Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14]2[CH:19]=[N:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1.[OH:23][C:24]([CH3:39])([CH3:38])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[O:36][CH3:37].Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]2[CH:19]=[N:18][N:17]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:24]([OH:23])([CH3:39])[CH3:38])=[C:28]([O:36][CH3:37])[CH:29]=3)[C:16](=[O:20])[CH:15]=2)=[CH:21][CH:22]=1
Reactant: O=c1cc(COc2ccc(Cl)cc2)cn[nH]1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-n2ncc(COc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O

Procedure:
Pyridine (0.123 mL, 1.52 mmol) was added in portions over 4 hr to a stirred mixture of 5-((4-chlorophenoxy)methyl)pyridazin-3(2H)-one Part B (36 mg, 0.15 mmol), copper(II) acetate (91 mg, 0.46 mmol), and 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (73.0 mg, 0.30 mmol) in CH2Cl2 (15 mL) at RT (flask left open to air). The mixture was poured into 3.0 N aqueous HCl (100 mL) and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated. The crude product was purified by prep-HPLC (C18 column/H2O:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) giving the title compound 5-((4-chlorophenoxy)methyl)-2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridazin-3(2H)-one E-2 (25 mg, 38% yield) as an off-white solid. LC/MS 431 (M+H)+, tR 0.93 min (method 5); 1H NMR (500 MHz, Chloroform-D) δ ppm 7.94 (1H, d, J=1.92 Hz), 7.30 (2H, d), 7.12-7.17 (2H, m), 7.09 (1H, br. s.), 6.98 (1H, d, J=8.25 Hz), 6.91 (2H, d), 4.97 (2H, s), 3.82-3.92 (5H, m), 1.35 (6H, s).
Reaction SMILES: ClC1C=C2C(CCN)=C([Si](CC)(CC)CC)NC2=[N:6]C=1.[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30]([NH2:6])=[O:31])[CH:26]=1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine (0.128 g; 0.413 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.104 g; 0.434 mmol), HATU (N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.165 g: 0.434 mmol) and N,N-diisopropylethylamine (0.108 mL; 0.619 mmol) in DMF (3 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The crude material was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) to give 0.108 g (49%) of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2, 3-1)]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@:6]1([C:26]([OH:28])=[O:27])[C@H:11]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([OH:24])=[O:23]>C(O)C1C=CC=CC=1>[CH2:26]([O:23][C:22]([C@:8]1([F:25])[C@@H:7]2[C@H:9]1[CH2:10][C@@H:11]([S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C@@:6]2([NH2:5])[C:26]([OH:28])=[O:27])=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: OCc1ccccc1
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 31.3 %

Procedure:
19 μL of thionyl chloride was added to 26 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid suspended in 0.3 mL of benzyl alcohol at ice-cooling, and then the mixture was stirred for 3.5 hours at 50° C. After standing to cool, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (Wako gel 50C18 (Wako Pharmaceutical Industries Ltd.), eluent: water to an aqueous 70% solution of acetonitrile), thereby yielding 5 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-benzyl ester. 2.19-2.43 (3H, m), 2.47-2.63 (1H, m), 2.96-3.12 (1H, m), 3.75 (1H, d, J=13.2 Hz), 3.81 (1H, d, J=13.2 Hz), 5.22 (2H, s), 7.23-7.54 (8H, m)
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1[O:22]C1.[H][H]>[Ru]>[CH2:2]1[O:3][CH2:1]1.[CH2:4]([C:13]1([OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCc1ccccc1O
Reactant: [H][H]
Agent: [Ru]
Solvent: C1CO1
Product: CCCCCCCCCC1(O)CCCCC1
Temperature: 100 °C

