Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1([F:7])[CH2:6][CH2:5][N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[O:21][CH3:22])[CH2:3]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: FC1(F)CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(F)(F)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
3,3-Difluoropyrrolidine (0.4589 g, 2.0859 mmol) and 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene (0.5757 g, 2.0859 mmol) were combined in DMF (5 mL). Triethylamine (0.6332 g, 6.2577 mmol) was added. The reaction was heated to 80° C. and stirred for 18 h. The reaction was cooled to RT and diluted with EtOAc (50 mL). The organics were washed with water (3×100 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatatron (1:1 Hex:EtOAc) to give 0.173 g (0.5728 mmol, 27%) of the product as a light yellow oil. 1H NMR (CDCl3) δ 7.90 (d, 1H, 9 Hz), 7.75 (s, 1H), 6.89 (d, 1H, J=9 Hz), 4.21 (t, 2H, J=5.6 Hz), 3.94 (s, 3H), 3.07 (t, 2H, J=13.3 Hz), 2.99 (t, 2H, J=5.7 Hz), 2.89 (t, 2H, J=7.1 Hz), 2.28 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1.O1CCCC1.C(N(CC)CC)C>O>[CH3:11][N:12]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:10]
Reactant: CNc1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Reactant: CCCCCCCN=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Temperature: 40 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
1.2 mL (7.43 mmol, 2 eq) of heptyl isocyanate are added to a solution of 1.0 g (3.7 mmol, 1 eq) of methyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (obtained as in 4c) in 15 mL of a 4/1 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 12 hours at 40° C. The reaction is stopped by addition of 10 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 1.15 g of methyl 3-[3′-(1-methyl-3-heptyl-ureido)biphenyl-4-yl]propanoate are obtained. Yield=76%
Reaction SMILES: [CH2:1]([C:5]1([CH2:18]OS(C)(=O)=O)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].[Li+].[B-](CC)(CC)CC.O>C1COCC1>[CH2:1]([C:5]1([CH3:18])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC1(C)CCN(C(=O)OC(C)(C)C)CC1
Yield: 28.2 %

Procedure:
To a solution of tert-butyl 4-(but-3-en-1-yl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (17 g, 48.9 mmol) in THF (250 mL) was added 1M solution of Superhydride (98 mL, 98 mmol) in THF and the resulting mixture was refluxed for 3 h. After cooling to room temp water was added and the mixture was extracted with ether (2×200 mL), washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by Biotage (0-20% EtOAc/hexane) to afford tert-butyl 4-(but-3-en-1-yl)-4-methylpiperidine-1-carboxylate (3.5 g, 13.81 mmol, 28.2% yield). 1H NMR (500 MHz, CDCl3) δ 5.88-5.80 (m, 1H), 5.03 (dq, J=17.1, 1.7 Hz, 1H), 4.96 (ddt, J=10.2, 2.1, 1.1 Hz, 1H), 3.62-3.49 (m, 2H), 3.23 (ddd, J=13.4, 9.3, 3.8 Hz, 2H), 2.09-1.97 (m, 2H), 1.48 (s, 9H), 1.43-1.22 (m, 6H), 0.96 (s, 3H). LCMS (M+H)=254.2. 8 g of starting material was also recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccccc1N
Reactant: O=Cc1ccc(O)cc1
Product: O=c1[nH]c(-c2ccc(O)cc2)nc2ccccc12

