Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:2]2[CH:3](O)[CH:4]=[CH:5][CH:6]1O.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH:8]12[CH2:11][CH2:12][CH:1]([CH:10]=[CH:9]1)[C:2]1[C:7]2=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1C=CC(O)C2C3C=CC(CC3)C12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C1=CC2CCC1c1ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.8 %

Procedure:
To a solution of 27.9 g of tricyclo[6.2.2.02,7]dodeca-4,9-diene-3,6-diol in 165 mL of pyridine were portionwise added 30 mL of POCl3 at 0° C. The reaction was stirred for 3 days at rt before it was quenched by careful addition of ice under cooling. The resulting mixture was extracted with Hept (4×50 mL). The combined organic phases were washed with H2O, 15% HCl solution and again with H2O. The organic phase was dried over MgSO4 and concentrated in vacuo to obtain 10.6 g of the desired compound as yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][OH:48])[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][O:48][S:59]([CH3:58])(=[O:61])=[O:60])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 187b (250 mg, 0.38 mmol) in DCM (4 mL) was added DIPEA (267 μL, 1.53 mmol) followed by methanesulfonyl chloride (60 μL, 0.77 mmol). The reaction mixture was stirred for 2 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.25 min, m/z 732 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12]([CH3:14])=[O:13].[N:22]([O-])=O.[Na+]>S(=O)(=O)(O)O.O>[NH:11]([CH2:10][CH2:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:3][C:2]=2[N:1]=[N:22]1)[C:12]([CH3:14])=[O:13]
Reactant: O=N[O-]
Reactant: CC(=O)NCCNc1ccc(C2=NNC(=O)CC2)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)NCCn1nnc2cc(C3=NNC(=O)CC3)ccc21

Procedure:
15.98 g (55.3 mmol) of 6-(3-amino-4-acetaminoethylamino-phenyl)-4,5-dihydro-3(2H)-pyridazinone are dissolved in 300 ml of 2N sulphuric acid, then cooled to 2°-5° C. and a solution of 4.2 g (61 mmol) of sodium nitrite in 70 ml of water is slowly added dropwise with stirring. After about one hour the cooling bath is removed and the mixture is stirred for a further hour at ambient temperature. The solids precipitated are suction filtered, stirred into 100 ml of a 5% sodium bicarbonate solution and suction filtered again after 10 minutes.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:14]=O>C(O)=O>[CH3:14][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=2)[CH2:1]1
Reactant: C=O
Reactant: COC(=O)c1ccc2c(c1)CNC2
Solvent: O=CO
Product: COC(=O)c1ccc2c(c1)CN(C)C2
Temperature: 70 °C
Reaction time: 16 h

Procedure:
1.2 g (6.6 mmol) methyl 2,3-dihydro-1H-isoindole-5-carboxylate are dissolved in 5 ml formic acid, combined with 2 ml formalin solution (37% solution in water), heated to 70° C. for 3.5 hours and stirred for 16 hours at RT. The reaction mixture is evaporated down i. vac. and combined with 0.1 N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]1([CH2:36][CH2:37]O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>>[ClH:1].[CH2:37]([O:24][C:23]([C:18]1([C:20]([O:22][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCCc1ccccc1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCc1ccccc1)(C(=O)OCCc1ccccc1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-phenylethanol accord-ing to the procedure of Example 1 as a colorless oil; 1H NMR (300 MHz, CDCl3): d 1.30-1.45 (brs, 3H), 2.80-2.90 (brm, 1H), 2.89 (t, J=6.9 Hz, 4H), 3.10-3.30 (brm, 2H), 3.39-3.69 (brm, H), 4.40 (t, J=6.8 Hz, 4H), 5.45-5.61 (brs, 2H), 6.70-6.91 (brm, 3H), 7.10-7.35 (complex m, 13H), 7.40-7.51 (brs, 1H), 8.60-8.85 (brs, 1H), 9.91-10.20 (brs, 1H); MS (ES) m/z (relative intensity): 630 (M+ -HCl, 40), 144 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (65) (58 mg, 0.26 mmol) was coupled to ethyl ester (60) (50 mg, 0.26 mmol) using Method C. The crude residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([NH:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[CH3:70]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:71]([CH2:69][CH3:70])[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)ethoxy]-5-chloro-benzoic acid (0.060 g), TBTU (0.096 g) and HOBt (0.030 g) in DMF (1 ml) was added DIPEA (0.052 ml) followed by N-ethylaniline (0.038 ml) after 15 min. The reaction mixture was stirred at room temperature for 66 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.080 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]=1[CH3:17].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]=1[CH2:17][Br:18]
Reactant: Cc1c(Br)cc(Br)nc1-c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: Fc1ccc(-c2nc(Br)cc(Br)c2CBr)c(Cl)c1
Temperature: 0 °C

