 g 4-(4-Acetylbenzyl)-3,5-dichloronitrobenzene and 3.8 g Tin (11) chloride dihydrate. The solution was allowed to proceed for one hour at temperatures ranging from 40-50° C. After completion of the reaction. The reaction mixture was poured into 100 ml ice-water, followed by extraction with 150 ml ethylacetate. The extract was washed with water and 25% ammonia solution, dried over anhydrous magnesium sulfate, and concentrated to afford the titled compound in a yield of 100%, m.p.97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:31]=[CH:30][C:17]4[O:18][CH2:19][C:20]5[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[F:32].[SH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[C:36]([CH2:35][CH2:34][S:33][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]#[N:29])[C:20]=2[CH2:19][O:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:32])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:38])=[O:37]
Reactant: O=C(O)CCS
Reactant: N#Cc1cccc2c1COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2O
Product: N#Cc1cccc2c1COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
2-(7-Chloro-6-fluoroquinolin-2-yl)methoxy-7-cyano-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])O>O>[C@@H:4]1([C:6]([OH:8])=[O:7])[O:5][C@@H:2]1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: O
Product: O=C(O)[C@H]1O[C@H]1C(=O)O

Procedure:
The resulting heterogeneous reaction mixture, which was lumpy and hardened, was neutralized by addition of 15% aqueous tartaric acid solution. The polymer was filtered and a small portion was ground thoroughly. The ground material was extracted with 2-propanol for 24 hrs in a Soxhlet extractor and dried to afford a pale brown solid which was not soluble to any extent in distilled water.
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]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH:28]([CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:27]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][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)[CH2:27][CH:28]1[CH2:33][O:34][Si:35]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)[Si](OCC1CN(Cc2nnc3ccc(F)cn23)CCN1C)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCC1CN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCN1C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Intermediate A (115.4 mg, 0.71 mmol) was added to a mixture of NaH (60% in mineral oil, 87.2 mg, 2.18 mmol) in DMF (4 mL) at RT and stirred for 15 min. Intermediate 56d (237 mg, 0.54 mmol) was then added and the resulting mixture heated to 60° C. for 2 h. After cooling, the reaction was quenched with sat. aq. NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 solution and brine, and concentrated in vacuo. The resulting residue was loaded onto an SCX-2 cartridge, washed with MeOH then eluted with 1M NH3 in MeOH; concentration in vacuo gave the title compound as a brown residue (91 mg, 29%). LCMS (Method 3): Rt 3.08 min, m/z 579 [MH+].
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:6])[CH3:5].[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH:15]2[N:19]([C:20](=[O:23])[CH2:21]Cl)[CH2:18][CH2:17][S:16]2)=[CH:11][CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH:15]2[N:19]([C:20](=[O:23])[CH2:21][S:6][CH2:4][CH3:5])[CH2:18][CH2:17][S:16]2)=[CH:11][CH:10]=1
Reactant: CCS
Reactant: COc1ccc(OCC2SCCN2C(=O)CCl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSCC(=O)N1CCSC1COc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.56 g of sodium methylate is MeOH (5 ml), cooled at 0° C., was treated with 0,71 ml of ethanethiol (CH3CH2SH). After 10 minutes, a solution of 3 g of 2-(4-methoxyphenoxymethyl)-3-α-chloroacetyl-1,3-thiazolidine in 10 ml MeOH was dropped into the mixture. After 30 minutes, the solvent was removed under reduced pressure and the residue was partitioned between 30% NaH2PO4 and ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and concentrated to dryness to yield 2,9 g of 2-(4-methoxyphenoxymethyl)-3-ethylmercaptoacetyl- 1,3-thiazolidine after crystallization from isopropyl ether, m.p. 98°-110° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:7]=1[N+:15]([O-])=O>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[NH2:15]
Reactant: COCCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: CO
Product: COCCOc1cccc(N)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.80 g (7.43 mmol) 1-(2-Methoxy-ethoxy)-2,3-dinitro-benzene were dissolved in 250 mL MeOH. The solution was evacuated and rinsed with argon several times. 250 mg palladium on charcoal (10%) were added and again the mixture was evacuated and rinsed with argon several times. Finally argon was exchanged by hydrogen (balloon filled with hydrogen) and the mixture was stirred for 2 h at room temperature. The reaction mixture was filtered over “Celite” and the filter residue was washed with 100 mL MeOH. The filtrate was concentrated under vacuo to give pure 3-(2-Methoxy-ethoxy)-benzene-1,2-diamine as a brown oil. Yield: 1.33 g MS (ES+): m/e=183.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2F)[N:3]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: Cc1ncc2c(F)cccc2n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ncc2c(N3CCNCC3)cccc2n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a stirred solution of 2-methyl-5-fluoro-quinazoline (WO2003068772, Chem. Abstr. 139:197493, 2 g; 12.3 mmol) in dry dimethylformamide (10 mL) were added triethylamine (3.4 mL; 2 eq) and piperazine (11 g; 10 eq). The reaction mixture was stirred under nitrogen at 120° C. for 4 h, then cooled to room temperature, poured into water (10 mL) and extracted with ethyl acetate (5×15 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by ion-exchange chromatography [SCX-2; MeOH-1M NH3/MeOH (1:0)→(0:1)] to afford the title compound as a yellow solid (1.8 g; yield 64%).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].[O:6]1[C:10]2([CH2:15][CH2:14][C:13](=[N:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1>O1CCCC1>[CH2:3]([C:13]1([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:12][CH2:11][C:10]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:15][CH2:14]1)[CH:2]=[CH2:1]
Reactant: C=CC[Mg]Cl
Reactant: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: C=CCC1(NS(=O)C(C)(C)C)CCC2(CC1)OCCO2
Temperature: -78 °C

