Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH3:44][S:45]([CH:48]1[CH2:51][NH:50][CH2:49]1)(=[O:47])=[O:46]>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:50]3[CH2:51][CH:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)C1CNC1
Product: COc1ccc(Nc2ncc(CN3CC(S(C)(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.200 g, 0.346 mmol) and 3-(methylsulfonyl)azetidine (PharmaBlock, Carrboro, N.C.) (0.070 g, 0.519 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.81 (s, 1H); 8.88 (br. s., 1H); 8.54 (d, J=2.74 Hz, 1H); 8.38 (d, J=1.76Hz, 1H); 8.13 (dd, J=8.90, 2.64 Hz, 1H); 7.77-7.94 (m, 2H); 6.85 (d, J=8.80 Hz, 1H); 4.09-4.58 (m, 7H); 3.85 (s, 3H); 3.12 (s, 3H); 2.44 (s, 3H). m/z (ESI, +ve ion) 456.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:13]=2)=[O:9])[CH:5]=[C:4]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)[N:3]=1.Cl.O1CCOCC1>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)[N:3]=1
Reactant: Nc1nc(C(=O)NCc2cccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc(-c2ccco2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(C(=O)NCc2cccc(CO)n2)cc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
A solution of 2-amino-6-(2-furyl)-N-(6-(triphenylmethoxymethyl)pyridin-2-ylmethyl)pyrimidine-4-carboxamide (3.41 g, 6 mmol) in MeOH (50 mL) was treated with 4-M HCl in dioxane (7.5 mL, 30 mmol), stirred at room temperature for 20 h and concentrated in vacuo. The residue was diluted with water (50 mL) basified with 5-M NaOH, extracted with EtOAc (2×25 mL) and the combined organic phase washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (1.19 g, 61%) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][N:28]=[CH:27][C:26]=2[CH2:30][CH2:31][C:32](O)=[O:33])[CH:21]=[CH:22][C:23]=1[F:24].ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][N:28]=[CH:27][C:26]=2[CH2:30][CH2:31][C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][P:7]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:14])=[CH:15][CH:16]=2)=[O:33])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)c(Cl)c1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(F)c(Cl)c2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (36 mg), 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid (27 g), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (20 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30 mg) and N,N-dimethylformamide (0.5 ml) was stirred at room temperature overnight. The reaction mixture was poured into 1N aqueous hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the obtained solid was purified by preparative HPLC to give 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)/C=C\c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C\c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
A solution of (z)-3-phenylpropenoic acid, methyl ester (0.8 g, 4.9 mmol) in 20% aqueous tetrahydrofuran (5 mL) was treated with lithium hydroxide hydrate (0.42 g, 9.9 mmol) and the reaction mixture was stirred under argon at room temperature for 20 hours. It was concentrated in vacuo, diluted with water (50 mL) and extracted with dichloromethane (2×50 mL). The organic extracts were discarded and the aqueous layer was acidified to pH~3 with 1N hydrochloric acid and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title B compound (0.5 g). 1H NMR (CDCl3) δ11.57 (brs, 1H), 7.48 (m, 2H), 7.25 (m, 2H), 6.94 (d, J=12.2 Hz, 1H), 5.84 (d, J=12.3 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15](I)[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[CH:18]=[CH:17][C:16]2[O:19][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(O)c(I)c1
Reactant: C#Cc1ccccc1
Product: CC(C)(C)c1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-tert-Butyl-2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (398 mg, 80% yield). 1H NMR (300 MHz, CDCl3) δ 7.83 (dd, J=7.16, 2H), 7.57-7.56 (m, 1H), 7.44-7.38 (m, 3H), 7.34-7.30 (m, 2H), 6.96 (s, 1H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 155.99, 153.12, 145.92, 130.65, 128.88, 128.72, 128.33, 124.82, 122.23, 117.06, 110.42, 101.48, 34.68, 31.83. Anal. Calcd. for C18H18O: C, 86.36; H, 7.25. Found C, 86.34; H, 7.13. m.p.: 103-104° C. (lit., 7102-103° C.).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19]Cl)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(CCCl)cc1OC
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCN2CCCNCC2)cc1OC
Yield: 77 %

Procedure:
32 27 g of homopiperazine, 13.2 g of 2-(3,4-dimethoxyphenyl)ethyl chloride and 71.3 g of potassium carbonate were added to 500 ml of acetonitrile. The obtained mixture was heated under reflux for 20 hours, cooled and filtered The filtrate was concentrated under a reduced pressure to obtain a residue. This residue was extracted with ether thrice. The extracts were combined, dried over anhydrous sodium sulfate and filtered The filtrate was concentrated under a reduced pressure The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol/isopropylamine (100:10:1)) to obtain 13.40 g of the title compound as a yellow oil (yield: 77%).
