Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-4-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.66–6.92 (m, 12H), 6.65 (d, 1H, J=3.2 Hz), 3.69 (s, 2H), 3.15–3.02 (m, 2H), 2.58–2.40 (m, 2H), 2.20–2.04 (m, 2H), 1.94–1.76 (m, 4H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 470.6 (M+H)+.
Reaction SMILES: [CH2:1]([S:13][C:14]1[O:18][C:17]([C:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:25]([NH:28][CH2:29][CH2:30]O)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([NH:28][CH2:29][CH2:30][O:23][C:22](=[O:24])[CH2:21][C:19]([C:17]1[O:18][C:14]([S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1)=[O:20])(=[O:27])[CH3:26]
Reactant: CCCCCCCCCCCCSc1ccc(C(=O)CC(=O)O)o1
Reactant: CC(=O)NCCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCSc1ccc(C(=O)CC(=O)OCCNC(C)=O)o1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 20.0 g (0.057 mole) of 2-[5-(dodecylthio)-2-furoyl]acetic acid, 9.2 g (0.057 mole) of N,N'-carbonyldiimidazole and tetrahydrofuran is stirred for 4 hours, after which 5.9 g (0.057 mole) of N-acetylethanolamine is added. The mixture is stirred at room temperature overnight, then is diluted with ice cold 5% aqueous hydrochloric acid and extracted with ether. The ether layer is washed in water and saturated sodium chloride solution, dried with sodium sulfate, and evaporated to dryness to yield 2-[5-(dodecylthio)-2-furoyl]acetic acid 2-acetamidoethyl ester.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:23][CH2:22][C@H:21]([OH:24])[C:20]2=[O:25])=[CH:16][CH:15]=1>ClCCl.O>[CH3:8][S:9]([O:24][C@H:21]1[CH2:22][CH2:23][N:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:27][CH:26]=2)[C:20]1=[O:25])(=[O:11])=[O:10]
Reactant: O=C1[C@@H](O)CCN1Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(Cl)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Triethylamine (0.825 mL, 5.92 mmol) and methansulfonyl chloride (0.338 mL, 4.34 mmol) was added to a stirred solution of (S)-1-(4-chlorobenzyl)-3-hydroxypyrrolidin-2-one (890 mg, 3.94 mmol) in dichloromethane (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was diluted with water and the aqueous mixture was extracted with dichloromethane. The combined organic layers were washed with 10% sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel column chromatography (0-100% EtOAc). The pure fractions were combined and concentrated in vacuo to afford (S)-1-(4-chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (1.1 g, 3.62 mmol, 92% yield) as a white solid: LC-MS (M+H)+ 304.1; 1H NMR (500 MHz, chloroform-d) δ 7.38-7.33 (m, 2H), 7.22-7.17 (m, 2H), 5.25 (dd, J=8.2, 7.6 Hz, 1H), 4.52-4.41 (m, 2H), 3.40-3.31 (m, 4H), 3.25 (dt, J=10.0, 7.3 Hz, 1H), 2.58 (dddd, J=13.7, 8.4, 7.5, 3.3 Hz, 1H), 2.33-2.20 (m, 1H).
Reaction SMILES: Cl.Cl.[CH2:3]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][N:4]1[C@H:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39](O)=[O:40])=[N:36][CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:5][N:4]([C@H:12]4[C:20]5[C:15](=[CH:16][C:17]([C:21]6[N:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=6)=[CH:18][CH:19]=5)[CH2:14][CH2:13]4)[CH2:3]3)[CH2:7][CH2:8]2)=[O:40])=[N:36][CH:37]=1
Reactant: COc1ccc(CC(=O)O)nc1
Reactant: NC(=O)c1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5cnc(C(N)=O)cn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 5-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyrazine-2-carboxylic acid amide (10-1c, 28 mg, 0.08 mmol) in 3 mL of DMF was added (5-methoxy-pyridin-2-yl)-acetic acid (SM-1aa, 13.0 mg, 0.08 mmol), HBTU (33.0 mg, 0.09 mmol) and triethylamine (0.06 mL, 0.46 mmol). The solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and coevaporated with toluene. The residue was partitioned between 10 mL of dichloromethane and 10 mL of 1N NaOH solution. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified by Biotage reverse phase column chromatography (Biotage, Inc.) using 100-60% water in acetonitrile to give the desired product 12.0 mg (27%). MS (ES+) 513.4 (M+H)+. 1H NMR (CD3OD) δ 1.56-1.81 (m, 4H), 1.81-2.09 (m, 1H), 2.11-2.35 (m, 1H), 2.93 (d, 1H), 3.12 (d, 1H), 3.20-3.27 (m, 2H), 3.31-3.41 (m, 1H), 3.43-3.66 (m, 4H), 3.69-3.89 (m, 5H), 4.06 (dd, 1H), 4.54-4.81 (m, 2H), 7.25 (d, 1H), 7.34 (dd, 1H), 7.50 (d, 1H), 7.97 (dd, 1H), 8.04 (s, 1H), 8.13 (d, 1H), 9.12 (d, 1H), 9.22 (d, 1H).
