Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17][CH3:18])[NH:10][C:9]=2C(O)=O)=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH3:18][S:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CSc1cccc2[nH]c(C(=O)O)c(-c3ccc(Cl)cc3)c12
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: CSc1cccc2[nH]cc(-c3ccc(Cl)cc3)c12
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of 1.4 g of the acid of Step 5 in quinoline (10 mL) was added 100 mg of copper powder. The reaction mixture was heated to reflux and stirred for 2 hours. The copper powder was removed by filtration and 6N HCl was added to the filtrate. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 10% EtOAc in Hexanes to provide 750 mg of the title compound as an orange solid foam.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[O:38][CH3:39]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([OH:29])=[C:31]([O:38][CH3:39])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1O

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-hydroxy-3-methoxy-benzaldehyde. MS (ESI) m/z 515.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[C:13]([NH:12][C:9]1[C:8]([I:16])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]=1[I:11])[C:17]([O:19][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:18])(=[O:14])[CH3:15]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.6 %

Procedure:
Sodium diatrizoate (16.1 g, 25.3 mmol) was dissolved in 180 ml of dry dimethylformamide and to this solution was added, in one portion, ethyl 6-bromohexanoate (4.5 ml, 25.3 mmol). The reaction mixture was stirred for 12 hr at ambient temperature and then poured into 1.6 1 of ice-water with stirring. The resulting white precipitate was collected by filtration, dissolved in 1:1 ethanol-ethyl acetate and the solution was treated sequentially with magnesium sulfate, decolorizing charcoal and then filtered through a short pad of silica gel. The filtrate was concentrated to dryness and dried to give 16 g (84%) of the desired product. Recrystallization from methanol-water gave analytically pure material, mp 235°-238° C. (decomp. at 275° C.); MS:M+ 756. The 1H-NMR (300 MHz) spectral data was consistent with the desired product. Calculated for C19H23I3N2O6 : C 30.18, H 3.07, I 50.35, N 3.70; Found: C 30.26, H 2.88, I 50.40, N 3.65.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[Cl:7][CH2:8][CH2:9][N:10]([N:16]=[O:17])[C:11](N=[N+]=[N-])=[O:12]>N1C=CC=CC=1>[Cl:7][CH2:8][CH2:9][N:10]([N:16]=[O:17])[C:11](=[O:12])[NH:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1
Reactant: Nc1nncs1
Reactant: [N-]=[N+]=NC(=O)N(CCCl)N=O
Solvent: c1ccncc1
Product: O=NN(CCCl)C(=O)Nc1nncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Ten grams of 2-amino-1,3,4-thiadiazole was dissolved in 100 ml of pyridine, and cooled with ice. While stirring the solution, 26.5 g of N-(2-chloroethyl)-N-nitrosocarbamoyl azide was gradually added, and after the addition, the stirring was continued for 60 minutes. The reaction solution was poured into ice water, and the precipitated crystals were washed with water, dried and recrystallized from methanol, to obtain 17.8 g (Yield 75%) of 2-{3-(2-chloroethyl)-3-nitrosoureido}-1,3,4-thiadiazole. The physical properties of this compound were identical with those of the compound obtained by Example 1.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:39]I>O.C(#N)C>[I:39][CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CCI)C1
Reaction time: 18 h
Yield: 69.1 %

