Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2([CH3:21])[O:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][O:12]2)[CH:5]=[CH:4][N+:3]=1[O-].C(N(CC)CC)C.C(OC(=O)C)(=[O:32])C>>[CH3:8][C:7]1[C:2]([CH2:1][OH:32])=[N:3][CH:4]=[CH:5][C:6]=1[O:9][CH2:10][C:11]1([CH3:21])[O:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][O:12]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CO
Temperature: 50 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
The 2,3-dimethyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methoxy)pyridine 1-oxide (1.20 g, 3.84 mmol) obtained in the step (5d) was mixed with acetic anhydride (10 ml). To the mixture, triethylamine (0.8 ml, 5.74 mmol) was added and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated and methanol (10 ml) was added to the residue. Thereafter a 5N aqueous sodium hydroxide solution (7 ml) was added to the mixture, and stirred at room temperature for 30 minutes. To the resultant mixture, a saturated aqueous ammonium chloride solution (7 ml) was added and the pH was adjusted to about 10. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a 2N aqueous sodium hydroxide solution, water, and a saline solution, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol=1/0-4/1 gradient) and a desired fraction(s) was concentrated to obtain the title compound (312 mg, 26.1% yield) as a light yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([CH3:39])[CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(c2nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c(-c3nc4ccccc4s3)c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Into a solution of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-(piperidin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.20 mmol, 1.00 equiv) and formaldehyde (30% in water, 22 mg, 0.73 mmol, 3.74 equiv) in dichloromethane (5 ml) was added sodium triacetoxyborohydride (62.3 mg, 0.29 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature, quenched with water (5 mL), and extracted with ethyl acetate (2×5 mL). The combined organic phases were washed with brine (10 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under vacuum, 100 mg of the title compound was obtained as a solid, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 525.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:5].C(O)(=O)C.[N:16]1([CH2:23][C:24]2[S:25][C:26]([C:29]([NH:31][NH2:32])=O)=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[NH:32][N:31]=[C:29]([C:26]2[S:25][C:24]([CH2:23][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:28][CH:27]=2)[N:5]=1
Reactant: N#Cc1ccccn1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(-c2nc(-c3ccc(CN4CCCCCC4)s3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.7 %

Procedure:
81 mg (1.5 mmol) of sodium methoxide was added to 13.5 ml of methanol solution containing 1.56 g (15.0 mmol) of 2-cyanopyridine and stirred at room temperature for 3.5 hours. The reaction mixture was ice-cooled, 0.085 ml (1.5 mmol) of acetic acid and 1.52 g (6.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide were added with ice-cooling, and then the mixture was stirred at room temperature for 24 hours. The thus precipitated crystals were collected by filtration to give 1.97 g of the crystals. A 894 mg (2.5 mmol) portion of them was dissolved in 13 ml of acetic acid and heated under reflux for 6.5 hours. The solvent was evaporated, 28% aqueous ammonia and chloroform were added, and then the thus separated organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 715 mg of the title compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Br[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([F:28])[CH:22]=1.C1(C)C=CC=CC=1>C(O)C>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([F:28])[CH:22]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Br)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 92.1 %

Procedure:
To a vigorously stirred solution of 4.27 g (16.6 mmol) of 2-(N-t-butylsulfamoyl)phenylboronic acid (from Step D), 32 mmol (26 mL of a 1.25N aqueous solution) of NaOH in 40 mL of ethanol was added 1.89 g (10 mmol, 1.27 mL) of 4-bromo-2-fluorotoluene, 60 mL of toluene, and 289 mg (0.25 mmol) of tetrakis(tfiphenylphosphine)palladium. The mixture was stirred at 90° C. for 4.5 h, cooled to room temperature, and the volatiles were removed in vacuo. The residue was extracted with ethyl acetate (3×) and the combined organic layers were washed with water, brine, and dried (Na2SO4). The crude product obtained after filtration and removal of solvents was flash chromatographed over silica gel (elution with hexane-EtOAc) to afford 2.96 g (92%) of the desired product cleanly (TLC in 4:1 hexane-EtOAc) as an off-white foam; mass spectrum (FAB) m/e 322 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[C:10]([CH3:24])([CH3:23])[C@H:11]([NH:15]C(OC(C)(C)C)=O)[C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[NH2:15][C@H:11]([C:12]1[NH:36][C:33]2[CH:34]=[CH:35][C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:31][C:32]=2[N:37]=1)[C:10]([CH3:23])([CH3:24])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C(=O)OCc1ccccc1
Product: CC(C)(C)c1ccc2[nH]c([C@@H](N)C(C)(C)C(=O)OCc3ccccc3)nc2c1