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([O:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:21][C@@:20]3([CH3:30])[C@@H:12]([CH2:13][C@H:14]([CH3:32])[C@:15]3([OH:31])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:34])[CH:4]=[CH:5][C:6](=[O:33])[CH:7]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C1COCC1.CN(C1C=CN=CC=1)C>[F:1][C@:2]12[C@@H:22]([O:23][C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH2:21][C@@:20]3([CH3:30])[C@@H:12]([CH2:13][C@H:14]([CH3:32])[C@:15]3([OH:31])[C:16](=[O:19])[CH2:17][O:18][C:35](=[O:37])[CH3:36])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:34])[CH:4]=[CH:5][C:6](=[O:33])[CH:7]=1
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(=O)C(F)(F)F)C[C@]2(C)[C@@]1(O)C(=O)CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(=O)C(F)(F)F)C[C@@]21C
Temperature: 35 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
To a solution of 1-3 (122.5 g) in THF (1 L) at RT was added DMAP (6.0 g, 49 mmol) and acetic anhydride (50.2 g, 491 mmol) and the mixture allowed to stir for 15 hours. The solvent was evaporated, and the residue diluted with 1 L of water. The precipitate was isolated by filtration and dried for 15 hrs in a warm (35° C.) vacuum oven to produce 123.4 g (94.7%) 1-4 as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([F:19])=[C:5]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[CH3:20]C(OC(C)=O)=O.C(OCC)(OCC)OCC.[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:1][O:2][C:3]1[C:4]([F:19])=[C:5]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:6]([C:8](=[CH:20][NH:42][CH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC)c1F
Reactant: NC1CCCC1
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)C(=CNC1CCCC1)C(=O)c1cc(F)c(F)c(OC)c1F
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
A solution of ethyl (3-methoxy-2,4,5-trifluorobenzoyl)acetate (12, 7.6 g, 27.5 mmol), Ac2O (6.5 mL, 69 mmol) and triethyl orthoformate (6.9 mL, 41 mmol) was heated at 150° C. for 1.5 h. The mixture was concentrated in vacuo and dried under high vacuum for 3 hours. The crude product 13 was dissolved in ethanol (50 mL) and cyclopentyl amine (2.8 mL, 27 mmol) was added very slowly at 0° C. After 1.5 h, the solvent was removed by evaporation to yield 14 as a dark yellow solid (9.55 g crude, quantitative).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Br.[CH3:16][C:17]1([CH3:24])[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1>>[CH3:16][C:17]1([CH3:24])[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CC1(C)CCN=C(N)N1
Agent: Br
Product: CC1(C)CCn2c(nc(-c3ccncn3)cc2=O)N1

Procedure:
A mixture of 2.39 g (12.31 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705582), 2.33 g (11.19 mmol) 6,6-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrobromide
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:1].[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:14]1[N:13]([CH3:25])[C:12]2[CH:26]=[CH:27][C:9]([N:8]([CH3:28])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:35]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1F)n2C)c1ccnc(Cl)n1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccccc3F)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(2-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (60 mg, 0.15 mmol) and 5-amino-2-methyl-benzenesulfonamide (28 mg, 0.15 mmol) as a white solid (69 mg, 79%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.71 (s, 1H), 8.55 (s, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.68 (dd, J=8.1 and 1.8 Hz, 1H), 7.44-7.54 (m, 2H), 7.16-7.36 (m, 7H), 7.07 (d, J=8.4 Hz, 1H), 5.68 (d, J=6.3 Hz, 1H), 4.73 (d, J=5.1 Hz, 2H), 3.67 (s, 3H), 3.47 (s, 3H), 2.50 (s, 3H). MS (ESI) m/z=547 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=O)[O:14][C:15](=[O:17])[CH:16]=2)=[CH:8][CH:7]=1>O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=[O:14])[NH:3][NH:4][C:15](=[O:17])[CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Reactant: NN
Agent: Cl
Solvent: O
Product: O=c1cc(-c2ccc(Cl)cc2)c(=O)[nH][nH]1
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 81.4 %

Procedure:
To a solution of hydrazine dihydrochloride (5.6 g, 53.3 mmol) in H2O (60 mL) at 120° C. was added 3-(4-chlorophenyl)-2,5-furandione (10 g, 48 mmol) in one portion. After addition, the reaction mixture was stirred at 120° C. for 40 min. After cooling to room temperature, the reaction became a pale yellow suspension. The precipitate was collected by filtration, washed with water (30 mL×3), hexanes (30 mL×3), and dried in a 50° C. vacuum oven for 16 h to afford 8.7 g (81%) of the title compound as a pale yellow solid. LC/MS (method A): retention time=2.57 min, (M+H)+=223.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[S:16])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1.[ClH:18].[C:19](OCC)(=O)[CH3:20]>CN(C)C=O.O1CCOCC1.ICC>[ClH:18].[ClH:18].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[NH:17])[S:16][CH2:19][CH3:20])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccnc(-c2cccc(NC(N)=S)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCSC(=N)Nc1cccc(-c2cc(C)ccn2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of N-(3-(4-methylpyridin-2-yl)phenyl)thiourea (243 mg) in N,N-dimethylformamide (5 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml) and iodoethane (0.4 ml), and the mixture was stirred at 50° C. for 2 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration and dissolved in water. To the solution was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(3-(4-methylpyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride (294 mg).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=O)C.ClCC1C=CC(CC(NC2C(=O)N3C2SCC(C)=C3C(O)=O)=O)=CC=1>>[NH2:14][CH:10]1[C:9](=[O:15])[N:8]2[CH:11]1[S:12][CH2:13][C:6]([CH3:5])=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CCl)cc3)C2SC1
Product: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1

Procedure:
By the procedure of Example 14, only substituted 1 g of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid for 3-acetyloxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained. M.P. 145°-146° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][C:12]([C:14]1[C:15]([CH3:23])=[C:16]([C:19]([F:22])=[CH:20][CH:21]=1)[C:17]#[N:18])=[O:13].[C:24]([N:31]1[CH2:36][CH2:35][NH:34][C@H:33]([CH2:37][OH:38])[CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CCOC(C)=O>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][N:34]2[C@H:33]([CH2:37][O:38][C@@:12]([C:14]3[CH:21]=[CH:20][C:19]([F:22])=[C:16]([C:17]#[N:18])[C:15]=3[CH3:23])([OH:13])[CH2:11]2)[CH2:32]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: Cc1c(C(=O)CBr)ccc(F)c1C#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c([C@]2(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropylethylamine (44.0 mL, 252 mmol) was added to a stirred, room temperature mixture of 72 wt % 3-(2-Bromo-acetyl)-6-fluoro-2-methyl-benzonitrile (69 g, 194 mmol) and (S)-4-N-Boc-2-hydroxymethyl-piperazine (42.0 g, 194 mmol) in THF (1000 mL) and the mixture was stirred at room temperature for 18 h. The reaction was diluted with 1 L EtOAc, washed 2× with 500 mL 10% w/w NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (40-80% EtOAc/Hexanes, linear gradient), to give the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-])[CH:3]=1.C[Si]([C:15]#[N:16])(C)C.CN(C)C(Cl)=O>ClCCl>[C:1]([C:2]1[CH:7]=[CH:6][C:5]([C:15]#[N:16])=[N:4][CH:3]=1)([OH:10])=[O:9]
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)O)cn1
Reaction time: 0.08 h

Procedure:
To a suspension of nicotinic acid N-oxide (0.7 g, 5 mmol) in 10 ml of dichloromethane is added trimethylsilylcyanide (0.55 g, 5,5 mmol), and the solution is stirred for 5 min. Then dimethylcarbamoyl chloride (0.54 g, 5 mmol) is added, and stirring is continued for 5 days under reflux. After cooling, the solution is evaporated to dryness under reduced pressure, and the residue is dissolved in 50 ml of hot water. After standing overnight, the white precipitate is filtered off and is purified by column chromatography (ethyl acetate/ethanol 1:1) to yield 5-carboxy-2-cyano-pyridine, m.p. 194°-195° C., Rf =0.54.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl) azetidin-2-one (J. Med. Chem. 1998, 41, 973-980; 50 mg, 0.122 mmol), tert-butylbromoacetate (24 μl, 0.165 mmol), sodium carbonate (80 mg, 0.76 mmol) and a catalytic amount of caesium carbonate were added to MeCN (3 ml) and the mixture was stirred for 1.5 hours at 50° C. The solids were filtered off and the solvent was evaporated under reduced pressure. Purification of the residue by column chromatography using DCM/EtOAc (100/7) as eluent gave 35 mg, (55%) of the title compound. NMR (300 MHz): 1.45 (s, 9H), 1.8-2.1 (m, 4H), 2.25-2.3 (m, 1H), 3.05-3.15 (m, 1H), 4.5 (s, 2H), 4.55-4.6 (m, 1H), 4.75 (bs, 1H), 6.9-7.3 (m, 12H); m/z 524.3.
