Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cccc(-c2csc(Br)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(Cl)c3)cs2)CC1
Yield: 58.9 %

Procedure:
A solution of 2-bromo-4-(3-chlorophenyl)-1,3-thiazole (6.36 g, 23.2 mmol), tert-butyl piperazine-1-carboxylate (6.47 g, 34.7 mmol) and potassium carbonate (3.20 g, 23.2 mmol) in dimethylformamide (80 ml) was stirred at 120° C. for 14 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 5.19 g (59.0%) of the desired product as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:51][CH3:52]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][O:46][CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:51][CH3:52])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCOCC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 65.6 %

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0451 g (0.18 mmole) of 4-amino-3-methoxy-N-(tetrahydro-2H-pyran-4-yl) benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give 0.0643 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-252) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:6]1[CH:7]=[C:3]([CH3:2])[N:4]=[N:5]1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1cn(CC(=O)O)nn1
Agent: Cl
Product: Cc1cn(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)nn1
Yield: 18 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-methyl-1,2,3-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 153, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-methyl-1H-1,2,3-triazol-1-yl)acetamido)propanamide (13 mg, 18%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.24 (br s, 1H), 8.84-8.82 (d, 1H), 7.76 (s, 2H), 7.63-7.59 (d, 2H), 7.32-7.27 (m, 5H), 7.23-7.19 (t, 2H), 7.04-6.98 (m, 4H), 5.15 (s, 1H), 4.75-4.70 (m, 1H), 4.54 (s, 2H), 3.70-3.68 (d, 2H), 2.23 (s, 3H). MS (EI) for C27H26FN5O4. found 504.0 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([C:15]=1Cl)=CN=CC=2)=[O:5])C.[Cl:18]C1C=CN=CC=1.C(O)(=O)C1C=CC=NC=1.[Li+].CC([N-]C(C)C)C>>[Cl:18][C:7]1[N:8]=[CH:9][CH:14]=[CH:15][C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1c(Cl)c2cnccc2[nH]c1=O
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)c1cccnc1
Agent: [Li+]
Product: O=C(O)c1cccnc1Cl

Procedure:
Alternatively, the intermediate 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester, depicted by formula 37 in Scheme 15 can be prepared from 4-chloro pyridine or nicotinic acid as shown in Scheme 16. Ortholithiation of 4-chloropyridine by LDA followed by quenching with dry ice or lithiation of nicotinic acid followed by quenching with hexachloroethane can give chloronicotinic acid intermediate, depicted by formula 39 in Scheme 16. Amination of this intermediate can give 3-(4-methoxy-benzylamino)-nicotinic acid, depicted by formula 40 in Scheme 16, which was converted to 1-(4-methoxy-benzyl)-1H-pyrido[4,3-d][1,3]oxazine-2,4-dione depicted by formula 41 in Scheme 16, by treating with trichloromethyl chloroformate. This intermediate can be converted into 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester, depicted by formula 37 in Scheme 15, as shown in Scheme 16.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][NH:29]1>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([N:29]2[CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28]2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Reactant: c1ccc2c(c1)CNC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1cc(Br)c2cccnc2c1O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-8-hydroxyquinoline-7-carboxylic acid of Preparation 4 (150 mg, 0.56 mmol) and di(1H-imidazol-1-yl)methanone (90.7 mg, 0.56 mmol) in THF (10 mL) was heated to reflux for 3 h, under nitrogen. The reaction mixture was allowed to cool to RT and isoindoline (53 mg, 0.45 mmol) was added. The resulting mixture was stirred at RT overnight. The reaction mixture was then quenched with H2O and an aqueous saturated solution of sodium hydrogen carbonate, and twice extracted with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by SPE-SI cartridge (2 g, DCM to DCM:MeOH 99:1) affording the title compound (39.1 mg, 0.11 mmol) as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:36]([O:38][C:39](Cl)=[O:40])[CH3:37]>C1COCC1>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:39]([O:38][CH2:36][CH3:37])=[O:40])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(CN)cc3)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
To 1.0 g (2.19 mmol) of {4-[3-(4-aminomethyl-phenoxy)-5-hydroxy-benzoyl-amino]-cyclohexyl}-carbamic acid tert-butyl ester, dissolved in 5 ml of THF, 0.13 g (5.47 mmol) of sodium hydride was added at 0° C. and the mixture was stirred for 15 min at same temperature. 0.26 g (2.40 mmol) of ethylchloroformate, dissolved in 2 ml of THF, was added dropwise to the stirred solution during 10 min and then the reaction mixture was stirred at RT for 6 h. After reaction completion, solvent was removed under reduced pressure and the obtained residue was dissolved in 200 ml of ethyl acetate. Organic layer was washed with (3×100 ml) of brine followed by water (2×100 ml). Organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 0.56 g of required product which was used for the next step witout further purification. Percentage purity (LCMS): 59.7%, (M+1)=527.2+1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12.Cl.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1.[OH-].[Na+]>CCO.CC#N>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=4)[N:30]=3)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12
Reactant: N=C(N)Nc1ccc(O)cc1
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2ccnc(Cl)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: CCn1cc(-c2ccnc(Nc3ccc(O)cc3)n2)c2ccnc(Cl)c21
Temperature: 150 °C

