Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26]([NH:29][C@@H:30]([C:32]([OH:34])=O)[CH3:31])(=[O:28])[CH3:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1.ClCCl>[C:26]([NH:29][CH:30]([CH3:31])[C:32]([N:2]([CH3:1])[CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N[C@H](C)C(=O)O
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NC(C)C(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), N-acetyl-D-alanine (7 mg, 0.053 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (13 mg, 0.068 mmol), 1-hydroxybenzotriazole (9 mg, 0.068 mmol), dichloromethane (1 mL) and THF (0.5 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column which was eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (13 mg, 65% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10]([CH:12]=O)=O>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:7]=1)=[N:8][CH:10]=[CH:12][N:9]=2
Reactant: Cc1ccc(N)c(N)n1
Reactant: O=CC=O
Solvent: CO
Product: Cc1ccc2nccnc2n1
Reaction time: 18 h
Yield: 80 %

Procedure:
6-Methyl-pyridine-2,3-diamine (1.01 g, 8.2 mmol) was dissolved in MeOH (40 ml) and glyoxal (14 ml of a 40% aqueous glyoxal solution). Allowed to stir 18 h. The MeOH was removed, and the crude was taken up in ethyl acetate. It was washed three times with a 1 N HCl solution. The combined acid washings were washed twice with ethyl acetate. The acidic water was made basic with the addition of solid sodium carbonate, and it was extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried using MgSO4, and concentrated under vacuum to yield the title product (980 mg, 80%) as a brown solid. 1H NMR (DMSO-d6): δ=9.09 (d, 1H,J=1.8 Hz), 8.99 (d, 1H, J=1.8 Hz), 8.47 (d, 1H, J=8.5 Hz), 7.82 (d, 1H, J=8.5 Hz), 2.78 (s, 3H). Calculated mass=145, [M+H]+=146.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Br)c2F)c1
Yield: 69 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.046 g, 0.158 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.032 g, 0.158 mmol) and DIEA (0.055 mL, 0.316 mmol) were combined in THF (3 mL) and treated with EDC (0.061 g, 0.316 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 4-bromo-N-({4-chloro-3-[(3-cyano-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.052 g, 0.109 mmol, 68.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6+1 drop D2O) δ ppm 7.38-7.49 (m, 2H), 7.31 (t, J=7.90 Hz, 1H), 7.15 (m, 1H), 7.11 (s, 1H), 4.47 (s, 2H), 2.31 (s, 3H), 2.24 (s, 3 H). LC-MS (ES−) m/z 475.07, 477.03, 479.03 [M−1]. LC-MS (ES+) m/z 477.11, 479.09, 481.07 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([CH3:12])[CH3:9]
Reactant: CC(C)=O
Reactant: Cc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(NC(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a stirred solution of 5.65 g (52.7 mmol) p-Toluidine and 3.21 g (55.4 mmol, 1.05 equiv) Acetone in 50 mL DCE is added 14.52 g (68.5 mmol, 1.3 equiv) Sodium triacetoxyborohydride and stirred 18 h at ambient temperature. The reaction mixture is diluted with DCM (200 mL), washed successively with H2O (75 mL), satd. NaHCO3 (75 mL), and brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo to give 7.67 g (51.4 mmol) of Isopropyl-p-tolyl-amine as a pale amber oil: 1H NMR (CDCl3, 300 MHz) δ7.00 (d, 2H, J=8.3), 6.54 (d, 2H, J=8.4), 3.61 (m, 1H), 2.25 (s, 3H), 1.21 (d, 6H, J=6.3); TLC Rf =0.50 (EtOAc/Hexanes, 1:9).
Reaction SMILES: O.[OH-].[Li+].C(OC([N:11]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=O)C(C)C.CO.O>O1CCCC1>[C:29]([CH:28]=[CH:27][C:24]1[CH:25]=[CH:26][C:21]([C:16]2[C:15]([S:12]([NH:11][C:33]3[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=3)(=[O:13])=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=1)([OH:31])=[O:30]
Reactant: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
Lithium hydroxide monohydrate (87 mg) was added to a solution of N-isobutoxycarbonyl-2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (250 mg) in tetrahydrofuran (6.2 ml) followed by methanol (2.5 ml) and water (2.5 ml). The reaction mixture was stirred at ambient temperature for 18 hours then evaporated to dryness. The residue was dissolved in water (50 ml), washed with ethyl acetate (50 ml), acidified with 8% aqueous citric acid to pH 3-4 and extracted with ethyl acetate (100 ml). The organic layer was extracted with saturated sodium bicarbonate solution (50 ml) and the aqueous phase separated, acidified with 8% aqueous citric acid and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 2-[-4-(2-carboxyvinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (108 mg) as a solid, m.p. 233-235° C.: 1H NMR (d6-DMSO): 2.2 (s, 3H), 3.8 (s, 3H), 6.55 (d, 1H), 7.35 (br s, 1H), 7.45 (d, 2H), 7.55-7.75 (m, 4H), 8.45 (dd, 1H), 8.8 (dd, 1H), 10.1 (br s, 1H); mass spectrum (+ve ESP) 427 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][OH:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reaction time: 1 h

