Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCBr
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K2CO3 (12.5 g), and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours and left standing at room temperature overnight. The solvent of the reaction was removed on a rotary evaporator, and the crude solid was extracted into methylene chloride (500 ml). The insolubles were filtered off. The dichloromethane solution was concentrated and the material was purified on a flash chromatography column (SiO2, 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichloromethane). The desired product thus purified weighed 7.74 g (52%). Recrystallization twice from ethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrile, m.p.=99°-101° C.
Reaction SMILES: [I-:1].[CH2:2]([N+:4]1[C:8]2[CH:9]=[C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:18])[CH3:3].[C:19]1([N:25](C2C=CC=CC=2)[CH:26]=N)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CC(C)=O>[I-:1].[NH:25]([CH:26]=[CH:18][C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][C:8]=2[N+:4]=1[CH2:2][CH3:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: CC[n+]1c(C)oc2ccc(NS(C)(=O)=O)cc21
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC[n+]1c(C=CNc2ccccc2)oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Yield: 94.5 %

Procedure:
Intermediate E (1.0 g) and diphenylformamidine (2.2 g) were combined in a flask and heated over a hot air gun with manual stirring until a yellow-orange color formed. The reaction was then heated for 1 minute at full heat until it became totally liquid. On cooling to room temperature, the reaction mixture solidified. This solid was dissolved in 20 ml hot acetone, poured into 100 ml diethyl ether with stirring, and stirred for 1 hour. The solid was then filtered out and washed with diethyl ether to give 1.2 g of 2-(2-anilinovinyl)-3-ethyl-5-methylsulfonamidobenzoxazolium iodide (Intermediate F).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([O:34][CH3:33])[CH:36]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)c1
Yield: 75.9 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-methoxybenzylamine (available from Aldrich Chemical Company, Inc.; 85 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-methoxy-benzylcarbamoyl)-biphenyl-2-carboxylic acid (94 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 9.08 (t, J=5.6 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.26 (t, J=7.9 Hz, 1H), 6.89-6.94 (m, 2H), 6.83 (d, J=8.3 Hz, 1H), 4.49 (d, J=5.8 Hz, 2H), 3.75 (s, 3H).
Reaction SMILES: [OH-].[K+].CO[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([O:9]CC)=O.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].S(=O)(=O)(O)O>CO>[OH:9][C:7]1[CH:6]=[C:5]([C:12]([F:13])([F:14])[F:15])[S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: CCOC(=O)C=C(OC)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1sc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
A solution of 1M potassium hydroxide in methanol (30 ml) is added to a cooled mixture of 5A (4.6 g), methyl thioglycolate (2.46 g) and methanol (10 ml). The resulting reaction mixture was stirred for 24 hours at room temperature. Then the mixture was poured on ice and acidified with 6N sulfuric acid (pH=2). The mixture is extracted with diethyl ether twice. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue is distilled under reduced pressure to yield the product as a clear liquid (3.4 g, 65%) with a boiling point of 42-45° C. at 0.10 mm.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1ccc(CCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 4.5 g (0.022 mole) 4-(acetylamino)benzenebutanol in 25 ml pyridine, add 8.3 g (0.044 mole) tosyl chloride and chill in the refrigerator overnight. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonium hydroxide, 90:10). At the completion of the reaction, pour the reaction mixture onto 500 ml ice water and stir for 15 minutes. Extract the aqueous mixture with 3×300 ml ether. Wash the combined organic layers with 1N hydrochloric acid, then with water, dry over potassium carbonate, filter and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:20][N:19]([CH3:21])[C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: CN(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: CN(C)c1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 51 %