Procedure:
The title compound was prepared according to Method 1 Steps 1 and 2 using (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethyl-4-oxobutanoic acid (Preparation 44) and 4-tert-butyl-1,2-diaminobenzene.
Reaction SMILES: O1CCOC1[N:6]1[N:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[N:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[NH:7]1.[C:23](=O)(O)[O-:24].[Na+]>O1CCCC1.Cl.[Cl-].[Na+].O>[CH3:14][S:11]([C:9]1[N:8]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[C:19]([CH:20]=2)[CH:23]=[O:24])[N:7]=[N:6][N:10]=1)(=[O:12])=[O:13]
Reactant: COc1ccc(N2NN(C3OCCO3)N=C2S(C)(=O)=O)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C=O

Procedure:
1-(3-[1,3]Dioxolan-2-yl(4-methoxy-phenyl)-5-methanesulfonyl-1H-tetrazole (800 mg) in tetrahydrofuran (13 ml) and hydrochloric acid (2N, 7.5 ml) was stirred at room temperature for 1.5 h. The solution was basified with sodium bicarbonate solution (8%), saturated with brine (50 ml), extracted with ether (3×50 ml), dried (Na2SO4) and evaporated to give the title compound as an orange solid (307 mg).
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.[O:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)[CH2:19][CH2:18]1.C(N1CCCC1=O)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: c1c[nH]c(C2CCOCC2)n1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN1CCCC1=O
Product: COC(=O)c1cc([N+](=O)[O-])c(-n2ccnc2C2CCOCC2)cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a mixture of 3 g of methyl 4-fluoro-2-methoxy-5-nitrobenzoate, 1.99 g of 2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole, and 15 mL of N-ethylpyrrolidone was added 3.6 g of potassium carbonate, followed by stirring at 100° C. for 3 hours. To the reaction mixture were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 4.12 g of methyl 2-methoxy-5-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-benzoate.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:35][C@@H:34]([OH:36])[C:33]([CH3:38])([CH3:37])[CH2:32]3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:35][C@@H:34]([OH:36])[C:33]([CH3:37])([CH3:38])[CH2:32]3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2C[C@@H](O)C(C)(C)C2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2C[C@@H](O)C(C)(C)C2)n1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1606 g, 0.296 mmol) in MeOH (5 mL) was added 10% Pd/C (50% water, 48 mg). The mixture was hydrogenated under balloon pressure for 1 h, and was then filtered. The solution was concentrated in vacuo and the residue was crystallized from EtOAc-hexanes to afford [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (0.1205 g, 90% yield) as a light pink solid. LCMS: (M+H)+: 453.3.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)(=O)C.Cl>CO.O1CCCC1.[OH-].[Li+]>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:14]#[N:15]
Reactant: CC(=O)OCCOc1cccc(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(OCCO)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-(3-Cyanophenoxy)ethyl acetate (3.01 g, 14.7 mmol) obtained in Step 1 was dissolved in a mixed solvent of methanol and tetrahydrofuran (1:1), and 2N lithium hydroxide solution (14.7 ml) was added under ice-cooling. The mixture was stirred at room temperature for 45 min, 3N hydrochloric acid (10 ml) was added under ice-cooling, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate 85:15-55:45) to give the title compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[CH:17]([OH:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:17]([O:30][C:10](=[O:11])[O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: OC(c1ccccc1)c1ccccc1
Product: O=C(OC(c1ccccc1)c1ccccc1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with benzhydrol.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:16]2[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COC(=O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of methyl 4-iodobenzoate, 9.38 g (35.8 mmol), 4-bromophenylboronic acid 7.18 g (35.8 mmol), Pd(PPh3)4, 2.07 g (1.79 mmol), in 180 mL of toluene and 100 mL of ethanol was heated to obtain a clear solution. To the solution was added 30 mL of 4.0M aq. Na2CO3. The reaction mixture refluxed for 4 h at 80° C. The mixture was cooled to room temperature and diluted with 300 mL ethyl acetate. The organic layer was washed with 2×300 mL portions of water, 2×300 mL portions of sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified by column chromatography (eluted with 7% EtOAc-Heptane) to afford the desired product in 7.8 g (78%) as a white solid. 1H NMR (CDCl3) 8.10 (d, 2H, J=9.0 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.59 (d, 2H, J=9.3 Hz), 7.48 (d, 2H, J=9.3 Hz), 3.95 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=[C:9]([O:19][CH3:20])[C:5]=1[C:6]([NH2:8])=[O:7])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>O1CCCC1.C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:8][C:6](=[O:7])[C:5]2[C:9]([O:19][CH3:20])=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:12][C:4]=2[CH:1]([CH3:3])[CH3:2])=[CH:26][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1cc(N2CCOCC2)cc(C(C)C)c1C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1cc(N2CCOCC2)cc(C(C)C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 90 °C
Yield: 40.9 %