Procedure:
To a solution of 4,6-dibromo-2-(2-chloro-4-fluorophenyl)-3-methylpyridine (3.55 g, 9.35 mmol, 1 eq) in 1,2-dichloroethane (90 mL) was added N-bromosuccinimide (2.0 g, 11.22 mmol, 1.2 eq) and benzoyl peroxide (226 mg, 0.9 mmol, 0.1 eq). The resulting mixture was degassed with argon then warmed to and maintained at reflux for 5.5 h. The mixture was cooled solvent was removed under reduced pressure, and the material was purified by flash column chromatography eluting with 2% Et2O in hexanes. The material was re-dissolved in CCl4 and N-bromosuccinimide (667 mg) and benzoyl peroxide (75 mg) were added. The mixture was brought to and maintained at reflux for 6.5 h. The mixture was cooled to 0° C., filtered to remove the succinimide, and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel eluting with 2% Et2O in hexanes to give 4,6-dibromo-3-(bromomethyl)-2-(2-chloro-4-fluorophenyl)pyridine. Mass spectrum (ESI) 456.1 (M+1); 458.0 (M+3); 460.1 (M+5); 462.1 (M+7). 1H NMR (500 MHz, CDCl3) δCHCl3: 7.85 (1H, s); 7.46 (1H, dd, J=8.5 Hz, J=5.7 Hz); 7.27 (1H, dd, J=8.5 Hz, J=2.5 Hz); 7.16 (1H, ddd, J=8.5 Hz, J=8.3 Hz, J=2.5 Hz); 4.55 (1H, ½ ABq, J=10.8 Hz); 4.17 (1H, ½ ABq, J=10.8 Hz,
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br>ClCCl>[Br:21][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: BrBr
Solvent: ClCCl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a solution of 9-phenylanthracene (10 grams) and ferric chloride (0.065 gram) in 100 milliliters of dichloromethane were added 6.70 grams of bromine in 30 milliliters of dichloromethane through an addition funnel at room temperature. The reaction mixture was stirred for 3 hours, and then washed with aqueous sodium thiosulfate and water. After removal of the solvents, the crude residue was recrystallized from ethanol to yield 12.5 grams of 10-bromo-9-phenylanthracene. The structure of this compound was confirmed by proton NMR analysis.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][O:6][CH2:7][CH3:8])[CH2:3][OH:4].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[CH3:1][C:2]([CH3:9])([CH2:3][O:4][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:5][O:6][CH2:7][CH3:8]
Reactant: CCOCC(C)(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CCOCC(C)(C)CO[Si](C)(C)C(C)(C)C