Procedure:
A mixture of (E)-1-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (0.5 mmol), 1-(4-hydroxyphenyl)guanidine hydrochloride (0.5 mmol) and NaOH (2 mmol) in a mixture of EtOH-MeCN (1:2, v/v, 3 mL) was heated in a microwave at 150° C. for 25 minutes. The residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to yield 4-(4-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-ylamino)phenol as white solid. 1H-NMR (DMSO-d6) δ: 1.43 (m, 3H, CH3), 4.49 (m, 2H, CH2), 6.74 (m, 2H, Ph-H), 7.11 (d, 1T-F=5.6 Hz, Pyrimidin-H), 7.52 (m, 2H, Ph-H), 7.74 (d, 1H, J=5.6 Hz, Ar—H), 8.10 (d, 1H, J=5.2 Hz, Ar—H), 8.29 (d, 1H J=5.6 Hz, Pyrimidin-H), 8.37 (s, 1H, Ar—H), 9.04 (s, 1H, OH), 9.09 (s, 1H, NH). MS (ESI+) m/z 362.1609 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH2:3][N:4]1C(=O)C2=CC=CC=C2C1=O.CO.O.NN>C(Cl)(Cl)Cl>[CH3:15][C:2]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(CN1C(=O)c2ccccc2C1=O)c1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)(CN)c1ccc([N+](=O)[O-])cc1
Yield: 78 %

Procedure:
To a mixture of the compound (152 mg) obtained in Example 179, methanol (10 ml) and chloroform (10 ml), hydrazine monohydrate (0.05 ml) was added and heated under reflux for 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; following addition of 2 N HCl, the mixture was washed with ethyl acetate. Then, the aqueous layer was made alkaline with a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 71 mg of the titled compound (yield, 78%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:18][O:19][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1>CN(C=O)C>[CH3:15][N:14]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:32]3[CH:36]=[CH:35][CH:34]=[CH:33]3)=[CH:8][CH:7]=2)=[CH:10][C:11]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[C:13]1=[O:16]
Reactant: Cn1c(-c2ccc(CBr)cc2)cc2onc(-c3ccccc3)c2c1=O
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(Cn3cccc3)cc2)cc2onc(-c3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.8 %

Procedure:
To a solution of 198 mg (0.5 mmol) of 6-(4-bromomethyl-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one in 2.5 ml of DMF is added 326 mg (1.0 mmol, 2.0 eq.) of caesium carbonate and 0.05 ml (0.6 mmol, 1.2 eq.) of pyrrole. After stirring 16 h at room temperature the solvent is removed in vacuo and the residue taken up in CH2Cl2. The organic phase is washed with NaHCO3-solution, dried over Na2SO4 and concentrated. Flash chromatography yields 34 mg (18%) of the desired compound as a white solid. Mass spectrum: m/z (M+H)+: 382.1
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].[Na+].[Cl-]>O.C(OCC)(=O)C.CN(C)C=O>[NH:18]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:10][CH:11]=2)=[N:17][N:20]=[N:19]1
Reactant: N#CCc1ccc(OCC2CCCCC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: c1cc(OCC2CCCCC2)ccc1Cc1nnn[nH]1
Temperature: 135 °C
Yield: 59 %

