Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].CS([C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1)(=O)=O>CN(C)C=O>[CH3:27][O:26][C:20]1[CH:21]=[C:22]([O:24][CH3:25])[N:23]=[C:18]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[S:2][CH3:1])[N:19]=1
Reactant: CSc1nc2ccccc2[nH]1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(-n2c(SC)nc3ccccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
2-Methylthiobenzimidazole (0.50 g) was dissolved in dimethylformamide (10 ml), and sodium hydride (60% purity, oily) (0.13 g) was added thereto at room temperature. After stirring for 1 hour, 2-methylsulfonyl-4,6-dimethoxypyrimidine (0.67 g) was added at room temperature, followed by stirring for 8 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.80 g of the desired product as a white powder (m.p. 135-137° C.)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[C:6]([O:8]C)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C.O>[I:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([S:10]([CH3:13])(=[O:11])=[O:12])[CH:3]=1
Reactant: COc1cc(I)cc(S(C)(=O)=O)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1cc(O)cc(I)c1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To a suspension of 3-iodo-1-methanesulfonyl-5-methoxy-benzene (1.03 g, 3.31 mmol) and sodium iodide (4.97 g, 33.15 mmol) in acetonitrile (30 mL) was added trimethylsilyl chloride (2.09 mL, 16.58 mmol) at room temperature. Then, the resulting light yellow suspension was heated to reflux for 48 h. Then, it was cooled to room temperature and diluted with water (50 mL). The organic compound was extracted into ethyl acetate (2×50 mL) and the combined ethyl acetate extracts were washed with saturated sodium thiosulfate solution (100 mL) to remove the iodine color and was also washed with brine solution (100 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 40 g column, eluting with 0-25% ethyl acetate in hexanes to obtain 3-iodo-5-methanesulfonyl-phenol (628 mg, 63.5%) as a light brown solid: ES(+)-HRMS m/e calcd for C7H7IO3S (M+H)+ 298.9234, found 298.9234.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:35])[N:17]([C:21]3[C:22]([CH3:34])=[CH:23][C:24]([F:33])=[C:25]([CH:32]=3)[C:26]([NH:28][CH:29]3[CH2:31][CH2:30]3)=[O:27])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:36][NH2:37].[I-].[K+]>O.O1CCOCC1>[CH:29]1([NH:28][C:26](=[O:27])[C:25]2[CH:32]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:13][CH2:12]4)[C:16]3=[O:35])[C:22]([CH3:34])=[CH:23][C:24]=2[F:33])[CH2:31][CH2:30]1
Reactant: CN
Reactant: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)c(F)cc3C)c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-2-fluoro-4-methylbenzamide (Example 318h, 100 mg) and methylamine, 40% by wt solution in water (0.1 mL) in dioxane (1 mL) was added potassium iodide (33.4 mg). The reaction mixture was stirred at room temperature overnight, then heated at 40° C. overnight. The reaction was heated at 50° C. for 48 h. Purification by preparative HPLC (Phenomenex Gemini, eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia, followed by Xbridge column eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title compound as a solid (17 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11]I.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]#[CH:21])[CH:17]=[CH:18][CH:19]=1>>[ClH:1].[C:20]([C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:18][CH:17]=1)#[CH:21]
Reactant: C#Cc1cccc(N)c1
Reactant: CI
Reactant: Clc1ncnc2[nH]ccc12
Product: C#Cc1cccc(Nc2ncnc3c2ccn3C)c1
Product: Cl

Procedure:
Following the procedure described in Example 1, the title compound was prepared from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and methyl iodide, and m-aminophenyl acetylene (75%). TS-MS: 249 (MH+); anal. RP18-HPLC RT: min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].CCOCC.[Br:16]Br>C(O)(=O)C>[BrH:16].[Br:16][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH2:5][NH2:6]
Reactant: COc1ccccc1CN
Reactant: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: Br
Product: COc1ccc(Br)cc1CN
Temperature: 0 °C
Reaction time: 1 h
Yield: 141.2 %