Procedure:
To 70 ml autoclave, 20 g (45.4 mmoles) of nonylphenol ethylene-oxide adduct having an ethylene oxide addition mole number of 5.0 and 2.0 g of powdery 5%-ruthenium alumina were charged. The reaction system was substituted with nitrogen, successively with hydrogen, and heated to 100° C. Hydrogen pressure was respectively controlled to the pressure shown in Table 2. Hydrogenation reaction was carried out for the time and at the temperature shown in Table 2 while feeding hydrogen so as to maintain the hydrogen pressure constant. After the reaction, the catalyst was filtered at 90° C. under increased pressure to obtain nonylcyclohexanol ethylene oxide adduct having an ethylene oxide addition mole number of 5.0. Table 2 shows amounts of consumed hydrogen, residual nonylphenol ethylene oxide adduct and nonylcyclohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[Cl:24][CH2:25][C:26](Cl)=[O:27].Cl>CC(C)=O>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]#[N:6])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(OCc2ccccc2)c(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)c(NC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A slurry of 3-amino-4-(benzyloxy)benzonitrile (7 g, 31.2 mmol) and anhydrous potassium carbonate (8.6 g, 62.4 mmol) in 50 mL of acetone was stirred under nitrogen as chloroacetylchloride (2.6 mL, 33 mmol) was added portion-wise. The reaction was stirred overnight. The reaction was poured into ice water and the liquid was neutralized with 6 N hydrochloric acid. The resulting solid was isolated by filtration, washed with water, and dried under reduced pressure to give 3-((chloromethyl)carbonylamino)-4-(benzyloxy)benzonitrile (8.3 g) as a white solid; NMR (CDCl3, TMS) δ4.22 (s, 2), 5.23 (s, 2), 7.03 (d, 1), 7.43 (m, 7), 8.73 (d, 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:12]=[C:11](S(C)(=O)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:29]#[N:30].[Na+]>CS(C)=O.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:12]=[C:11]([C:29]#[N:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1
Yield: 67.5 %

Procedure:
4-Benzyloxy-2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (92 mg) and sodium cyanide (22 mg) were stirred at room temperature in dimethylsulphoxide (500 μl) for 20 minutes. The reaction mixture was diluted with dichloromethane (40 ml) and washed with water (3×50 ml). Organics were separated, dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product (86 mg) as a yellow oil. Purification by flash chromatography on silica gave product 4-benzyloxy-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (54 mg).
Reaction SMILES: I[C:2]1[CH:22]=[N:21][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH:10]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=3[F:20])[CH3:11])[C:4]=2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:22]=[N:21][C:5]4[NH:6][CH2:7][CH2:8][N:9]([CH:10]([C:12]5[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=5[F:20])[CH3:11])[C:4]=4[CH:3]=3)=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1
Reactant: CC(c1cc(F)c(F)cc1F)N1CCNc2ncc(I)cc21
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CC(c1cc(F)c(F)cc1F)N1CCNc2ncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)cc21
Yield: 2 %

Procedure:
7-Iodo-1-[1-(2,4,5-trifluorophenyl)ethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (30 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid (2% yield). LCMS: m/z=560.73 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.26 (8H, m), 2.44 (7H, m), 3.64 (4H, m), 7.38 (1H, m), 7.47 (4H, m), 7.61 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][CH:19]=[C:20]([C:22]([O:24]C)=O)[CH3:21])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:22](=[O:24])[C:20]([CH3:21])=[CH:19][NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)C(C)=CNC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1c[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(methoxycarbonyl)propenyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 170°-173° C.,
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([O:41][C@H:42]1[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[CH:45](OC(=O)C)[O:44][C@@H:43]1[C:55]1[N:56]=[N:57][N:58]([CH2:60][CH3:61])[N:59]=1)(=[O:40])[CH3:39]>>[C:48]([O:47][C@@H:46]1[C@H:42]([O:41][C:38](=[O:40])[CH3:39])[C@@H:43]([C:55]2[N:56]=[N:57][N:58]([CH2:60][CH3:61])[N:59]=2)[O:44][C@H:45]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:22])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:50])[CH3:49]
Reactant: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCn1nnc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNC(=O)NCCN5CCCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1

Procedure:
Prepared from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea (Preparation 42) and (2R,3R,4R)-4,5-bis(acetoxy)-2-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (WO 9967265) by a similar procedure to Preparation 26. The title compound was obtained as a white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CO.O.O>[OH:3][CH:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:1]([O:9][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:8]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Reaction time: 8 h