Procedure:
A stirred solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (254 mg, 1.26 mmol), Ph3P (381 mg, 1.45 mmol.15), imidazole (129 mg, 1.89 mmol0) and acetonitrile (6.5 mL) at 0° C.; was treated with iodine (368 mg, 1.45 mmol.15). Mixture was allowed to reach 25° C. and stirring continued for 18 h. The reaction mixture was then diluted with water and extracted with hexanes (6×25 mL). The combined organics were dried (MgSO4) and concentrated, then purified by chromatography (40 g column, 50 μm from Analogix, 0-30% EtOAc in hexanes over 15 min to give tert-butyl 3-(2-iodoethyl)azetidine-1-carboxylate (271 mg, 871 μmol, 69.0%) as a colorless oil. 1H NMR (CDCl3) δ: 4.03 (t, J=8.3 Hz, 2H), 3.56 (dd, J=8.7, 5.7 Hz, 2H), 3.10 (t, J=7.0 Hz, 2H), 2.63 (quint, J=7.8, 5.4 Hz, 1H), 2.13 (q, J=7.1 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][C:24]=1[NH:34][CH3:35]>O1CCCC1>[CH2:30]([NH:29][C:27]([C:26]1[CH:32]=[CH:33][C:23]2[N:22]=[CH:35][N:34]([CH3:1])[C:24]=2[CH:25]=1)=[O:28])[CH3:31]
Reactant: CCOC(OCC)OCC
Reactant: CCNC(=O)c1ccc(N)c(NC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc2ncn(C)c2c1

Procedure:
Triethyl orthoformate (4 ml) and p-toluenesulfonic acid (200 mg) were added to a solution of 4-amino-N-ethyl-3-(methylamino)benzamide (1.92 g) in tetrahydrofuran (40 ml), followed by heating to reflux for one hour. The solvent was evaporated under reduced pressure and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was washed with diisopropylether to obtain N-ethyl-1-methyl-1H-benzimidazole-6-carboxamide (1.16 g), as a colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH2:11])([CH3:3])[CH3:2].[Br:12]Br>C(O)(=O)C.C(Cl)Cl>[Br:12][C:8]1[CH:7]=[C:6]([CH3:10])[C:5]([NH2:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: Cc1cccc(C(C)C)c1N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Isopropyl-6-methyl-phenylamine (5 g, 33.5 mmol) was dissolved in acetic acid (20 mL). To this solution was added a solution of bromine (1.8 mL, 35.14 mmol) in acetic acid (5 mL) dropwise over 10 min. After stirring for 1 h at room temperature, the reaction mixture was diluted with methylene chloride, washed with water (2×), saturated sodium thiosulfate (2×), saturated sodium bicarbonate (2×), and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel afforded 7.6 g (quantitative) of the desired product. LC/MS: tR=1.37 min, 230.07 (MH)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[F:28])([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[F:28])([CH3:1])[CH3:3]
Reactant: COC(=O)c1ccc(-c2cc(OC3CCCCO3)ccc2F)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CO)ccc1-c1cc(OC2CCCCO2)ccc1F
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a cooled solution of 35.2 (0.080 g, 0.30 mmol) in THF (3.00 mL) at 0° C., was added LAH (1.0 M solution in THF, 0.60 mL, 0.60 mmol). Stirring was continued for 1 hour. 1N NaOH (5 mL) was carefully added to quench the reaction. The resulting solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-30% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 35.3 as a colorless oil (0.055 g, 54%). MS ESI (pos.) m/e: 739.3 (2M+Na)+, 376.1 (M+H2O)+.
Reaction SMILES: [C:1]([N:4]([C:6]1[N:11]=[C:10]([C:12]([O:14]C)=[O:13])[C:9]([O:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)=[CH:8][CH:7]=1)C)(=O)C.[OH-].[K+].O>CO>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([O:25][CH3:26])[N:18]=[C:17]([O:16][C:9]2[C:10]([C:12]([OH:14])=[O:13])=[N:11][C:6]([NH:4][CH3:1])=[CH:7][CH:8]=2)[N:22]=1
Reactant: COC(=O)c1nc(N(C)C(C)=O)ccc1Oc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1ccc(Oc2nc(OC)cc(OC)n2)c(C(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
195.6 g (0.54 mol) of methyl 6-(N-acetyl-N-methylamino)-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate was dissolved in 1.5 l of methanol. The solution was added to 335 g of a 20% potassium hydroxide aqueous solution, and the mixture was stirred for one hour at 50° C. The reaction solution was concentrated, and 1 l of ice water was added thereto. The mixture was acidified (to about pH4) with an aqueous citric acid solution and left to cool. Precipitated crystals were collected by filtration and washed with cool water and diisopropyl ether. Then, the crystals were dissolved in 1 l of methanol, and 45.6 g (0.69 mol) of potassium hydroxide and 50 ml of water were added thereto. The mixture was stirred at room temperature for 28 hours. The reaction solution was concentrated, and ice water was added thereto. The mixture was acidified with an aqueous citric acid solution to obtain crude crystals. The crystals were washed with diisopropyl ether and then dried under reduced pressure at 90° C. for 24 hours to obtain 112 g (yield: 68%) of the desired product as a white powder.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>C(O)(=O)C>[Br:18][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]([F:16])([F:17])[F:15]
Reactant: O=c1cc(C(F)(F)F)nc(-c2ccccc2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)nc(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 1.0 g (3.94 mmol) of 2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone and 20 mL of glacial acetic acid was added 1.0 g (5.6 mmol) N-bromosuccinimide and the mixture was left to stir at room temperature for 16 h. The reaction was poured onto ice water and vacuum filtered, washing well with water. The crude product was recrystallized from ethyl acetate to yield 1.05 g (83.5%) of 5-bromo-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO) δ7.6 (3H, m); 8.15 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH3:34])=[C:16]([CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:35][C:36]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH3:34])=[C:16]([CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH:35]=[CH2:36])[C:3]=12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1nn(C(C)c2cc(Cl)c(F)c(C3CN(C(=O)OC(C)(C)C)C3)c2OC)c2ncnc(N)c12
Temperature: 100 °C
Yield: 74.3 %