Reaction SMILES: [CH2:1]([O:3]C1C=CC(N)=C([N+]([O-])=O)C=1)[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2[CH:25]=[CH:26][C:27](C(F)(F)F)=[CH:28][C:23]=2[N:22]=[C:21]1/[CH:33]=[CH:34]/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>C(OCC)(=O)C>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[O:3]([C:27]1[CH:26]=[CH:25][C:24]2[N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)[C:21](/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:22][C:23]=2[CH:28]=1)[CH2:1][CH3:2]
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-ethoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:27])=[CH:3]\[C:4]([O:6][CH2:7][CH2:8][O:9][CH2:10]/[C:11](/[CH3:26])=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)=[O:5].[N+:28]([C:31]1[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=1)[CH:34]=[C:35]([C:42]([CH3:44])=O)[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])([O-:30])=[O:29]>C(O)(C)C>[CH3:27][C:2]1[NH:1][C:42]([CH3:44])=[C:35]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:34]([C:33]2[CH:45]=[CH:46][CH:47]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=2)[C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH2:10]/[C:11](/[CH3:26])=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:17][CH:18]=1)=[O:5]
Reactant: C/C(N)=C/C(=O)OCCOC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCOC/C(C)=C/c2ccc(Cc3cccnc3)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Yield: 75.9 %

Procedure:
In 1.36 ml of isopropanol were dissolved 340 mg of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl 3-aminocrotonate and 257 mg of isopropyl 2-(3-nitrobenzylidene)acetoacetate, and the resulting solution was subjected to reaction under refulx for 2 hours. The reaction mixture was thereafter stirred with ice-cooling, and the crystals thus precipitated were collected by filtration to obtain 440 mg (yield 75.8%) of 3-[2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl] 5-isopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate having a melting point of 124°-126° C. The physical properties of this product were identical with those of the compound obtained in Example 29.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:11]=[C:10](Br)[S:9][C:8]=1[CH3:13].C([O:18][B:19](OCCCC)[O:20]CCCC)CCC>CCCCCC.CCOCC>[Br:6][C:7]1[CH:11]=[C:10]([B:19]([OH:20])[OH:18])[S:9][C:8]=1[CH3:13]
Reactant: Cc1sc(Br)cc1Br
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1sc(B(O)O)cc1Br
Reaction time: 0.5 h

Procedure:
n-Butyl lithium in hexane is added to a stirred solution of compound 2 in dry ether (150 mL) at −78° C. under argon atmosphere. After stirring for 30 min, boric acid tri-butyl ester is quickly added to the reaction mixture. The mixture is extracted with 4% aq. NaOH (100 mL), the extract is collected and neutralized by with 10% HCl. The solid residue is washed, filtrated, and dried. Compound 3 is obtained as a yellowish solid. M.p. 229° C.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH:19]2[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]2)=[CH:12][C:11]=1[N+:26]([O-:28])=[O:27])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:24][C:21]1([CH3:25])[O:20][CH:19]([CH2:18][C:13]2[C:14]([O:16][CH3:17])=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([N+:26]([O-:28])=[O:27])[CH:12]=2)[CH2:23][O:22]1
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1CC1COC(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO)c([N+](=O)[O-])cc1CC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
358 mg of t-butyl(4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrobenzyloxy)dimethylsilane was dissolved in 10 ml of tetrahydrofuran. While cooling on ice, 1 ml of a tetrahydrofuran solution containing 1.0 M tetrabutyl ammonium fluoride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, the reaction solution was diluted with ethyl acetate and then washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 253 mg of (4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrophenyl)methanol.