Procedure:
Allylmagnesium chloride (2 mol/L in tetrahydrofuran, 17.0 mL) is added to a solution of 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide (7.0 g) in tetrahydrofuran (70 mL) cooled to −78° C. The resulting solution is stirred with cooling for 3 h and then quenched by the addition of 10% aqueous NH4Cl solution.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].[CH3:12][O:13][C:14]([CH2:16][C:17](=[CH2:21])[C:18]([O-:20])=[O:19])=[O:15].[Na+]>CO>[CH3:12][O:13][C:14]([CH2:16][CH:17]([CH2:21][S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:18]([OH:20])=[O:19])=[O:15]
Reactant: C=C(CC(=O)OC)C(=O)[O-]
Reactant: Sc1ccc2ccccc2c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(CSc1ccc2ccccc2c1)C(=O)O
Yield: 53.2 %

Procedure:
A mixture of 2-naphthalenethiol (0.38 g), sodium 3-methoxycarbonyl-2-methylenepropionate (0.39 g), methanol (20 ml), and triton B (40% methanol solution, 10 drops) was refluxed for 12 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was acidified with a dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica eluting with chloroform/methanol (20:1), and recrystallized from isopropyl ether to give 0.38 g of 2-methoxycarbonylmethyl-3-(2-naphthylthio)propionic acid.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:13](O)[CH3:14]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:13]([C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6])=[CH2:14]
Reactant: CCO
Reactant: COc1c(Br)ccc(F)c1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc(F)c(C#N)c1OC