Procedure:
To 2-methoxybenzylamine (30 mmol, 4.12 g) was added ether (6 ml) and acetic acid (glacial, 10 ml). The resulting solution was cooled on an ice-batch and Br2 (30 mmol, 4.79 g, 1.54 ml) was added dropwise. After 1 h the ice-bath was removed and the mixture was stirred for another 1 h before addition of ether (20 ml). The resulting mixture was left in the cold for 0.5 h, the solids were filtered off and washed with ether (20 ml) to give a cream colored solid (6.29 g). The crude product was crystallized in ethanol/ether to give the title compound (4.62 g, 52%) as white crystalline material. 1H NMR (DMSO, 500 MHz) δ 3.84 (s, 3H), 3.98 (s, 2H), 7.05 (s, 1H), 7.58 (m, 2H) and 8.16. (br, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:12][CH:11]=1)=[O:8].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:30][C:5]1[CH:4]=[CH:3][C:2]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:29][C:6]=1[C:7]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:12][CH:11]=1)=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: C1COCCN1
Product: Cc1ccc(N2CCOCC2)cc1C(=O)Nc1ccc(OCCN2CCOCC2)c2ccccc12

Procedure:
Compound is formed by reacting 5-bromo-2-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with morpholine under conditions described in general procedure B. 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H, J=6.9), 7.85 (t, 2H, J=7.8), 7.61 (s, 1H), 7.54 (m, 2H), 7.34 (m, 2H), 7.19 (d, 1H, J=7.5), 6.88 (d, 1H, J=8.4), 4.33 (t, 2H, J=5.7), 3.88 (t, 4H, J=3.9), 3.75 (t, 4H, J=4.5), 2.95 (m, 6H), 2.66 (t, 4H, J=4.5), 2.63 (s, 3H). MS: 476.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOCC>O1CCCC1>[OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([O:11][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:10]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12

Procedure:
3-Hydroxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (500 mg.) was dissolved in dry tetrahydrofuran and treated with a solution of diphenyldiazomethane (300 mg., 1.1 equiv.) in petrol. Nitrogen was evolved slowly, and after 21/2 hours the solution was evaporated, the residue dissolved in ethyl acetate, and the solution was washed with bicarbonate solution and re-evaporated. This gave a gum which solidified on trituration with ether (0.5 g.). A sample was recrystallised from methanol, m.p. 164°, [α]D23 = + 25° (c, 1.0, dioxan), +22° (c 1.0, tetrahydrofuran). λλmax. ethanol 234 nm. E1 cm1% = 255, (ε = 13,300), 259 nm. E1cm1% = 151 (ε 7,850), νmax. (bromoform) 3420 (OH), 3280 (NH), 1750 (β-lactam), 1722 cm-1 (COOR). (Found, C, 62.2; H, 4.5; N, 5.4; S, 12.1. C27H24N2O5S2 requires C, 62.3; H, 4.7; N, 5.4; S, 12.3%) RF = 0.83 (Kieselgel G plates; ethyl acetate:benzene=1:2).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[N+:22]([C:18]1[CH:17]=[C:16]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of 1-Boc-hexahydro-1,4-diazepine (150 mg), 3-bromonitrobenzene (125 mg) and cesium carbonate (507 mg) in 1,4-dioxane (3 mL), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (26 mg) was added at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 70% hexane in ethyl acetate) to obtain tert-butyl 4-(3-nitrophenyl)-1,4-diazepane-1-carboxylate (C27, 15 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][C:12]2[N:16]([C:17]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][N:18]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[C:26](#N)C.O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][C:12]2[N:16]([C:17]3[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][N:18]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CC#N
Reactant: CCc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1Cl
Solvent: O
Product: CCc1ccc(COc2ccnn2-c2cc(C(=O)OC)ccn2)cc1Cl