Procedure:
A mixture of 4-(cyclohexylmethoxy)phenylacetonitrile (15 g, prepared in the preceding paragraph), sodium azide (21.3 g), ammonium chloride (17.4 g) and dimethylformamide (325 mL) was heated to 135° C. under a nitrogen atmosphere for 40 hours. The mixture was then cooled to room temperature and enough water was added to dissolve all the salts. The homogeneous solution was then poured into a separatory funnel containing saturated aqueous NaCl and ethyl acetate. After extraction of the aqueous phase with additional ethyl acetate, the combined extracts were washed with saturated brine solution, dried over MgSO4 and concentrated. The dark amber oil so obtained was treated with a little water and the resulting solid filtered off and crystallized from dichloromethane-diethyl ether mixture to afford 10.5 g (59% yield) of the title compound; m.p. 156°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:3]=1.[C:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C@@H:19]([CH3:21])O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:19]([CH3:21])[C:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:4]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:3]=1
Reactant: CC1(C)OB(c2cc(Cl)ccc2O)OC1(C)C
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Product: C[C@H](Oc1ccc(Cl)cc1B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared by the method of Example 2 step a) using the product from step e) and tert-butyl (R)-(+) lactate.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=O)=[CH:9][CH:8]=2)[C:3]=1[C:16]#[N:17].[OH2:18].[CH:19]([NH2:21])=O>>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]2[C:3]3[C:2](=[N:1][CH:19]=[N:21][C:16]=3[NH2:17])[S:6][N:5]=2)=[CH:12][CH:11]=1)([O-:15])=[O:18]
Reactant: O
Reactant: NC=O
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1N
Product: Nc1ncnc2snc(-c3ccc([N+](=O)[O-])cc3)c12
Yield: 84 %

Procedure:
A mixture of Example 96E (200 mg) in formamide (5 mL) in a capped vial was heated to 210° C. in a Smith microwave oven at 300W for 25 minutes, poured into water, and filtered. The filter cake was dried to provide 2.02 g (84% yield) of the desired product. MS(ESI(+)) m/e 274 (M+H)+.
Reaction SMILES: [C:1](OC(N1CCN(CC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2)CC1)=O)(C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:47][CH:46]=2)[CH2:38][N:39]2[CH2:44][CH2:43]N[CH2:41][CH2:40]2)=[CH:33][CH:32]=1.C(N1CCNCC1)(OC(C)(C)C)=O>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:47][CH:46]=2)[CH2:38][N:39]2[CH2:40][CH2:41][CH2:1][CH2:43][CH2:44]2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Reactant: Clc1ccc(C(CN2CCNCC2)c2ccc(-c3cn[nH]c3)cc2)cc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Clc1ccc(C(CN2CCCCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedure described in Example 33A, 33B and 33D but substituting piperidine for N-BOC-piperazine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.21 [M+H]+ 366.09. 1H NMR (Me-d3-OD) δ 1.44 (2H, m), 1.53 (4H, m), 2.39-2.57 (4H, m), 2.94-3.09 (2H, m), 4.26 (1H, t), 7.22-7.35 (6H, m), 7.50 (2H, d), 7.91 (2H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[CH:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CCCCCCC.C(Cl)Cl>[C:24]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1)#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Reactant: C#CCCCCC
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCCCC#Cc1cc(-c2ccccc2)nn1C