Procedure:
According to the procedure as described in Example 3,2,2-dimethyl-1-ethoxy-3-[(tert-butyldimethylsilyl)oxy]propane was prepared from intermediate 2,2-dimethyl-3-ethoxy-1-propanol and reagent tert-butyidimethylsilyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([C:19]([OH:21])=O)[CH2:14][CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([C:19]([N:31]([CH2:30][C:27]3[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=3)[C:32]3[CH:33]=[CH:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=3)=[O:21])[CH2:14][CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCOc2cc(OCc3ccccc3)ccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3cc(OCc4ccccc4)ccc32)cc1
Yield: 106.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-benzyloxychroman-4-carboxylic acid (0.6 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) as starting materials, 7-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (1.2 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc2ccccc2n1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCc2ccc3ccccc3n2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-aminomethyl-quinoline dihydrochloride and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[F:17][C:18]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:19]=1[CH:20]=[C:21](Cl)[C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:17][C:18]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:19]=1[CH:20]=[CH:21][C:22]([NH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:5]=1)[CH3:3])=[O:23]
Reactant: O=C(O)C(Cl)=Cc1cc(F)ccc1F
Reactant: C[C@H](N)c1cccc(Nc2ccncc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1cc(F)ccc1F)c1cccc(Nc2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A mixture of (S)-[3-(1-amino-ethyl)-phenyl]-pyridin-4-yl-amine (0.1 mmol), 2.5-difluoro-chlorocinnamic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.1 mmol), triethylamine (0.3 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography with 5% methnol in ethyl acetate to provide the title compound (31 mg) as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH:21]=[C:7]1[C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1=[O:1])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(=O)CC(=O)C1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1C(=O)CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
To a solution of 122 (12.39 g, 58.11 mmol) in toluene (120 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (11.62 mL, 87.16 mmol) and the reaction was heated to 80° C. for 30 min then at 50° C. for 1 h. The reaction was concentrated to afford 16.5 g (105%) of crude tert-butyl 4-((dimethylamino)methylene)-3,5-dioxopiperidine-1-carboxylate (124) which was used without additional purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:8]1[CH:7]=[C:6]([B:10]([OH:12])[OH:11])[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1)([O-:15])=[O:14]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(B(O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred slurry of m-carboxyphenylboronic acid (5 g, 0.03 mol) in concentrated sulfuric acid (15 ml) was added fuming nitric acid (15 ml, d=1.54). The reaction mixture was stirred at room temperature for 45 minutes and poured on ice (150 g). The nitro acid formed was filtered, washed with water and dried. M.P. 235°-37° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[OH-].[K+].C(Cl)(Cl)=[O:20]>O>[C:11]1([C:7]2[S:6][C:5]3[C:3](=[O:4])[O:2][C:1](=[O:20])[NH:10][C:9]=3[CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(-c3ccccc3)sc2c(=O)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Methyl-3-amino-5-phenylthiophene-2-carboxylate (0.25 g, 1.07 mmol) in water (6 mL) was reacted with potassium hydroxide (0.12 g, 2.14 mmol) at 90° C. for 24 hours. The reaction was cooled to 0° C. and phosgene (1.9M in toluene, 0.70 mL, 1.40 mmol) was added dropwise. After stirring at room temperature for 1 hour, the resulting solid was collected by filtration, washed with excess water and dried to give the title compound as a tan solid (0.175 g, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[C:4]([F:9])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a mixture of 4-bromo-2-fluoroaniline (5.0 g) in concentrated hydrochloric acid (25 mL) was added a mixture of sodium nitrite (1.9 g) in water (2.5 mL) at −20° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was added dropwise to a mixture of tin chloride (19 g) in concentrated hydrochloric acid (25 mL) at −20° C., and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed by filtration, the filtrate was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.4 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([C:10]#[C:9][C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:12]2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(C#CC2CCCNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCCC(C#Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a mixture of 3-(4-Fluoro-phenylethynyl)-piperidine hydrochloride (0.14 g, 0.58 mmol) in THF (2.3 ml, 0.5M) was added DIEA (0.5 ml, 2.92 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (0.139 g-0.87 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (DCM/MeOH:98/2) to afford 0.86 mg (45%) of (4-Fluoro-phenyl)-[3-(4-fluoro-phenylethynyl)-piperidin-1-yl]-methanone as a brown oil. Rf=0.39 (DCM/MeOH:98/2); LCMS (Tr): 4.14 min (Method C); MS (ES+) gave m/z: 326.2;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[S:23][C:24]([CH3:27])=[CH:25][N:26]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=2)[N:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:47]=2N=N1>CO>[CH3:47][O:35][C:34]([C:30]1[CH:29]=[C:28]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]3[S:23][C:24]([CH3:27])=[CH:25][N:26]=3)(=[O:21])=[O:20])[N:6]=2)[CH:33]=[CH:32][N:31]=1)=[O:36]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ncc(C)s2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: COC(=O)c1cc(-c2nc(NS(=O)(=O)c3ncc(C)s3)c(Oc3ccccc3OC)c(OC)n2)ccn1

Procedure:
In analogy to example 22, from 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-thiazole-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 61, by coupling with MeOH and benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) as regent there was obtained 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-thiazole-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl ester as an off-white solid. ISP mass spectrum, m/e 544.2 (M+1 calculated for C23H21N5O7S2: 544).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][NH2:25])=[O:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[C:27](=N)(N)[CH3:28]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:27]([CH3:28])=[N:25][NH:24][C:22]4=[O:23])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3)CC2)cc1
Reactant: CC(=N)N
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc(-n4c(C)n[nH]c4=O)cc3)CC2)cc1
Temperature: 130 °C

Procedure:
A mixture of 53 parts of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide, 53 parts of ethanimidamide hydrochloride and 135 parts of N,N-dimethylformamide is stirred and heated for 3 hours at 130° C. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off, washed with water and with methanol, and crystallized from N,N-dimethylformamide. The product is filtered off and recrystallized from 1,4-dioxane, yielding 19.5 parts of 2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-5-methyl-3H-1,2,4-triazol-3-one; 298.4° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c([N+](=O)[O-])c2)CC1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
A suspension of 350 mg of 2-amino-6-chloro-3-nitropyridine, 744 mg of N-(tert-butoxycarbonyl)piperazine and 552 mg of potassium carbonate in 4 ml of N-methylpyrrolidone was stirred in nitrogen atmosphere for 15 minutes at 160° C. The suspension was cooled to room temperature, to which 10 ml of water was added. Whereupon formed solid was recovered by filtration, washed with hexane and dried to provide 323 mg of the title compound.