Procedure:
To a stirred solution of 2-isopropyl-6-methoxy-4-morpholin-4-yl-benzamide (0.31 g, 1.1 mmol) in tetrahydrofuran/benzene (1:2) (10 ml) is added tetrabutylammonium hydrogen sulfate (38.0 mg, 0.10 mmol) followed by the addition of 30% aqueous sodium hydroxide (10 ml) at room temperature. A solution of 4-chloro-benzyl bromide (0.23 g, 1.1 mmol) in tetrahydrofuran (4 ml) is slowly added to the solution and the resulting mixture is heated to 90° C. for 45 min. The mixture is cooled to room temperature and extracted with ethyl acetate (3×10 ml). The combined organic layers are washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to get crude product, which is purified by flash column chromatography (silica gel, 10% acetone/hexane) to yield N-[(4-chlorophenyl)-methyl]-2-isopropyl-6-methoxy-4-morpholin-4-yl-benzamide (example 40) (0.115 g, 0.45 mmol, 28%). [M+H]+ 403.2.
Reaction SMILES: [CH:1](=[C:8]([C:13]([O:15]C)=O)[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:27])[CH:21]=[C:22]([NH2:26])[CH2:23][CH2:24][CH3:25])[CH3:18].[O-]CC.[Na+]>>[CH2:17]([O:19][C:20]([C:21]1[CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13](=[O:15])[NH:26][C:22]=1[CH2:23][CH2:24][CH3:25])=[O:27])[CH3:18]
Reactant: COC(=O)C(=Cc1ccccc1)C(=O)OC
Reactant: CCCC(N)=CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2)C(C(=O)OC)C(=O)N1

Procedure:
26.2 g (0.128 mol) of dimethyl benzylidenemalonate and 20.1 g (0.128 mol) of ethyl-3-amino-hex-2-en-oate are stirred at 140° C. for 3 days with a spatula tip full of sodium ethoxide. The mixture is chromatographed on silica gel using methylene chloride and crystallised from petroleum ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)=[CH:13][CH:12]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: Fc1ccc(I)cc1
Product: Fc1ccc(-n2ccc3cnccc32)cc1