Procedure:
The entitled compound was obtained according to the method of Example 1-(2) but starting from 2-aminobenzamide and 4-hydroxybenzaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)n[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 14.0 g methyl 3-nitro-1H-pyrazole-5-carboxylate in 200 ml methanol are added 1.2 g Pd/C (10% w/w). The mixture is stirred under H2-atmosphere at room temperature for 18 h. The mixture is filtrated over kieselgur. The filtrate is concentrated and the crude product is used without further purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:8][C:7]=1[CH:21]=[CH2:22])(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][CH2:10][C:9]1[CH:19]=[CH:20][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:7]([CH:21]=[CH2:22])[CH:8]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)ccc1NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(CN)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
tert-butyl N-[4-(methanesulfonylamino)-3-vinylbenzyl]carbamate (100 mg, 0.23 mmol) and TFA (0.4 ml) were added in methylene chloride (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to yield title compound (100%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[NH:9][C:8]([CH3:18])([CH3:17])[CH2:7]3)[CH2:4]1.[CH2:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][NH:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].[ClH:37].CO>CN(C)C(=O)C.CO.O>[ClH:37].[CH3:19][C:3]1([CH2:2][CH:24]2[CH2:25][CH2:30][C:29]3[CH:28]=[CH:27][CH:26]=[CH:20][C:21]=3[NH:22][CH2:23]2)[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[NH:9][C:8]([CH3:18])([CH3:17])[CH2:7]3)[CH2:4]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CI)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CC1CCc3ccccc3NC1)O2
Temperature: 180 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A suspension of 1,6,7,8-tetrahydro-2-(iodomethyl)-2,4,5,7,7-pentamethyl-2H-furo[3,2-e]indole (520 mg, 1.40 mmol), 2,3,4,5-tetrahydro-1H-3-benzazepine (309 mg, 2.10 mmol) and potassium carbonate (387 mg, 2.80 mmol) in N,N-dimethylacetamide (3 mL) was stirred at 180° C. for 3 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate two times, The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane-ethyl acetate 10:1) to obtain an oil. This was dissolved in methanol, a 10% hydrogen chloride-methanol solution was added to obtain 464 mg of the title compound.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:12][S:13][CH2:14][S:15]([CH3:17])=[O:16].[Cl-].[NH4+]>>[CH3:17][S:15]([C:14]([S:13][CH3:12])=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([NH2:3])=[CH:5][CH:6]=1)=[O:16]
Reactant: Nc1ccc(C=O)cc1
Reactant: CSCS(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CSC(=Cc1ccc(N)cc1)S(C)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Flakes of sodium hydroxide (55 mg) were added to a mixture of 201 mg of p-aminobenzaldehyde and 798 mg of FAMSO, and the mixture was stirred at 80° C. for 30 minutes. After adding 50 ml of a saturated aqueous solution of ammonium chloride, the reaction mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using methylene chloride as an eluant to afford oil-containing orange crystals. Washing of the crystals with acetone afforded 235 mg of 1-methylsulfinyl-1-methylthio-2-(p-aminophenyl)ethylene as pale yellow crystals in a yield of 62%. Samples for analysis were obtained as colorless crystals by recrystallization.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[N:6]=1)=[O:4].ClC1C=C(C=CC=1)C(OO)=[O:20]>ClCCl.CCOC(C)=O.O>[O:20]=[C:11]1[NH:10][CH:9]=[CH:8][C:7]2[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:14]=[CH:13][C:12]1=2
Reactant: COC(=O)c1ccc2cnccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)c1ccc2c(=O)[nH]ccc2n1
Reaction time: 2 h

Procedure:
Treat a solution of [1,6]naphthyridine-2-carboxylic acid methyl ester (2.00 g, 10.4 mmol) in DCM (dichloromethane) (50 mL) with mCPBA (m-chloroperoxybenzoic acid) (65%, 3.10 g, 12.0 mmol)) at rt (room temperature) and stir for 2 h. Dilute the reaction mixture with EtOAc and water. Wash the organic layers with sat. NaHCO3 and brine. Extract the organic layer with DCM (4×50 mL) and dry the combined organics over MgSO4, filter and concentrate. Purify the compound by silica gel chromatography eluting with a gradient of 0% to 100% EtOAc/hexanes to obtain the desired product 6-oxy-[1,6]naphthyridine-2-carboxylic acid methyl ester in (930 mg, 4.56 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCCCCC>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCOc1ccc2ccccc2c1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCCCCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 57.5 %