Procedure:
The title compound was prepared from 2-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 95) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.76 (2H, q, J=7.6 Hz), 3.97 (3H, s), 5.18 (2H, s), 5.75 (1H, s), 7.26 (2H, s), 7.45 (1H, s), 7.58 (1H, s), 7.78 (1H, d, J=8.0 Hz), 8.33 (1H, s), 8.72 (1H, d, J=0.8 Hz). LCMS (mobile phase: 20%-95% Acetonitrile-Water-0.02% NH4OH): purity is >95%, Rt=4.602 min.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]2O[CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].[C:13]([O-:16])([O-])=[O:14].[K+].[K+].[CH3:19]N(C)C=O>>[CH2:7]([O:8][C:4]1[CH:5]=[CH:9][C:10]2[O:14][CH2:13][O:16][C:2]=2[C:3]=1[CH:11]=[O:12])[CH3:19]
Reactant: O=Cc1c(O)ccc2c1OCO2
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Product: CCOc1ccc2c(c1C=O)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under argon to a stirred solution of 5-hydroxy-1,3-benzodioxole-4-carbaldehyde (0.151 g, 0.91 mmol) and K2CO3 (1 eq) in dry N,N-dimethylformamide (2 ml) ethyl-bromide (1 eq) was added. The mixture was stirred at room temperature for 18 h until the starting material had been consumed (monitored by TLC). Then the mixture was poured onto ice water (15 ml). This aqueous phase was extracted with ethyl acetate (1×40 ml, then 2×15 ml) and the combined organic phases were washed with water and dried over anhydrous MgSO4. The solvent was evaporated in vacuo, and the crude product was purified by column chromatography with a mixture of n-hexane:ethyl acetate (4:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1C(N1CCC[C@@H]1CC(O)=O)=O)[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[CH3:34][N:35]([C:37]([O:41]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([N:59]([CH:62]([CH3:64])[CH3:63])[CH2:60][CH3:61])(C)C.CN.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[N:59]1[CH2:60][CH2:61][CH2:64][C@@H:62]1[CH2:63][C:37]([NH:35][CH3:34])=[O:41])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)C[C@H]1CCCN1c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 60 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[(2R)-2-(hydroxycarbonylmethyl)pyrrolidin-1-ylcarbonyl]benzamide, TBTU, diisopropylethylamine, and methylamine in tetrahydrofuran. Yield: 60%; Rf value: 0.44 (silica gel: dichloromethane/ethanol=9:1); C24H25Cl2N5O3 (502.405); mass spectrum: (M+H)+=502/504/506 (chlorine isotope) and (M−H)−=500/502/504 (chlorine isotope).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11]Cl)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:13]([CH:16]([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([C:16]([CH2:11][N:8]1[CH:9]=[CH:10][C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:7]1)([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15]
Reactant: CC(C)(C)c1ccn(CCl)n1
Reactant: C=CCC(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1ccc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
1.24 g of 3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.63 g of allyl malononitrile were dissolved in 18 ml of N,N-dimethylformamide. 1.63 g of potassium carbonate was added to the solution, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.38 g of allyl [(3-t-butyl-1H-pyrazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (4), hereinafter) shown by below formula.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:12](F)(F)F)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[Na+].[OH2:18]>>[C:1]1([C:7]2[NH:8][C:9]([C:12]([OH:18])=[O:16])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cnc(-c2ccccc2)[nH]1
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cnc(-c2ccccc2)[nH]1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenyl-5-(trifluoromethyl)-1H-imidazole (47.1 mmol) and NaOH (63.8 mmol) in water (20 mL) was allowed to stir at 95° C. overnight. The reaction mixture was allowed to cool to rt and was diluted with water and extracted with DCM. The pH of the aqueous solution was adjusted to pH=7 with 1N HCl and the solution was extracted again with DCM. The aqueous solution was concentrated to give 2-phenyl-1H-imidazole-5-carboxylic acid as a white solid which was used without further purification.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13]3[CH2:14][O:15][C:16](=[O:17])[C:12]=3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pd]>[C:1]1([C@@H:7]([N:9]2[C@H:13]3[CH2:14][O:15][C:16](=[O:17])[C@H:12]3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](c1ccccc1)n1c2c([nH]c1=O)C(=O)OC2
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.6 %