Reaction SMILES: N(OC(C)(C)C)=O.C[Si]([Cl:12])(C)C.N[C:14]1[C:18]([CH:19]2[CH2:21][C:20]2([Br:23])[Br:22])=[CH:17][N:16]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[Cl:35])[N:15]=1>ClCCl>[Cl:12][C:14]1[C:18]([CH:19]2[CH2:21][C:20]2([Br:23])[Br:22])=[CH:17][N:16]([C:24]2[C:25]([Cl:35])=[CH:26][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:28][C:29]=2[Cl:30])[N:15]=1
Reactant: Nc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br
Reactant: C[Si](C)(C)Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C3CC3(Br)Br)c(Cl)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
t-Butyl nitrite (0.07 ml) was added dropwise to a stirred solution of trimethylsilyl chloride (0.08 ml) in anhydrous dichloromethane (2.5 ml) at about -5° C. After a further 5 minutes, a solution of the title compound of Example 8 (0.10 g) in anhydrous dichloromethane (4.5ml) was added dropwise, whilst maintaining the reaction temperature below -5° C. Next, the reaction mixture was allowed to warm to room temperature, stirred for 45 minutes more and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using mixtures of hexane:dichloromethane (9:1 then 4:1) as eluants, to afford the title compound as a colourless gum. δ (CDCl3): 1.85 (t,1H), 2.25 (dd,1H), 2.70 (dd,1H), 7.35 (s,1H), 7.75 (s,2H). MS (thermospray): M/Z [M+H] 510.7; C13H6Br2Cl3F3N2 +H requires 510.80.
Reaction SMILES: C[N:2](C)[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1.IC.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[N+:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:3]#[N:2])([O-:16])=[O:15]
Reactant: CN(C)CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: N#CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve the N,N-dimethyl-5-nitrotryptamine obtained above in 200 mL dry DMSO, treat with iodomethane (7.7 mL, 17.5 g, 124 mmol), and stir for 1 hour at ambient temperature. Add KCN (40 g, 621 mmol) and 18-crown-6 (0.5 g). Warm the reaction to 110° C. for 45 minutes, cool, poured onto ice then saturate with NaCl. Extract the quenched reaction mixture with EtOAc, combine the extracts, and wash 3 times with brine. Dry over MgSO4 and concentrate under vacuum. chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give (5-nitro-1H-indol-3-yl)acetonitrile as a solid: FDMS 201 (M+); Analysis for C10H7N3O2: calcd: C, 59.70; H, 3.51; N, 20.89; found: C, 59.32; H, 3.52; N, 20.56.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2(O)[CH:16]3[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[CH:6]=[CH:7][CH:8]=1)[CH3:2].C[Si]([C:24]#[N:25])(C)C.B(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([C:24]#[N:25])[CH:16]3[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CCc1cccc(C2(O)C3CC4CC(C3)CC2C4)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C2(C#N)C3CC4CC(C3)CC2C4)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A solution of 2-(3-ethylphenyl)-2-adamantanol (1.82 g, 7.14 mmol) in dry CHCl3 (5 mL) under argon, was treated with trimethylsilyl cyanide (1.00 mL, 7.5 mmol), cooled to 0° C., treated with BF3 etherate (1.10 mL, 8.57 mmol), allowed to warm to room temperature and stirred for 2 h. The mixture was treated with dilute NaHCO3 (10 mL), extracted with CHCl3 (2×10 mL), the combined extracts washed with water (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (9:1)] to give the product (1.54 g, 82%) as a colourless oil: IR νmax (thin film)/cm−1 2922, 2860, 2226, 1604, 1487, 1453, 1105, 799 and 704; NMR δH (400 MHz, CDCl3) 1.24 (3H, t, J 7.5 Hz), 1.62-1.65 (2H, m), 1.70-1.82 (5H, m), 1.98-204 (3H, m), 2.45-2.48 (2H, m), 2.66 (2H, q, J 7.5 Hz), 2.79 (2H, s), 7.15 (1H, d, J 7.5 Hz) and 7.25-7.34 (3H, m); Anal. Calcd for C19H23N: C, 85.99; H, 8.73; N, 5.28. Found: C, 85.85; H, 8.77; N, 5.23.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]3[CH2:27][CH2:26][SiH:25](Cl)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C@H:22]3[CH2:27][CH2:26][Si@H:25]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc(OC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1
Reactant: CCCCCBr
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(Cl)cc3)CC2)CC1

Procedure:
The general procedure of Example 30 was repeated using n-pentyl bromide and 4-(trans-4-(4-chlorophenyloxymethyl)cyclohexyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][C:4]=1[CH:5]=[O:6].Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([S:39]([N:36]1[CH2:35][CH2:34][CH:33]([C:24]2[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=[C:21]([C:8]4[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:5]=[O:6])[CH:7]=4)[CH:22]=3)[NH:26][CH:25]=2)[CH2:38][CH2:37]1)(=[O:41])=[O:40])[CH3:43]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C=O
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(C=O)c4)cc23)CC1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (610 mg, 2.33 mmol) in dioxane (19 mL) and H2O (6.3 mL), was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (963 mg, 2.33 mmol), and sodium carbonate (1.48 g, 13.9 mmol). After flushing with Agron for 10 min, tetrakis(triphenylphosphine)palladium(0) (134 mg, 0.166 mmol) was added. The reaction was heated in the microwave 120° C. for 120 min. Compound was purified by flash chromatography using DCM and MeOH to give 632 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1H-indole-7-carboxamide (58%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[OH-].[K+]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccccc1

Procedure:
Aryl ethers have been formed by reacting aryl halides with phenols under various conditions. Roberts and Turner disclose (J. Chem. Soc., 1925, Vol. 127, p. 2004) that 2, 4-dichloronitrobenzene reacts with phenol in aqueous KOH, at 100° C., to give a quantitative yield of 4-chloro-2-phenoxynitrobenzene.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Br-].[CH:10]1([Zn+])[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[S:6][N:5]=1
Reactant: CSc1nsc(Cl)n1
Reactant: [Zn+]C1CCCC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CSc1nsc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.00 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 244 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex were dissolved in 12 ml of tetrahydrofuran under nitrogen atmosphere, 13.2 ml of solution of cyclopentyl zinc bromide in tetrahydrofuran (0.5 mol/l) was added thereto under ice-cooling taking for about 15 minutes, and the reaction mixture was stirred for 13 hours at room temperature. Then, the reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 710 mg of 3-methylthio-5-cyclopentyl-1,2,4-thiadiazole.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.[CH2:14]([N:16]1[C:22]2[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:19][CH2:18][C:17]1=[O:37])[CH3:15].[N+:38]([C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH2:43]Br)([O-:40])=[O:39].O>C1COCC1>[CH3:28][O:27][C:25]1[C:24]([O:29][CH3:30])=[CH:23][C:22]2[N:16]([CH2:14][CH3:15])[C:17](=[O:37])[CH:18]([CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[N+:38]([O-:40])=[O:39])[N:19]=[C:20]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:21]=2[CH:26]=1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCN1C(=O)CN=C(c2ccccc2)c2cc(OC)c(OC)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(Cc2ccccc2[N+](=O)[O-])N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of 920 μl (1.84 mmol) of 2M LDA/THF in 5 ml of anhydrous THF, add dropwise at −78° C. under an inert atmosphere a solution of 300 mg (0.92 mmol) of 1-ethyl-7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbd) in 2 ml of THF. Allow to equilibrate to room temperature for 30 minutes. Add dropwise at −30° C. a solution of 220 mg (1.01 mmol) of 2-nitrobenzyl bromide in 2 ml of THF. Stir at room temperature for 12 hours. Add 1 ml of H2O. Evaporate the THF. Purify by silica chromatography (AcOEt 1/hexane 4, 1/1, then AcOEt). Recrystallize in EtOH/cHexane. Yield: 35%. M: 158–160° C. 1H-NMR (DMSO, 300 MHz): d 0.87–0.91 (m, 3H, CH3), 3.61–3.99 (m, 10H, NCH+CHCH2+2OCH3), 4.35–4.40 (m, 1H, NCH), 6.60 (s, 1H Ar), 6.82 (s, 1 H Ar), 7.37–7.90 (m, 9H Ar). Mass: (M+H)+=460.88.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]=[CH2:13]>CO.[Pd]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH3:13]
Reactant: C=Cc1c(Br)ccc2c1COC2=O
Agent: [Pd]
Solvent: CO