Procedure:
To D/L-leucic acid (7.58 g, 57.36 mmol) in MeOH/H2O (9:1, 100 mL) was added a 20% solution of Cs2CO3 in water until the pH reached 7.0. The reaction mixture was concentrated in vacuo to dryness, DMF was added and concentrated in vacuo to dryness again. The solid was suspended in DMF (100 mL) at 0° C., 4-methoxybenzyl chloride (7.8 mL, 51.6 mmol) was added dropwise and the reaction mixture stirred overnight. The mixture was added to water and the product extracted with Et2O, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8, then 3/7) to afford 4-methoxybenzyl 2-hydroxy-4-methylpentanoate.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])=[O:33])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:18][CH2:19][S:20](=[O:23])[CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Yield: 43.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline (117 mg, 0.35 mmol) and 2-chlorophenylisocyanate (58 mg, 0.28mmol) were coupled to form the desired urea (58 mg, 35%). LC-MS (m/z) 478.0 (M+).
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH2:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH3:17])[CH:13]=[CH:12][N:11]=1)[CH3:8]>CO>[CH2:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=[N:2][OH:3])[CH3:17])[CH:13]=[CH:12][N:11]=1)[CH3:8]
Reactant: CCNc1cc(C(C)=O)ccn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNc1cc(C(C)=NO)ccn1
Yield: 87 %

Procedure:
To a mixture of 7 g. (0.1 mole) of hydroxylamine hydrochloride in 40 ml. of water and 50 ml. of 2 N sodium hydroxide was added 11.5 g. (70 mmoles) of 1-(2-ethylamino-4-pyridyl)-1-ethanone, and the resulting mixture heated to boiling. Methanol was carefully added until the mixture became homogeneous. Heating was continued until the mixture became cloudy. The mixture was cooled and the resulting precipitate filtered, washed with water and dried. Recrystallization from toluene gave 10.9 g. (87%) of the desired product, m.p. 155°-156° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH3:10])=[O:8].S.[Na].BrC[C:20]([OH:22])=[O:21]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][C:20]([OH:22])=[O:21])=[O:8]
Reactant: COC(=O)C(c1cccs1)c1cccs1
Reactant: O=C(O)CBr
Agent: S
Agent: [Na]
Solvent: CO
Product: O=C(O)COC(=O)C(c1cccs1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a well stirred solution of methyl dithiophenylacetate (16.2 grams, 0.089 mole) in methanol (50 mL) was added anhydrous sodium hydrogen sulfide (5.6 grams, 0.10 mole). The mixture was stirred overnight at room temperature, and the solvent removed in vacuo. The solid salt thus obained was taken up in tetrahydrofuran (125 mL). To the solution was added bromoacetic acid (12.4 grams, 0.089 mole). The resulting mixture was stirred for 2 hours at room temperature, and the solvent removed in vacuo. The resulting solid was taken up in 5% (w/v) aqueous sodium bicarbonate, then washed twice with chloroform. The aqueous layer was acidified by the addition of concentration HCl and then extracted three times into diethyl ether. The combined ethereal extracts were dried over anhydrous Na2SO4. The solvent was then finally removed in vacuo to afford carboxymethyl dithiophenylacetate, an orange solid, in 94.5% yield.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=O.[N+]([O-])(O)=O.[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:21])[F:20].[OH-].[Na+]>C(O)C(C)C>[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[NH:8][CH:9]=[CH:10][CH:11]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:20])[F:21]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)CO
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccc[nH]3)n2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 100 mg (0.61 mmol) of 3-dimethylamino-(1H-pyrrol-2-yl)2-propen-1-one [described in EP-A-0 233 461]in 4 ml of isobutanol are added 185 mg (0.60 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate. Following the addition of 32.5 mg (0.81 mmol) of sodium hydroxide, the reaction mixture is stirred for 3 hours at 110° C. The suspension is concentrated under reduced pressure, the residue is dissolved in 4 ml of methylene chloride/tetrahydrofuran (1:1 ), and the solution is extracted with 2.4 ml of water. The organic phase is dried over sodium sulfate and concentrated on a rotovap. Recrystallisation from diethyl ether/tetrahydrofuran gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-(1H-pyrrol-2-yl)-2-pyrimidine-amine; FAB-MS:353 (M+ +1 ), m.p. 142-143, Rf =0.83 (methylene chloride:methanol=9:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[C:26]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([O:24][C:41](=[O:42])[CH2:40][NH:39][C:37](=[O:38])[CH2:36][NH:35][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCC(=O)NCC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(CC(=O)OC(C)(C)C)OC(=O)CNC(=O)CNC(=O)CCCCCCC
Yield: 29.6 %