Procedure:
To a mixture of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-(phthalimidoacetyl) amino]benzene (399 mg) and triethylamine (0.17 ml) in methylene chloride (8 ml) was added methanesulfonyl chloride (0.086 ml) under -20° C., and the mixture was stirred for 1 hour. The mixture was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give 2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (561 mg).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](C#CC3C=CC=CC=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.FC1C=CC=CC=1.[Br:31]C1C=CC(CCl)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:31][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: ClCc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Fc1ccccc1
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Yield: 86 %

Procedure:
Synthesis of 4-fluoro-4'-phenylethynylbenzophenone In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser was placed fluorobenzene (117 g, 1.2 mol), and 4-bromobenzyl chloride (39.8 g, 0.181 mol). The mixture was cooled to 0° C. an anhydrous aluminum chloride (27 g, 0.20 mol) was added. The mixture was stirred at 23° C. for 16 hours. The resulting slurry was poured into 2 L of acidic (HCl) water. The organics were extracted with methylene chloride, and dried over magnesium sulfate. The slurry was filtered and the methylene chloride was removed under reduced pressure. Recrystallization from ethanol afforded 43.3 g (86%) of 4-bromo-4'-fluorobenzophenone as white crystals: mp 106°-107° C. (Lit 107°-108° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].C1CCCCC=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred suspension of 8-fluoro-5-(4-methoxyphenylsulfonyl)-6-methyl-5,6-dihydrophenanthridine (1.26 g, 3.29 mmol) and cyclohexene (6.0 mL, 59 mmol) was treated drop-wise with a solution of 1 M boron tribromide (20 mL, 20 mmol) in dichloromethane at room temperature under nitrogen. After stirring for 20 hours at room temperature, a saturated, aqueous, sodium bicarbonate solution (300 mL) was added drop-wise, and the resulting mixture extracted with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:19 to 1:4 gradient), followed by re-crystallization from a mixture of dichloromethane-hexane to yield the title compound as a homogeneous, white, crystalline, solid (1.1 g, 90%). The melting point, mass spectum, and NMR spectrum of this product were identical to the authentic material prepared in Example 32, Method A, Step e.
Reaction SMILES: C([N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH2:14]Br)[NH:6][C:5]1=[O:16])(=O)C.[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:35]>CC(O)C.O.C(O)C>[ClH:35].[C:17]1([CH:23]2[CH2:24][CH2:25][N:26]([CH2:14][C:7]3[NH:6][C:5](=[O:16])[NH:4][C:8]=3[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1c(CBr)[nH]c(=O)n1C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)c1[nH]c(=O)[nH]c1CN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.4 g (15 mmole) of ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate 2.5 g (16 mmole) of 4-phenylpiperidine, 2.1 g (15 mmole) of potassium carbonate and 75 ml of ethanol is stirred at 25° C. for 16 hours. Water (100 ml) is added and a precipitate forms. This is separated by filtration and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated by filtration and recrystallized from 2-propanol containing a little water to give ethyl 2,3-dihydro-5-[(4-phenyl-1-piperidinyl)methyl]-2-oxo-1H-imidazole-4-carboxylate hydrochloride melting at about 240°-241° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3C=O)[CH2:20][C:19]2=[O:33])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[C:34](=[O:37])([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:49][N:50]=[C:51]=O)(=O)=O)=CC=1>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[C:49]3[N:50]=[CH:51][O:37][CH:34]=3)[CH2:20][CH:19]2[OH:33])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7]
Reactant: O=Cc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(=O)C1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: [K+]
Solvent: CO
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3-c3cocn3)CC2O)CCCCC1)c1ccco1
Yield: 107.4 %

Procedure:
The mixture of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-formylhenyl)piperidin-3-ol (3.0 g, 6 mmol) obtained in Example 79, potassium carbonate (2 g, 20 mmol) and p-toluenesulfonylmethyl isocyanate (TosMIC; 1.8 g, 9 mmol) was refluxed in 500 ml of methanol for about 2 hours. The reaction mixture was concentrated, added water thereto, and extracted with dichloromethane. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 3.2 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:16])([F:17])[F:18])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[CH2:20][O:21][CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]
Reactant: Cn1nc(-c2cc(CO)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)OC(=O)COCc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
At 25° C., 1.7 g (5.0 mmole) 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol, 0.8 g (5.5 mmole) K2CO3 and 0.7 mL (5.5 mmole) isopropyl bromoacetate were slurried in 15 mL DMSO. The mixture was stirred overnight at 45° C. The mixture was cooled, diluted with 100 mL cold water and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4 and stripped in vacuo. The residue was purified chromatographically using 10% ethyl acetate in hexane as the eluent to give 0.9 g (41%) of ((2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenyl)methoxy)acetic acid, 1-methylethyl ester as a white solid; mp 55° C.
Reaction SMILES: C[Si](C)(C)[Br:3].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Br:3])=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: C[Si](C)(C)Br
Reactant: COCCCOc1cc(CO)ccc1OC
Solvent: ClC(Cl)Cl
Product: COCCCOc1cc(CBr)ccc1OC