Procedure:
Mitsunobu coupling is carried out as follows: 4-hydroxybenzaldehyde (0.92 g), 6-(2-naphthyloxy)hexanol (1.83 g), and triphenylphosphine (1.97 g) are dissolved in THF (25 ml) and cooled to 15° . Diethyl azodicarboxylate (1.2 ml) is added dropwise, and the mixture stirred at room temperature for 60 hrs. The reaction mixture is diluted with hexane and filtered to remove solids. The filtrate is concentrated and chromatographed with 25% v/v hexane in dichloromethane to provide 4-[6-(2-naphthyloxy)hexyloxy] benzaldehyde (1.5 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:25]/[O:26][CH2:27][CH3:28])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[Na+].[C:30]([CH2:33][S:34][CH2:35][CH2:36][N:37]1[C:41]([SH:42])=[N:40][N:39]=[N:38]1)(=[NH:32])[NH2:31]>CN(C=O)C>[C:30]([CH2:33][S:34][CH2:35][CH2:36][N:37]1[C:41]([S:42][CH2:18][C:15]2[CH2:16][S:17][C@@H:12]3[C@H:11]([NH:10][C:8](=[O:9])/[C:7](/[C:4]4[N:3]=[C:2]([NH2:1])[S:6][N:5]=4)=[N:25]\[O:26][CH2:27][CH3:28])[C:23](=[O:24])[N:13]3[C:14]=2[C:20]([OH:22])=[O:21])=[N:40][N:39]=[N:38]1)(=[NH:31])[NH2:32]
Reactant: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1nsc(N)n1
Reactant: N=C(N)CSCCn1nnnc1S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCSCC(=N)N)CS[C@H]12)c1nsc(N)n1
Temperature: -20 °C
Yield: 31.6 %

Procedure:
To a solution of sodium 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-ethoxyiminoacetamido]-3-hydroxymethyl-3 -cephem-4-carboxylate (360 mg) and 1-(2-amidinomethylthioethyl)-5-mercapto-1H-tetrazole (262 mg) in 8 ml of DMF was added 1.0 g of ethyl o-phenylenephophate under stirring at -20° C. After stirring under ice-cooling for 1.5 hours, the reaction mixture was subjected to a column chromatography (silica gel, 100 g), being washed with acetonitrile and eluted with acetonitrile/water (4:1). The eluate was concentrated under reduced pressure and then subjected to a column chromatography (XAD-II, 150 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and lyophilized to give 159 mg of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[N:36]O)[NH2:35])=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:34]([CH2:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: NC(Cc1ccc(F)cc1)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(Cc4ccc(F)cc4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 37 mg (0.22 mmol, 1.1 eq.) of 2-(4-fluorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 44 mg (45% of theory)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1.[H][H]>[Ni].CO>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1
Reactant: CSc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CSc1ccc(N)cc1
Yield: 92.7 %

Procedure:
A suspension of 1-(methylsulfanyl)-4-nitrobenzene (10.5 g, 0.062 mol) and Raney nickel (5 g) in methanol (250 ml) was hydrogenated in a round flask equipped with a balloon filled with hydrogen at room temperature for 16 hours. The resulting mixture was filtered and concentrated in vacuo to afford 8.0 g of 4-(methylsulfanyl)aniline as colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:4]([C:9]([CH3:11])=[O:10])=[CH:5]OCC)=[O:3].[NH2:12][C:13]1[C:14]([Cl:24])=[C:15]([C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=1)[C:16]([OH:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:11][C:9]([C:4]([C:2]([CH3:1])=[O:3])=[CH:5][NH:12][C:13]1[C:14]([Cl:24])=[C:15]([C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=1)[C:16]([OH:18])=[O:17])=[O:10]
Reactant: Nc1cc(Cl)c(Cl)c(C(=O)O)c1Cl
Reactant: CCOC=C(C(C)=O)C(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)C(=CNc1cc(Cl)c(Cl)c(C(=O)O)c1Cl)C(C)=O
Temperature: 10 °C
Yield: 741.6 %

Procedure:
46.8 g (0.3 mole) of methyl 1-methylcarbonyl-2-ethoxyvinyl ketone were added dropwise to a suspension of 48.1 g (0.02 mole) of 3-amino-2,5,6-trichlorobenzoic acid in 100 ml of toluene. The mixture was heated for 2 hours to 80° C and was then cooled to 10° C, and the precipitate was filtered off. After digesting with acetonitrile, 52 g (74% of theory) of 3-[2,2-bis-(methylcarbonyl)-vinylamino]-2,5,6-trichlorobenzoic acid were obtained in the form of colourless crystals of melting point 242°-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:32]1([C:38](=[O:46])[CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][C:38]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[O:46])[CH2:41][CH2:42]3)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ncccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 1) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H37N6O4Cl2 [(M+H)+] 651.2248, observed 651.2250.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][OH:14])[C:5]2=[N:4][C:3]=1[C:15]([O:17]CC)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:15]([C:3]2[N:4]=[C:5]3[N:11]([CH2:12][CH2:13][OH:14])[CH2:10][CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:17])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCN2CCO
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCN2CCO
Yield: 81.6 %