Procedure:
3-bromo-6-fluoro-2-methoxybenzonitrile (4.40 g, 19.1 mmol), potassium vinyl trifluoroborate (5.12 g, 38.3 mmol), PdCl2(dppf)-CH2Cl2 Adduct (0.7 g, 1 mmol) and TEA (5.33 mL, 38.3 mmol) were added to 80 mL ethanol in a 200 mL flask. The reaction mixture was degassed and heated to reflux for 4 h. The reaction mixture was cooled and then most of the EtOH was removed. The residue was diluted with ethyl acetate. The mixture was washed with brine twice. The organic layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified through a 330 g RediSep column and eluted with 10% EtOAc/hexane solvent system to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=[CH:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1COCC1.O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH:9]([S:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(=Cc1c(F)ccc(F)c1F)C(=O)OC
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(Sc1ccc(Cl)cc1)c1c(F)ccc(F)c1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-(2,3,6-Trifluoro-benzylidene)-malonic acid dimethyl ester (6.5 g, 23.7 mmol) and 4-chlorothiophenol (5.1 g, 35.5 mmol) were dissolved in 100 mL THF. K2CO3 (5 g, excess) was added, the reaction mixture was stirred at 60° C. for three hours. 300 mL of EtOAc and 300 mL of water were added. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/hexane as the eluent. (Gradient from 0/100 to 25/75 in 45 min, 7.1 g, 72%). 1H NMR (CDCl3 400 MHz) δ 7.26 (m, 4H), 7.03 (m, 1H), 6.75 (m, 1H), 5.08 (d, J=11.7 Hz, 1H), 4.34 (d, J=12.4 Hz, 1H), 3.84 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([C:11]#[N:12])=[N:5][C:4]=1[C:13]#[N:14])#N.[CH3:15][N:16]([C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[CH3:15][N:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][C:1]([C:3]2[N:8]=[C:7]([C:9]#[N:10])[C:6]([C:11]#[N:12])=[N:5][C:4]=2[C:13]#[N:14])=[CH:27][CH:28]=1
Reactant: CN(c1ccccc1)c1ccccc1
Reactant: N#Cc1nc(C#N)c(C#N)nc1C#N
Solvent: CS(C)=O
Product: CN(c1ccccc1)c1ccc(-c2nc(C#N)c(C#N)nc2C#N)cc1
Temperature: 100 °C
Yield: 9 %

Procedure:
A mixture of 18 g of tetracyanopyrazine and 18.3 g of N-methyl-N-phenylaniline in 200 ml of dimethylsulfoxide was heated at 100°C for 21 hours, the solution was cooled and poured onto 6 liters of ice water to give a sticky precipitate. The mixture was extracted with ethyl acetate. The ethyl acetate solution was back-extracted with water, dried over sodium sulfate and concentrated to give a dark brown solid. Unreacted tetracyanopyrazine was removed by recrystallization of the solid from toluene, from which TCP was the first to crystallize. The toluene solution was concentrated and the residue was rinsed with hexane to partially remove unreacted N-methyl-N-phenylaniline. The residue was dissolved in aqueous tetrahydrofuran (THF) (75% tetrahydrofuran) at 50°C, the THF removed by distillation, and the residual solid washed with water to remove water-soluble by-products. The remaining product was chromatographed on a column of neutral silicic acid using hexane/benzene/ acetonitrile eluents. Red fractions were combined, concentrated, and the product recrystallized from heptane-toluene to give 3.02 g of red-purple 6-[p-(methylphenylamino)phenyl]-2,3,5-pyrazinetricarbonitrile, mp 187.3°- 1.88.8°C after drying at 111°C (0.1 mm). Another 1.93 g of this product was recovered from mother liquors. Silica paper chromatography revealed only one colored product.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][CH2:7][CH2:6][N:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:10]([CH:9]1[CH2:8][CH2:7][CH2:6][N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]1=[O:3])[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)CCCN1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)CCCN1c1ccccc1
Reaction time: 1.5 h

Procedure:
Under inert atmosphere, to a stirred solution of NaH (2.5 mg, 0.05 mmol) in 0.10 ml anhydrous DMF at 0° C., was added a solution of compound of Example 8 (0.02 g, 0.05 mmol) in 0.20 ml anhydrous DMF. After 1.5 h at 0° C., benzyl bromide (7 μl, 0.05 mmol) was added to the reaction mixture. This mixture was stirred for 2 h, and then solvent was completely removed. The crude was chromatographically purified over SiO2 using Hexane/AcOEt 50/50 as the eluant, yielding 0.016 g (71%, purity 92%) of the desired product.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[C:3]=1C.[OH:19][CH2:20][CH2:21][N:22]1[CH:31]=[C:30](I)[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[C:23]1=[O:33]>>[OH:19][CH2:20][CH2:21][N:22]1[CH:31]=[C:30]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:4][CH:3]=2)[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[C:23]1=[O:33]
Reactant: O=c1c2cnccc2c(I)cn1CCO
Reactant: Cc1c(I)c2cccnc2n1C(=O)OC(C)(C)C
Product: O=c1c2cnccc2c(-c2c[nH]c3ncccc23)cn1CCO