Procedure:
97 ml of trimethylbromosilane are added, with stirring at room temperature, to 113.1 g of 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcohol in 1.31 liters of chloroform. After 10 minutes the solvent is evaporated off and the residue is immediately purified by means of FC (900 g of silica gel, eluant: ethyl acetate/hexane 1:3). The title compound is obtained: Rf (ethyl acetate/hexane=1:2)=0.34; m.p. 50°-51° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.O1CCOCC1.[C:18](=O)([O-:20])[O-:19].[Na+].[Na+]>O.CCOC(C)=O>[CH3:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=2)[NH:8][N:9]=1
Reactant: Cc1n[nH]c2ncc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ncc(C(=O)O)cc12
Temperature: 165 °C
Reaction time: 0.01 h
Yield: 28.8 %

Procedure:
A microwave tube was charged with 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (515 mg, 2.43 mmol), dioxane (2 mL), Hermann's catalyst (72.1 mg, 0.12 mmol) and a solution of sodium carbonate (772 mg, 7.29 mmol) in water (5 mL). The mixture was stirred for 20 sec, heated at 165° C. for 15 minutes in a microwave reactor at very high absorption setting. The reaction was vented before handling. The mixture was diluted with EtOAc and stirred for 5 minutes before filtering through diatomaceous earth to provide the title compound (124 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:26]([N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]1)[CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH2:26]([N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(CC)CC1CCCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)CC1CCCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(N-butyl-N-ethylaminomethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.23 minutes; C29H37Cl2N5O2 (558.55); mass spectrum: (M−H)−=558/560 (chlorine isotope).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:34][C@H:12]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[OH-].[K+].[CH2:40](I)[CH3:41]>C1C=CC=CC=1.O1CCOCC1>[CH2:40]([O:11][C@@H:10]1[C@@H:12]([CH2:13][O:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:34][C@@H:8]([N:7]2[CH:35]=[C:3]([CH2:1][CH3:2])[C:4](=[O:37])[NH:5][C:6]2=[O:36])[CH2:9]1)[CH3:41]
Reactant: CCI
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 6 g of 2'-deoxy-5-ethyl-5'-O-trityluridine, 1.347 g of powdered potassium hydroxide and 1.95 ml of ethyl iodide in a mixture of 60 ml of benzene and 20 ml of dioxane was stirred and heated under reflux for 14 hours. The solvents were removed by evaporation, the residue was taken up in 6 ml of methanol and the solution was poured into 250 ml of water. The resulting mixture was extracted four times with 150 ml of chloroform each time and the combined chloroform extracts were evaporated to give 2'-deoxy-3'-O-ethyl-5-ethyl-5'-O-trityluridine which was used directly in the next step.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.Cl[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1>CN(C=O)C>[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1
Reactant: O=Cc1c[nH]cn1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2cnccn2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.4 %

Procedure:
Sodium hydride (60% in oil, 720 mg, 18.0 mmol) was added to a 0° C. solution of 1H-imidazole-4-carboxaldehyde (2.20 g, 18.0 mmol) in DMF (8 mL). After stirring for 20 min at 0° C., the mixture was allowed to warm to RT and a solution of 2-chloropyrazine (2.06 g, 17.9 mmol) in DMF (4 mL) was added. The resulting mixture was heated to 100° C. for 18 h. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated to provide 3.10 g (86%) of the title compound. MS 175 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:34][C:35](=O)[CH2:36][CH2:37][N:38]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]1=[O:48])[C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:54]>C(O)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[CH:34]=[C:35]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])[N:54]=[C:25]1[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: Cc1ccc(C(=O)N(CC(=O)CCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc(CCN3C(=O)c4ccccc4C3=O)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 4.9 %

Procedure:
A solution of N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-N-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-oxo-butyl]-4-methyl-benzamide (641 mg, 9.948 mmol) and ammonium acetate (3.65 g, 47.4 mmol) in acetic acid (30 mL) was refluxed for 6.0 h using a Dean-Stark trap and condenser. The reaction was concentrated in vacuo and the residue was triturated with water, dried in a Buchner funnel, and recrystallized from ethanol to provide the title compound as a white solid (320 mg, 51%). MS(ES+) m/e 656 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[OH:28][CH2:29][CH:30]([CH2:32]O)[OH:31].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:32][CH:30]([OH:31])[CH2:29][OH:28])=[O:24])=[CH:26][CH:27]=1
Reactant: OCC(O)CO
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A solution of 11.8 g. of 4-(16-bromohexadecylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(16-bromohexadecylamino)benzoate as a white solid.