Procedure:
1.96 g of 3-hydroxyoctadecanoic acid tert-butyl ester and 1.43 g of N-octanoylglycylglycine were mixed with 40 ml of methylenechloride. By following the same procedure as in Example 23-(i) after adding 60 mg of DMAP and 1.14 g of DCC, 970 mg of 3-(N-octanoylglycylglycyloxy)octadecanoic acid tert-butyl ester was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][O:5][C:6](=[O:25])[CH:7]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:19])=[CH:11][CH:10]=1.C1C=CC([I+][C:35]2[C:40]([C:41]([O-:43])=[O:42])=[CH:39][CH:38]=[CH:37][CH:36]=2)=CC=1.Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:24][O:23][C:21]([NH:20][CH:7]([C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:26])[CH3:27])=[O:25])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH:19][C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:40]=2[C:41]([OH:43])=[O:42])=[CH:11][CH:10]=1)=[O:22]
Reactant: COC(=O)NC(Cc1ccc(N)c2ccccc12)C(=O)OCC[Si](C)(C)C
Reactant: O=C([O-])c1ccccc1[I+]c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)NC(Cc1ccc(Nc2ccccc2C(=O)O)c2ccccc12)C(=O)OCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
A mixture of 3-(4-amino-naphthalen-1-yl)-2-methoxycarbonylamino-propionic acid 2-trimethylsilanyl-ethyl ester (0.93 g, 2.40 mmol), diphenyliodonium-2-carboxylate (1.22 g, 3.8 mmol, 1.5 eq) and copper(II) acetate (25 mg, 0.14 mmol, 0.06 eq) in N,N-dimethylformamide (25 mL) was heated to 100° C. for 14 hours, then cooled to room temperature. The mixture was acidified to a pH <3 with 1N HCl, extracted with ethyl acetate (3×35 mL). The combined organic layers were washed with 1N HCl (1×25 mL), water (1×25 mL), brine (1×25 mL), and dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 4:1 toluene/ethyl acetate to provide the titled compound. MS ESI(−)) m/e 507 (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.F[C:25]1[C:30]([C:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:25]2[C:30]([C:31]3[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH:32]=3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:19][CH:18]=1
Reactant: OC1CC=C(c2cccnc2F)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: OC1CC=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 200 °C
Yield: 6.3 %

Procedure:
To a vial containing cesium carbonate (1391 mg, 4.27 mmol) was added 4-(benzo[d]thiazol-2-ylamino)phenol (1035 mg, 4.27 mmol), and 4-(2-fluoropyridin-3-yl)cyclohex-3-enol (330 mg, 1.708 mmol) followed by NMP (2.2 mL). The reaction was heated at 200° C. for 2 h with microwave irradiation. The black mixture was diluted with ethyl acetate and washed with 5N NaOH before drying over sodium sulfate, filtering, and concentrating under reduced pressure to a brown residue. Purification by column chromatography (ethyl acetate/dichlormethane) afforded 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)cyclohex-3-enol (44.8 mg, 0.108 mmol, 3, steps, 6.31% yield) as a pale brown oil. MS (ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mg].II.CN([CH:26]=[O:27])C.Cl>C1COCC1.ClCCl>[C:1]12([C:11]3[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH:26]=[O:27])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
11.09 g 37 mmoles) of 2-(1-adamantyl)-4-bromo anisole dissolved in 85 ml of THF are slowly added to 1 g of magnesium and an iodine crystal. At the beginning of the addition, the reaction mixture is heated until the reaction begins, then the remainder of the solution is added in a manner to maintain a regular reflux. This reaction mixture is heated at reflux for 30 minutes after the end of the addition at which point 2.70 g (37 mmoles) of dry DMF are added. The reaction mixture is then stirred for 30 minutes without heating and then poured into 300 ml of mixture of 2N aqueous HCl and dichloromethane.