Procedure:
A solution of ethyl 6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.110 g, 0.408 mmol) and 4-fluorobenzylamine (0.200 g, 1.6 mmol) in anhydrous ethanol (5 ml) was heated under reflux for 6 h. The reaction mixture was then diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethanol gave 0.116 g (82% yield) of the title amide as white cubes; mp 203° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.54 (2H, t, J=5.0 Hz, CH2), 3.80 (2H, t, J=8.5 Hz, CH2), 3.89 (2H, t, J=5.0 Hz, CH2), 4.15 (2H, t, J=8.5 Hz, CH2), 4.57 (2H, d, J=6.0 Hz, NCH2), 7.07 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.92 (1H, broad t, NH), 11.68 (1H, s, OH). Anal. Calcd for C16H17FN4O4: C, 55.17; H, 4.92; N, 16.08. Found: C, 55.22; H, 5.06; N, 15.89.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]1[C:9]=2[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:29][C@H:28]([CH3:30])OS1(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:28]([CH3:30])[CH2:29][NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[C:8]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]1[C:9]=2[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc3c(c2[nH]1)CCC3
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc3c(c2n1[C@H](C)CNC(=O)OC(C)(C)C)CCC3

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from b) 1,6,7,8-tetrahydro-1-aza-as-indacene-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=O)[NH:7][CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].S(Cl)(Cl)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:28]([C:34]([NH:36][NH2:37])=O)=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:38]([F:41])([F:40])[F:39]>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:28]([C:34]3[N:7]([CH:8]([CH3:10])[CH3:9])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:37][N:36]=3)=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:38]([F:39])([F:41])[F:40]
Reactant: CCOC(=O)C(=O)NC(C)C
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 3.2 %

Procedure:
To a vial containing ethyl(isopropylcarbamoyl)formate (160 mg, 1.0 mmol) was added thionyl chloride (1.0 mL, 13.8 mmol). The vial was capped with a teflon coated septa and heated to 80° C. for 5 h. After cooling to room temperature, the volatiles were removed in vacuo. A solution of 4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (342 mg, 0.80 mmol) in toluene (3 mL) was added. The mixture was stirred at 40° C. for 16 h. After cooling to room temperature, the toluene was removed in vacuo. Ethanol (9 mL) and triethylamine (1 mL) were added, and the solution heated to 90° C. for 4 h. After cooling to room temperature, the volatiles were removed in vacuo, and the resulting residue purified by flash chromatography on 4 g of silica gel (0→20% gradient of MeOH in DCM). The pure fractions were collected, and the solvent removed in vacuo to afford the title compound (14 mg, 3% yield). HPLC retention time=3.17 minutes. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.4, 1H), 8.19 (d, J=2.4, 1H), 8.04 (d, J=2.4, 1H), 7.89 (dd, J=2.0, 8.4, 1H), 7.53 (d, J=8.0, 1H), 5.66 (sept, J=7.0, 1H), 4.52 (q, J=7.4, 2H), 1.52 (d, J=7.0, 6H), 1.50 (t, J=7.4, 3H). MS (ES) [M+H]+ expected 552.0, found 552.0.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])=[N:8][N:7]=1)=O.N#N>CO>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[CH2:18][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6]([C:4]([NH2:1])=[O:3])=[N:7][N:8]=1
Reactant: N
Reactant: COC(=O)c1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Agent: N#N
Solvent: CO
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C(N)=O)c2c1
Reaction time: 48 h
Yield: 67.7 %

Procedure:
An excess of NH3 was bubbled into a suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-carboxylic acid methyl ester (1.6 g, 4.23 mmoles), prepared as described in example 102, in dry CH3OH, under stirring and dry N2 at 10° C., and the mixture was left for 3 hours at room temperature, then refluxed for 1.5 hours in environment saturated of NH3. After 2 days at room temperature, the mixture was dried to give 1.48 g of the title compound (yield: 67.7%).