Procedure:
To a solution of tert-butyl 3-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (0.55 g, 0.91 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.281 g, 1.82 mmol), sodium carbonate (0.580 g, 5.47 mmol) in N,N-dimethylformamide (5 mL)/water (2.73 mL) under N2 was added tetrakis(triphenylphosphine)-palladium(0) (0.105 g, 0.0910 mmol). The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with water, and extracted with EtOAc. The combined organic layers were concentrated and purified on silica gel (eluting with 0 to 100% EtOAc in hexanes followed by 0 to 10% MeOH in dichloromethane) to give the desired product (0.34 g, 74%). LCMS calculated for C24H29ClFN6O3 (M+H)+: m/z=503.2; Found: 503.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: CN
Reactant: Cc1cccc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Solvent: CCO
Product: CNc1cc2ncnc(Nc3cccc(C)c3)c2cc1[N+](=O)[O-]

Procedure:
After repetition of the previous steps, a mixture of 7-chloro-4-(3'-methylanilino)-6-nitroquinazoline (10.5 g), an ethanolic solution of methylamine (30% weight/volume; 100 ml) and ethanol (100 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated to give 7-methylamino-4-(3'-methylanilino)-6-nitroquinazoline which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[CH2:15][OH:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[C:15]([OH:20])=[O:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCc1cc(=O)c2cc(C(C)CO)ccc2o1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cc(=O)c2cc(C(C)C(=O)O)ccc2o1

Procedure:
2-(2-Ethyl-4-oxo-4H-1-benzopyran-6-yl)propan-1-ol (3.0 g; 0.0129 mol) was dissolved in acetone (20 ml) and Jones Reagent (Example 2) was slowly added until the solution attained a permanent brown colour. Water (100 ml) was added and the mixture was extracted with chloroform (4×70 ml). The combined chloroform phases were extracted with saturated sodium bicarbonate solution (4×30 ml). The aqueous phases were combined, washed with chloroform (100 ml) and then acidified with concentrated hydrochloric acid. The precipitated product was extracted with chloroform (3×100 ml) and the combined extracts dried over magnesium sulphate. After removing solvent, the product was recrystallised from benzene/hexane (1;1) to yield a pale yellow amorphous solid (1.4 g) mp 128°-128.5°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:23]1[CH2:26][CH:25](O)[CH2:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH:25]3[CH2:26][O:23][CH2:24]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OC1COC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2C1COC1
Temperature: 85 °C
Yield: 39.6 %