Procedure:
A solution of 3.7 g (15.16 mmol) of 1-[(S)-(1-phenylethyl)]-1H-furo[3,4-d]imidazol-2,4(3H,6H)-dione in 100 ml of acetic acid is placed in a 250-ml autoclave and 0.4 g of palladium on activated carbon (5 percent) was added. Then the autoclave was flushed twice successively with hydrogen and filled to 50 bars. This mixture was stirred for 15 hours at room temperature. The catalyst was then filtered off. The solvent was evaporated at 20 mbars and the residue was chromatographed over silica gel with ethyl acetate. 2.0 g (54 percent yield) of the title product was eluted. Recrystallization in methanol yields white needles. Concerning the product: Melting point: 123°-125° C.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1.[CH2:22]([NH:29][C:30]([C:32]1[S:36][C:35]([N:37]2[CH2:41][CH2:40][NH:39][C:38]2=[O:42])=[N:34][C:33]=1[CH3:43])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:30]([C:32]1[S:36][C:35]([N:37]2[CH2:41][CH2:40][N:39]([CH2:12][C:13]3[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[C:38]2=[O:42])=[N:34][C:33]=1[CH3:43])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)o3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 2-(bromomethyl)-5-(trifluoromethyl)furan to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 27% yield: mp 143-145° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35-7.28 (m, 5H), 6.76-6.75 (m, 1H), 6.39 (d, J=3.0 Hz, 1H), 5.90 (t, J=6.0 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.51 (s, 2H), 4.11 (t, J=9.0 Hz, 2H), 3.64 (t, J=9.0 Hz, 2H), 2.62 (s, 3H); MS (ES+) m/z 465.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2.[H-].[Na+]>C(Cl)Cl.CN(C=O)C.O>[CH:29]1[C:30]2[C:25](=[C:24]([NH:23][C:11](=[O:13])/[CH:10]=[C:9](/[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:8][CH:7]=3)\[CH3:14])[CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][N:28]=1
Reactant: Nc1cccc2cnccc12
Reactant: C/C(=C\C(=O)O)c1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C/C(=C\C(=O)Nc1cccc2cnccc12)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The product from Example 142C (0.23 g, 1.00 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.15 g, 1.2 mmol), 1 drop of DMF, and stirred at ambient temperature for 45 minutes. The mixture was treated with a solution of 5-aminoisoquinoline (0.14 g, 1.0 mmol) and 98% NaH (0.048 g, 1.2 mmol) in DMF (5 mL) prepared separately by stirring for 45 minutes. The resulting mixture was stirred for 15 minutes, poured into water, and extracted with CH2Cl2. The organic phase was dried (MgSO4), evaporated, and the residue triturated with diethyl ether. The solid was dried under reduced pressure to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 2.61 (s, 3H), 2.73 (s, 0.45H, DMF)), 2.89 (s, 0.45H (DMF)), 6.82 (br s, 1H), 7.70 (t, 1H), 7.83 (s, 4H), 7.95 (d, 1H), 8.04 (d, 1H), 8.21 (d, 1H), 8.56 (d, 1H), 9.33 (s, 1H), 10.20 (s, 1H); MS (ESI+) 357 (M+H)+; Elemental: Calculated for C20H15N2OF3.HCl.0.15C3H7NO: C66.87, H4.40, N8.20; Found: C66.83, H4.20, N8.27.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>O1CCCC1>[CH2:28]([Sn:23]([C:18]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH3:31]
Reactant: c1ccnnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
n-Butyllithium (2.76 mL, 6.9 mmol, 2.5 M in hexane) was added dropwise to a cooled (0° C.) solution of diisopropylamine (0.97 mL, 6.9 mmol) in tetrahydrofuran (2 mL) under a nitrogen atmosphere. After stirring for 30 minutes the reaction mixture was cooled to −78° C. and a solution of pyridazine (452 μL, 6.3 mmol) and tributyltin chloride (1.9 mL, 6.9 mmol) were added simultaneously while the temperature was kept below −70° C. The reaction mixture was stirred for 2 hours at −78° C.; subsequently, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated to dryness. The crude product was purified by LCMS to give tributylstannylpyridazine (197 mg, 0.53 mmol, 8% yield). This stannylpyridazine (183 mg, 0.49 mmol), (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one (100 mg, 0.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (3 mg, 0.004 mmol) were dissolved in dioxane (3 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 110° C. and then cooled to room temperature. Water was added and the mixture was extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification by LCMS followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-3-one (78 mg, 0.16 mmol, 79% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.85-2.84 (m, 26H), 4.48 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.33-7.37 (m, 2H), 7.60-7.64 (m, 3H), 9.21 (dd, J=5 and 1 Hz, 1H), 9.46 (dd, J=3 and 1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1.C(OC(=O)C)(=O)C>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:7]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:24])[CH3:1])=[CH:23][CH:22]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:8]1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 95 °C
Yield: 73.6 %

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (20.3 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (88%, 9.3 g.) and acetic anhydride (74 ml.) was heated (to 95° C.) during one hour, then cooled, affording 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=Y4 =(CH3)2N, Y2 =H, Z4 =Z5 =Z6 =Z7 =Cl) (20.3 g., m.p. 227°-229° C.).