Product: CCc1c(Br)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-4-vinyl-2-benzofuran-1(3H)-one (2.0 g, 8.37 mmol) and Pd/C (400 mg) in 50 mL of MeOH was stirred at room temperature under H2 (1 atm) overnight, and then filtered. The filtrate was concentrated. The resulting oil was purified by column chromatography to give 5-bromo-4-ethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH:3]=[CH2:4].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[O:21]1[CH2:4][CH:3]1[CH2:2][CH2:1][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCC1CO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.9 %

Procedure:
To a mixture of 2-(but-3-en-1-yl)isoindoline-1,3-dione obtained in step 1 (0.65 g, 3.22 mmol) in dichloromethane (10 ml), was added m-chloroperoxybenzoic acid (1.11 g, 6.44 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 10 hours. After the reaction complete, the reaction mixture thus obtained was filtered through a plug of Celite. The filtrate was washed with 1 N sodium hydroxide solution and brine. The organic phase thus separated was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.65 g). The compound was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OB(O)c1ccccc1F
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccccc1F
Yield: 74 %

Procedure:
Prepared in 74% yield from 2-chloro-3-cyanopyridine and 2-fluorophenylboronic acid according to the procedure described for Example 153A. MS (ESI+) m/z 199.0 (M+H)+; 1H NMR (CDCl3) δ 7.22-7.34 (m, 2H), 7.42-7.55 (m, 2H), 7.57-7.63 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.91 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10](OC(=O)C2C=CC=CC=2)[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7]1)=[O:5])[CH3:2].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1OC(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of the crude 4-benzoyloxy-pyrrolidine-1,3-dicarboxylic acid 1-tert.-butylester 3-ethylester from the benzoylation described above in 75 ml dry toluene was added 4.11 g (27 mmol) DBU. The dark, heterogeneous mixture was stirred at room temperature for 16 h. After this time no starting material was detectable by TLC and GC analysis. The mixture was filtered through a short column of silica (elution with petrolether/ethyl acetate 1:1) and evaporated. Bulb-to-bulb distillation of the residual slightly yellow oil gave 4.16 g (86%) 2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-tert.-butylester 3-ethyl ester as a colorless oil b.p. 110° C./0.2 mbar, which slowly solidified to a waxy mass on standing in the freezer.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([S:21][CH2:22][C:23]([OH:25])=O)[CH:17]=[CH:18][C:19]=1[Cl:20].FC(F)(F)C([O-])=O.[NH2:33][C@@H:34]1[C:41](=[O:42])[N:40]2[C@@H:35]1[S:36][CH2:37][C:38](/[CH:46]=[C:47]1/[C:48](=[O:71])[N:49]([CH2:52][C:53]3[CH:58]=[CH:57][N+:56]([CH2:59][C:60](=[O:70])[NH:61][C:62]4[CH:67]=[CH:66][C:65]([OH:68])=[C:64]([F:69])[CH:63]=4)=[CH:55][CH:54]=3)[CH2:50][CH2:51]/1)=[C:39]2[C:43]([OH:45])=[O:44]>CN(C)C(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][CH2:22][C:23]([NH:33][C@@H:34]2[C:41](=[O:42])[N:40]3[C@@H:35]2[S:36][CH2:37][C:38](/[CH:46]=[C:47]2/[C:48](=[O:71])[N:49]([CH2:52][C:53]4[CH:54]=[CH:55][N+:56]([CH2:59][C:60](=[O:70])[NH:61][C:62]5[CH:67]=[CH:66][C:65]([OH:68])=[C:64]([F:69])[CH:63]=5)=[CH:57][CH:58]=4)[CH2:50][CH2:51]/2)=[C:39]3[C:43]([O-:45])=[O:44])=[O:25])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccc(Cl)c(Cl)c5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
With 60.0 mg (0.36 mmol) 1,1′-carbonyldiimidazole, 85.0 mg (0.36 mmol) [(3,4-dichlorophenyl)thio]acetic acid and 200.0 mg (0.30 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2 .0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([N:11]=[C:12]=[O:13])=[CH2:10].[N-]=C=O>C(OCC)(=O)C>[CH:9]([NH:11][C:12]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])=[O:13])=[CH2:10]
Reactant: C=CN=C=O
Reactant: O=C1CCCCCN1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CNC(=O)N1CCCCCC1=O
Temperature: 50 °C

Procedure:
113 parts of ε-caprolactam and 91 parts of ethyl acetate (+0.015% of dibutyl-tin dilaurate) are introduced into a reaction vessel and the mixture is heated to about 50° C. A mixture of 69 parts of vinyl isocyanate and 91 parts of ethyl acetate is then added dropwise in the course of 1 hour, after which the mixture is allowed to react for 5 hours. A pale yellow clear solution is obtained. Blocked isocyanate content: 11.5%.