Procedure:
A solution of 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (50 mg, 0.16 mmol) in dioxane (0.5 mL) was treated with oxetan-3-ol (24 mg, 0.32 mmol), triphenylphosphine (84 mg, 0.32 mmol) and diethyl azodicarboxylate (DEAD, 56 mg, 0.32 mmol) and heated in the microwave at 85° C. for 30 min. The crude mixture evaporated down under reduced pressure and purified by preparative HPLC, and subsequently by column chromatography (silica gel, gradient 0 to 15% diethyl ether/CH2Cl2) to give 23 mg of Compound 93 as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[CH:6]=1)C.[OH-].[K+].Cl>C(O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:22])=[O:3])(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2cccc(Cl)c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(NS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 3-(3-chloro-benzenesulfonylamino)-benzoic acid ethyl ester (4.03 g, 12.0 mmol) in ethanol (20.0 ml) was treated with 3N KOH (12.0 ml) and stirred at room temperature overnight. The mixture was then acidified with 3N HCl and the resulting slurry cooled to 0° C. The precipitated solid was filtered, washing with ethanol and dried under vacuum, yielding 3-(3-chloro-benzenesulfonylamino)-benzoic acid (2.61 g, 70%) as an off-white solid, MS (ISP): m/e=310.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]([N:9]([CH3:24])[C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH3:27][NH:28][CH2:29][CH2:30][CH3:31]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7](=[O:8])[N:9]([CH3:24])[C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][N:28]([CH3:27])[CH2:29][CH2:30][CH3:31])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCCNC
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Solvent: CC(=O)N(C)C
Product: CCCN(C)CC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 235 mg (corresponds to 0.5 mmol) of trans-Methanesulfonic acid 3-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester in 2.5 ml of DMA was cooled at 0° C., treated with 0.76 ml (1 mmol) of N-methylpropylamine and stirred over night at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 98:2) gave 153 mg (81%) of pure trans-Methyl-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexyl}-carbamic acid 4-chloro-phenyl ester, MS: 377 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].Cl[CH2:11][CH2:12][C:13](Cl)=[O:14].[Al+3].[Cl-].[Cl-].[Cl-].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:11][CH2:12][C:13]2=[O:14])=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Cl
Reactant: O=C(Cl)CCCl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)C(=O)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-2-methoxybenzene (12.8 mL, 100 mmol) and 3-chloropropanoyl chloride (10.5 mL, 110 mmol) in CH2Cl2 (100 mL) at 0° C. was added AlCl3 (14.6 g, 110 mmol) portionwise during about 1 minute. After 30 minutes, sulfuric acid (300 mL) was poured slowly into the reaction mixture during about 3 minutes. The CH2Cl2 was removed by rotary evaporation under reduced pressure and the viscous residue was stirred at 100° C. for 2 hours. After cooling to −50° C., the viscous reaction mixture was poured cautiously onto 1.5 L of ice and allowed to stand overnight. The mixture was filtered and the cake of crude product was washed with water. The crude product was dissolved in 500 mL of 2% MeOH in CH2Cl2, dried over a mixture of Na2CO3 (˜10 g) and Na2SO4 (˜20 g), filtered and concentrated under vacuum to give 6-chloro-5-methoxyindan-1-one as an off-white solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-:20])[O-:19].[K+].[K+].[C]=O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)([OH:20])=[O:19]
Reactant: CCOC(=O)C1=Cc2cccc(I)c2OCC1
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Yield: 88.7 %

Procedure:
To a mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (5.62 g), potassium carbonate (9.03 g), and palladium(II) acetate (0.73 g) in aqueous N,N-dimethylformamide (48 ml, 67% v/v) was introduced carbon monoxide for 30 minutes. The reaction mixture was stirred for 2 days at ambient temperature in an atmosphere of carbon monoxide and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1H hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium thiosulfate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a solid of ethyl 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (3.8 g).