Procedure:
Analogously to Example 5, tert-butyl 3-iodo-2-methylpyrrolo[2,3-b]pyridine-1-carboxylate is reacted with 2-(2-hydroxyethyl)-4-iodo-2H-2,7-naphthyridin-1-one, giving 2-(2-hydroxyethyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-2,7-naphthyridin-1-one as colourless solid; MS (ESI): 307 [M+H]+.
Reaction SMILES: C(O)C.[Na].[CH2:5]([N:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25](OCC)(=[O:31])[C:26](OCC)=[O:27]>C(O)(=O)C>[CH2:5]([N:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:26]([OH:27])[C:25]([OH:31])=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1Cc1ccccc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Into a 20L three-necked flask, 2.7L of ethanol was put, and 139.2 g (6.05 moles) of small cuts of metallic sodium were gradually added thereto with stirring at room temperature. After the addition was completed, the mixture was stirred under reflux until the metallic sodium became dissolved completely. The mixture formed was cooled to room temperature, and 770.7 g (2.760 moles) of the diethyl N-benzyliminodiacetate and 405.8 g (2.775 moles) of diethyl oxalate were added thereto, which were then stirred under reflux for 8 hours. After the reaction was completed, the reaction product was left to cool, and its pH was adjusted to 5.5 by adding 4.5L of acetic acid. The precipitate formed was collected by filtration and washed with water. This precipitate was washed with acetone to obtain 532.8 g of diethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate (yield: 57.9%), having a melting point of 143.5 to 145.0° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:8]([S:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)(=O)C.[OH-].[Na+]>C(O)C>[OH:4][CH2:5][C:6]1[N:7]([CH2:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[C:8]([S:14][C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1
Reactant: CC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a suspension of the compound (11) (0.35 g, 0.77 mmol) obtained in Example 7 in ethanol (3.5 ml) was added 1N aqueous sodium hydroxide (0.82 ml) under ice-cooling. The reaction mixture was stirred for 30 minutes, concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure to yield the objective (12) (0.31 g). Yield 96.9%.
Reaction SMILES: [C:1]([OH:9])(=O)/[C:2](=[C:4](\[CH:6]=O)/[Cl:5])/[Cl:3].S(O)(O)(=O)=O.[NH2:15][NH2:16].C([O-])(=O)C.[Na+]>O>[Cl:3][C:2]1[C:1](=[O:9])[NH:15][N:16]=[CH:6][C:4]=1[Cl:5]
Reactant: NN
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc(Cl)c1Cl
Yield: 78.8 %

Procedure:
A stirred solution of 3.9 grams of mucochloric acid in water is warmed to 8°-100° C., and a mixture of 3.1 grams of hydrazine sulfate and 3.0 grams of sodium acetate is added. A solid is collected by filtration and recrystallized from water to yield 3.0 grams of 4,5-dichloro-3-pyridazone; m.p. 199°-200° C. The reaction is repeated several times.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([OH:14])[C:10]=1[C:15]#[N:16].C(N(CC)CC)C.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>ClCCl>[F:29][C:28]([F:31])([F:30])[S:25]([O:14][C:11]1[C:10]([C:15]#[N:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[S:13][N:12]=1)(=[O:26])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(-c2snc(O)c2C#N)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2snc(OS(=O)(=O)C(F)(F)F)c2C#N)c(F)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 5-(2-fluoro-4-methylphenyl)-3-hydroxy-1,2-thiazole-4-carbonitrile (700 mg, 2.99 mmol, 1.00 equiv), dichloromethane (20 mL), triethylamine (302 mg, 2.98 mmol, 1.00 equiv). This was followed by the addition of Tf2O (1.69 g, 5.99 mmol, 2.00 equiv) at 0-5° C. The resulting solution was stirred overnight at 20° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 800 mg (73%) of 4-cyano-5-(2-fluoro-4-methylphenyl)-1,2-thiazol-3-yl trifluoromethanesulfonate as colorless oil.