Procedure:
2-chloro-1-(4-dimethylaminophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-dimethylaminophenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (51% yield). ESI/MS 349 (M+H); RT=2.44 min; NMR (CDCl3) 10.24 (1H, s); 8.25 (1H, d, J=9 Hz); 7.20 (3H, m); 7.10 (1H, m); 6.97 (1H, d, J=9 Hz); 6.83 (2H, d); 3.29 (4H, m); 3.05 (6H, s); 2.82 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:26]([O-])=O)[CH:5]=[C:6]([Cl:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:10]=1>[Pt].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:10]=1)[NH2:26]
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1Cc1ccc(F)cc1
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(Oc2c(Cl)cc(N)cc2Cl)cc1Cc1ccc(F)cc1

Procedure:
3,5-Dichloro-4-[3'-(4-fluorobenzyl)4'-methoxyphenoxy]nitrobenzene (3.64 g) and 360 mg of 10% platinum on carbon in 200 ml ethanol is hydrogenated on a Parr shaker. Catalyst is removed by filtration through Celite and the filtrate stripped to afford 3,5-dichloro-4-[3'-(4-fluorobenzyl) 4'-methoxyphenoxy]-aniline. This is redissolved with 1.10 ml ethyl bromoacetate and 1.28 g of diisopropylethylamine in 30 ml dimethylformamide and heated at 140° for 18 hours. Solvent is removed with high vacuum and the residue dissolved in ethyl acetate and extracted twice with water. The ethyl acetate is dried, filtered and stripped to give crude product. Chromatography on silica gel with 80:20 to 70:30 hexane:ethyl acetate affords pure ethyl N-[3,5-dichloro-4-[3'-(4-fluorobenzyl)-4'-methoxyphenoxy]-phenyl]aminoacetate; NMR (CDCl3): δ1.3 (3H, t), 3.7 (3H, s), 3.9 (2H, s), 3.9 (2H, s), 4.3 (2H,q), 6.6 (1H, d of d), 6.7 (1H, d), 6.8 (1H, d), 6.9 (2H, m), 7.1 (2H, m), 7.3 (2H, s).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]3=[CH:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:38].[Na+].ClC1C=CC=C(C(OO)=O)C=1.O>COC(C)(C)C>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:38][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 24.55 kg amount of (3β,5α)-cholesta-7,14-dien-3-ol benzoate (2) (prepared in the manner described in Example 1) and 6.41 g of sodium bicarbonate were suspended under nitrogen with good agitation in 240 liters of t-butyl methyl ether in a 200-gallon reactor and chilled to 0° C. A solution of 13.0 kg of m-chloroperbenzoic acid in 100 liters of t-butyl methyl ether at about 20° C. was added to the steroid-bicarbonate suspension over a 10 minute period. A mild exothermic reaction which raised the reaction mixture temperature to 10° C. was noted. The mixture was stirred for 2 hours then 150 liters of water were added. The mixture was stirred an additional hour and agitation was halted to allow separation of the phases. The lower aqueous layer was drained off and the remaining organic phase was treated with 50 liters of water, agitated vigorously, and then the aqueous portion was drained off. The product was filtered at about 10° C., washed with three 10 liter portions of methanol and air-dried to yield 19.1 k9 of (3) batch-A.
Reaction SMILES: [C:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br-].[Mg+2].[Br-].Cl>C1COCC1>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][CH2:11][C:12](=[O:13])[CH:5]=[C:4]([CH3:7])[CH3:6])[C:14]([OH:16])=[O:15])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Agent: Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC(C)=CC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-Boc-pyroglutamic acid (0.23 g 1.0 mmol) in 10.0 ml of anhydrous THF was added 2-methylprop-1-enyl)magnesium bromide (0.5 M in THF, 5 mL, 2.5 mmol) at −78° C. slowly. The reaction mixture was stirred for 1 h at −78° C. 1 N HCl (2.5 ml) aqueous solution was added and the mixture was slowly warmed up to RT. The pH was adjusted to ˜3 by 1 N HCl. The THF was then removed under vacuum and the remaining aqueous was extracted by DCM (3×20 mL). The organic layer was dried over Na2SO4, filtered and the solvent was removed to provide the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][C@@H:13](OC(=O)C)[O:12][C:11](=[O:23])[C:10]2[C:24]([CH3:31])=[C:25]([O:29][CH3:30])[CH:26]=[C:27]([OH:28])[C:9]=2[CH:8](C)[S:7][CH2:6]1)=[O:4].