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (120 mg, 95%); 1H NMR δ (CDCl3): 7.78 (d, J=8.20 Hz, 2H), 7.42-7.33 (t, J=8.05 Hz, 2H), 7.32 (m, 1H), 6.62 (s, 1H), 3.93 (s, 3H), 2.48 (t, J=7.25 Hz, 2H), 1.65 (p, J=7.18 Hz, 2H), 1.5-1.32 (m, 4H), 0.94 (t, J=7.22 Hz, 3H); LCMS m/z: 252.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][CH:22](O)[CH3:23])=[CH:15][C:14]=1[N+:25]([O-:27])=[O:26].[CH2:28]([N:30](CC)CC)C>ClCCl>[CH3:28][NH:30][CH:22]([CH2:21]/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([CH3:12])=[C:14]([N+:25]([O-:27])=[O:26])[CH:15]=1)[CH3:23]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(/C=C/CC(C)O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNC(C)C/C=C/c1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
p-Toluenesulfonyl chloride (1.91 g, 10.0 mmol) was added, in one portion, to a stirred solution of (4E)-5-(4-methyl-3-nitropheny)-4-penten-2-ol (1.70 g, 7.69 mmol) in triethylamine (5 mL) and dichloromethane (10 mL) at 10° C. under nitrogen. The cooling bath was removed, and the mixture was stirred at 25° C. for 16 h. Saturated aqueous NaHCO3 (10 mL) was then added and the biphasic mixture was vigorously stirred for 2 h. The layers were separated and the aqueous layer was extracted once with dichloromethane (10 mL). The combined organic layers were dried (Na2SO4) and evaporated, and the residue was combined with DMF (7 mL) and 40% aqueous methylamine (20 mL). This mixture, also biphasic, was vigorously stirred at 25° C. for 18 h, poured into a mixture of 30% aqueous NaOH (2 mL) and saturated aqueous NaCl (50 mL), and extracted with ether (3×30 mL). The ether extracts were dried (Na2SO4) and evaporated, and the residue was column chromatographed on 100 g of Merck silica gel 60 (70-230 mesh) with 5% (v/v) methanol, 5% triethylamine (v/v) in benzene. This gave 453 mg (25.2% yield) of yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][N:27]([CH3:41])[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:38]([C:31]4[C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:28]([N:27]([CH3:41])[CH3:26])=[CH:29][CH:30]=4)=[O:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CN(C)c1ccc(C(=O)O)c2ccccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(N(C)C)c5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-(dimethylamino)naphthalene-1-carboxylic acid as starting compounds. The crude product is purified by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:16]2[CH:17]=[CH:18][O:19][C:15]=2[C:14]([F:20])=[CH:13][CH:12]=1>C(#N)C>[F:20][C:14]1[CH:13]=[CH:12][C:11]([CH:10]=[O:5])=[C:16]2[C:15]=1[O:19][CH:18]=[CH:17]2
Reactant: Fc1ccc(CBr)c2ccoc12
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(F)c2occc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the N-methylmorpholine-N-oxide (22.24) in acetonitrile (250 ml) containing 3 Å molecular sieves (8.71 g) was stirred at room temperature overnight, then cooled in ice. A solution of 4-bromomethyl-7-fluoro-benzofuran (23.45 g) in acetonitrile (50 ml) was added and the mixture stirred for 4 h. The mixture was filtered and the filtrate evaporated to dryness. Water and ether were added to the residue and the organic phase separated, washed with brine (2×200 ml), dried (MgSO4) and evaporated. The residue was triturated under ether (50 ml) and filtered to give the title compound as a pale yellow solid (5.45 g)
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:5][C:4]=1[CH3:21])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:20])=[CH:5][C:4]=1[CH3:21])[CH3:2]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C
Yield: 65 %

Procedure:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([O:11][Si](C(C)(C)C)(C)C)=[O:10])/[O:3]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([OH:11])=[O:10])/[O:3]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O[Si](C)(C)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Reaction time: 1 h

Procedure:
The crude (Z)-2,2-dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (72.4 mmol) in tetrahydrofuran (50 ml) was treated at 22° C. with acetic acid (13 ml, 0.227 mmol) followed by 73 ml (73.0 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate (500 ml), washed with water, brine and dried (anhydrous magnesium sulfate). Evaporation of the solvent under reduced pressure and trituration of the residual solid with toluene (50 ml) gave 7.70 g (62% for 3 steps) of the title Z-isomer as a white crystalline solid. Concentration of the mother liquors yielded another 0.2 g of a 75:25 mixture of Z and E isomers. Z-Isomer; 1H NMR (400 MHz, CDCl3) δ: 1.78 (s, 3), 5.89 (s, 1). E-Isomer: 1H NMR (400 MHz, CDCl3) δ: 1.80 (s, 3), 6.03 (s, 1).