Procedure:
The title compound was prepared from 5-azaindole (1.00 g, 8.47 mmol) and 1-fluoro-4-iodobenzene analogously as described in example 1, step 1. Yield: 1.23 g.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][N:42]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[Cl:28])[N:4]=3)[CH2:41]2)[N:32]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(N4CCCC(Nc5ccc(C#N)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.17 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidine hydrochloride (Example 52A), 56.3 mg (0.2 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 20A) and 0.17 ml (0.99 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 47 mg (44% of theory) of the product as a solid.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].[CH2:17]([C:21]1[CH:32]=[CH:31][C:24]([CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1)[CH2:18][C:19]#[CH:20].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[N:9][C:2]([C:20]#[C:19][CH2:18][CH2:17][C:21]3[CH:32]=[CH:31][C:24]([CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:23][CH:22]=3)=[C:3]([CH:6]=2)[C:4]#[N:5])=[CH:11][CH:12]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)cnc1Cl
Reactant: C#CCCc1ccc(CN2CCCC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(-c2ccc(Cl)cc2)cnc1C#CCCc1ccc(CN2CCCC2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Under an argon atmosphere 1.9 mg (0.1 mmol) CuI and 7 mg (0.1 mmol) Pd(PPh3)2Cl2 are added to a solution of 50 mg (0.2 mmol) 2-chloro-5-(4-chloro-phenyl)-nicotinonitrile and 43 mg (0.2 mmol) 1-(4-but-3-ynyl-benzyl)-pyrrolidine in 2 mL DMF and 5 mL (20 mmol) triethylamine and the reaction mixture is stirred for 18 h at 50° C. The mixture is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is is purified by HPLC.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH:15]1[NH:19][CH2:18][CH2:17][S:16]1>ClCCCl.C(N(CC)CC)C>[Cl:1][CH2:2][C:3]([N:19]1[CH2:18][CH2:17][S:16][CH:15]1[CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][C:3](=[O:4])[CH2:2][Cl:1])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Oc1ccccc1CCC1NCCS1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Oc1ccccc1CCC1SCCN1C(=O)CCl
Temperature: -10 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
α-Chloroacetylchloride (13.4 g, 9.5 ml) is added, with exclusion of humidity, under stirring, in 30 minutes, to a solution of the above thiazolidine (12 g) in 1,2-dichloroethane (120 ml) and triethylamine (18 ml), cooled at -10° C. Stirring is continued for 1 hour at 0° C. and the mixture is partitioned with water. The organic phase is separated, washed with water, dried on CaCl2 and the solvents are evaporated to dryness in vacuum. Crystallization from Et2O gives 3-α-chloroacetyl-2-[2'-(o-α-chloroacetoxy-phenyl)ethyl]thiazolidine (12 g), m.p. 88°-89° C. (hexane/AcOEt 7:3, Rf =0.5). A solution of this compound (6 g) in acetone (30 ml) is treated with potassium thioacetate (4.1 g) under stirring for 30 minutes. The mixture is filtered from the inorganic materials, the acetone is evaporated under vacuum and the residue is partitioned between water and EtOAc. From the organic phase after the usual work-up it is obtained 3-acetylthioacetyl-2-[2'-(o-acetylthioacetoxyphenyl)ethyl]thiazolidine as a colourless oil (hexane/AcOEt 7:3, Rf =0.4).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][O:5]1)#[N:2].C(O)C>[Pd].C(O)(=O)C>[NH2:2][CH2:1][CH2:3][CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][O:5]1
Reactant: N#CCC1C=CC=CO1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: NCCC1C=CC=CO1

Procedure:
A mixture of rac 2-cyanomethylpyran (4.2 g) and 10% Pd/C (4.0 g) in 1:1 ethanol:acetic acid (150 ml) was hydrogenated at 55 psi overnight. The reaction mixture was filtered through Celite and the solvents were then removed in vacuo. The residue was partitioned between chloroform and 10% sodium carbonate solution. The organic phase was dried over sodium sulfate. Removal of the solvent gave the title compound:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13]O)[CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>C(Cl)Cl>[Cl:35][CH2:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:12][N:11]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(-c2ccc(F)cc2)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2cc(CCl)no2)cc1
Temperature: 65 °C

Procedure:
To a solution of [5-(4-fluorophenyl)-3-isoxazolyl]methanol (0.2 g, 1.04 mmol) in 5 mL of CCl4 and 0.5 mL of CH2Cl2 was added Ps-triphenylphosphine (3 mmol/g, 0.69 g, 2.08 mmol), and the mixture was heated at 65° C. for 3 h. Upon cooling, the resin was filtered off and washed with CH2Cl2 and EtOAc. The filtrate was concentrated to dryness to afford the title compound as a light brown solid, which was used in the next reaction without further purification: 1H NMR (400 MHz, CDCl3) δ 7.75 (t, J=6.6 Hz, 2H), 7.14 (t, J=8.3 Hz, 2H), 6.55 (s, 1H), 4.6 (s, 2H).