[C:33](=O)([O-])[O-:34].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][C@@H:13]([CH2:33][OH:34])[O:12][C:11](=[O:23])[C:10]2[C:24]([CH3:31])=[C:25]([O:29][CH3:30])[CH:26]=[C:27]([OH:28])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1CSC(C)c2c(O)cc(OC)c(C)c2C(=O)O[C@H](OC(C)=O)CCC(=S)N1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)O[C@H](CO)CCC(=S)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 24 mg of the product of Example 11 and 8.3 mg of potassium carbonate in 0.5 ml of methanol was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and with water. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to yield 16 mg of (4R,9S)-15-hydroxy-9-hydroxymethyl-13-methoxy-12-methyl-11-oxo-6-thioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[CH:17]\I)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[CH:17][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:13]
Reactant: C#Cc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc(C(C)=O)cc1

Procedure:
The general procedure was used to convert 1-(4-Ethynyl-phenyl)-ethanone and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (440 mg, 20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (92% yield). 1H NMR (400 MHz, CDCl3) δ 7.93-7.90 (d, J=8.5, 2H), 7.60-7.58 (d, J=8.5, 2H), 6.38-6.35 (d, J=11.4, 1H), 6.20-6.18 (d, J=11.4, 1H), 4.28-4.23 (q, J=7.1, 2H), 2.58 (s, 3H), 1.34-1.30 (t, J=7.1, 3H). 13C NMR (100MHz, CDCl3) δ 197.09, 164.54, 136.87, 132.09, 129.43, 128.24, 127.39, 122.22. 99.65, 89.11, 60.53, 26.59, 14.29. Anal. Calcd. for C15H14O3: C, 74.36; H, 5.82; Found C, 74.31; H, 5.97.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:19]([OH:23])[C:20]([OH:22])=O)=[O:16])[NH:12][C:9]2=[CH:10][N:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:24]([C@H:18]([NH:17][C:15]([C:13]1[NH:12][C:9]2=[CH:10][N:11]=[C:6]([Cl:5])[CH:7]=[C:8]2[CH:14]=1)=[O:16])[C@@H:19]([OH:23])[C:20](=[O:22])[NH:4][CH2:1][CH2:2][CH3:3])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCN
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
n-Propylamine (16 μL, 0.19 mmol) was added to a solution of 3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(R)-hydroxy-4-phenylbutyric acid (EXAMPLE 44, 40 mg, 0.11 mmol), HOBt (16.4 mg, 0.11 mmol), DIPEA (41 μL, 0.24 mmol) and EDCI (25 mg, 0.13 mmol) in DMF (3 mL). After stirring for 72 h at room temperature the solvent was removed in vacuo and the remaining residue was purified by preparative LCMS to give the title compound as colourless solid. m/z (ES+)=415.34 [M+H]+; RT=3.10 min.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25].O>CN(C)C=O>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:30])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 59.3 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (234 mg, 1.00 mmol) prepared in Process 3 of Example 12 in N,N-dimethylformamide (2 mL) was added with potassium carbonate (277 mg, 2.00 mmol) and ethylbromoacetate (167 mg, 1.00 mmol) at room temperature, and the resultant was stirred at 80° C. for 20 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=2:1), and ethyl [4,4-dimethyl-3-oxo-2-(adamantan-2-yl)-1,2-diazetidin-1-yl]acetate (190 mg, 59.4%) was obtained as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Si:7]([O:14][CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@H:17]1[NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)=[O:44]>C(#N)C.CN(C)C=O>[Si:7]([O:14][CH2:15][C@H:16]1[N:19]([CH2:42][C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)=[O:44])[C:18](=[O:20])[C@H:17]1[NH:21][C:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(COC(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)CN2C(=O)[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.7 %

Procedure:
Cesium carbonate (1.58 g) was added to a stirred solution of(3S,4S)-4-t-butyldimethylsilyloxymethyl-3-tritylaminoazetidin-2-one (1.45 g) (IV) (H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190-1196) in a mixture of acetonitrile (44 ml) and dimethylformamide (35 ml). 4-Methoxybenzyl bromoacetate (1.44 g) was then added and the mixture stirred at room temperature for 48 h. The mixture was then partitioned between ethyl acetate and water, the organic phase was washed four times with water, and then with brine. The solution was dried over magnesium sulphate and evaporated. The title compound (2.29 g) was isolated by column chromatography of the residue (Silica gel, 3:1 hexane:ethyl acetate as eluent). [α]D21 -9.0°; νmax (CHCl3) 3352, and 1755 cm-1 ; δ(CDCl3) -0.04 (3H, s), 0.00 (3H, s), 0.88 (9H, s), 1.69 (1H, br s), 2.54 (1H, dd, J 3.33 and 11.68 Hz), 3.19 (1H, dd, J 2.05 and 11.68 Hz), 3.38 (1H, m), 3.51 (1H, d, J 17.98 Hz), 3.90 (3H, s), 4.46 (1H, d, J 17.98 Hz), 4.54 (1H, m), 5.06 (1H, d, J 11.79 Hz), 5.15 (1H, d, J 11.81 Hz), 6.94 (2H, d, J 8.68 Hz), 7.2-7.65 (17H, m).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:19]=[CH:18][CH:17]=1
Reactant: CCc1cnccc1C
Reactant: Clc1cccc(CCCBr)c1
Product: CCc1cnccc1CCCCc1cccc(Cl)c1
Yield: 61 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 3.53 g (15.1 mmol) of 1-bromo-3-(3-chlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.52 g of the desired compound (yield: 61.0%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:14].[Cl:15][C:16]1[CH:17]=[C:18]([C:28](O)=O)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:14][C:3]1[CH:4]=[C:5]2[CH:6]=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:28]([C:18]1[N:19]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:20]=[C:16]([Cl:15])[CH:17]=1)[O:12][C:11]2=[O:13]
Reactant: Nc1c(Cl)cc2cn[nH]c2c1C(=O)O
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc3cn[nH]c3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a suspension of 1.00 g (4.58 mmol) of 6-amino-5-chloro-1H-indazole-7-carboxylic acid in 40 mL of anhydrous acetonitrile is added 1.18 g (4.58 mmol) of 5-chloro-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid followed by 1.7 mL (20.6 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 1.25 mL (16.0 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at ambient temperature for 6 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. Purification by flash chromatography (SiO2, toluene/methylene chloride/ethyl acetate 10:10:3) affords 910 mg (39%) of the product as a yellowish solid; LC/MS:433/435 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH3:11][C:12]1[S:29][C:15]2=[N:16][C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:18]([C@@H:20]([NH2:22])[CH3:21])[CH:19]=[C:14]2[CH:13]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:11][C:12]1[S:29][C:15]2=[N:16][C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:18]([C@@H:20]([NH:22][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:21])[CH:19]=[C:14]2[CH:13]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1cc2cc([C@H](C)N)c(-c3ccccn3)nc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc2cc([C@H](C)Nc3ncnc4[nH]cnc34)c(-c3ccccn3)nc2s1
Temperature: 120 °C

Procedure:
6-Chloropurine (26.4 mg, 0.171 mmol), (S)-1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethanamine (40 mg, 0.148 mmol) and hunig's base (38.9 μL, 0.223 mmol) was dissolved in 2 mL of n-butanol and heated to 120° C. overnight. The reaction was cooled to rt and purified by reverse phase chromatography to afford (S)—N-(1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine. 1H NMR (400 MHz, CDCl3) δ 12.5 (br s, 1H), 8.78 (br m, 1H), 8.55-7.80 (series of m, 6H), 7.60-7.30 (br m, 1H), 7.26 (m, 1H), 6.89 (br s, 1H), 6.40-6.00 (br m, 1H), 2.60 (br s, 3H), 1.60-1.25 (series of M, 3H). LC/MS (M+1, found=388.1).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]([NH2:12])[CH2:3][CH2:2]1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])[CH3:15]>C(OCC)(=O)C>[CH3:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[C:17]=1[NH:25][C:26]([NH:12][CH:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3]1)=[O:27])[CH3:13]
Reactant: NC1CCOc2ccccc2C1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1CCOc2ccccc2C1
Reaction time: 20 h
Yield: 51.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-benzoxepin-4-amine (0.95 g, 5.8 mmol) in 50 ml of ethyl acetate was added 1.18 g (5.8 mmol) of 2,6-bis(1-methylethyl)phenyl isocyanate. The resulting mixture was stirredat room temperature for 20 hours. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried to yield 1.1 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(2,3,4,5-tetrahydrobenzoxepin-4-yl)urea, mp 184°-186° C.