Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
In a dry round-bottomed flask, 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 25.2 mmol) was dissolved in DMF (50 mL). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 1.22 g, 30.6 mmol). The reaction mixture was warmed to room temperature and stirred for 15 min then cooled back to 0° C. and SEM-Cl (5.4 mL, 30.4 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with 50 mL water and extracted with 150 mL diethyl ether (2×). The combined organic layers were washed twice with 30 mL water and once with 30 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on ˜20 g SiO2 and chromatographed over 200 g SiO2 with EtOAc/Hexanes (gradient: 0-15% EtOAc). All fractions containing product were combined and concentrated to afford 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (6.61 g, 80%) as a pale yellow oil which gradually solidified. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.38 (s, 1H), 7.70 (d, J=3.8 Hz, 1H), 6.76 (d, J=3.8 Hz, 1H), 5.68 (s, 2H), 3.50-3.65 (m, 2H), 0.88-1.03 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: CO.[CH3:3][NH2:4].CO.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[CH3:3][NH:4][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: CN
Reactant: N#Cc1ccc(F)cc1
Solvent: O
Solvent: CO
Product: CNc1ccc(C#N)cc1

Procedure:
A 40% methylamine methanol solution (7.5 mL) was added to a methanol (2.5 mL) solution of 4-fluorobenzonitrile (2.00 g) and the mixture was heated under reflux for fifteen hours under nitrogen atmosphere. After the solvent was removed under reduced pressure, to the residue obtained was added water (15 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous sodium sulfate. The oil obtained by removal of the solvent under reduced pressure was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain the titled compound (0.48 g) as crystals.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[CH:13]=2)(=[O:20])=[O:19])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 3-methylbenzenesulfonyl chloride (1.60 g, 8.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×40 mL). The organic phase was washed with brine (2×30 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a yellow oil (2.1 g, 76%). 1H-NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 6.32 (s, 1H), 5.33 (s, 1H), 2.41 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH:11]([CH:13]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:14](OCC)=O)=[O:12]>CO>[N+:1]([NH:4][C:5]1[NH:7][C:11](=[O:12])[C:13]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[CH:14][N:6]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C=O)Cc1ccc(OC)nc1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1

Procedure:
Nitroguanidine (4.7 g) was added to a solution of sodium methoxide (prepared from 1.15 g sodium) in methanol (50 ml) and the mixture was refluxed for 45 minutes. Ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (10.7 g) was added and the mixture was refluxed for 34 hours and evaporated to a residue. This residue was dissolved in water and the solution was extracted with chloroform (subsequently discarded). The aqueous solution was adjusted to pH 5 with acetic acid, and the solid which precipitated out was filtered off to give 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone m.p. 183.5°-186°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)([OH:3])=[O:2].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>CO.C1C=CC=CC=1>[CH3:15][O:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)=[O:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccnc(NC(C)=O)c1

Procedure:
4-Carboxy-2-acetylaminopyridine (3.4 g, 19 mmol) was dissolved in methanol/benzene (100 mL, 1:1). TMS-diazomethane was added (1M, Aldrich) with cooling until the yellow color just persisted, then the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (50/50 hexane/ethyl acetate) and 3.0 g of product was recovered.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=O)[C:8](=[O:17])[CH2:7][CH2:6]1)=[O:4].[CH2:18]([OH:21])[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH2:18]1[O:21][C:12]([CH:9]2[CH2:10][CH2:11][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7][C:8]2=[O:17])([O:14][CH2:15][CH3:16])[O:20][CH2:19]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCN(C(=O)OC)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC1(C2CCN(C(=O)OC)CCC2=O)OCCO1
Reaction time: 4 h

Procedure:
A mixture of ethyl 1-methoxycarbonyl-4-oxoperhydroazepine-5-carboxylate (VI; cf: Krogsgaard-Larsen, et al., Eur. J. Med. Chem.. 14 (1979) pp. 157-164) (26.9 g; 0.11 mol), ehtylene glycol (30.7 mL; 0.55 mol), 4-toluenesulphonic acid hydrate (2.11 g; 11 mmol), and toluene (200 mL) was refluxed in a Dean-Stark water separator for 4 h. Upon addition of toluene (200 mL) the reaction mixture was washed with a saturated solution of sodium bicarbonate (50 mL), dried (K2CO3) and evaporated to give crude (V), which was used without further purification as starting material for the synthesis of (IV).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][CH:10]=O>CCO>[N:1]1[CH:9]=[CH:10][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: Nc1cnccn1
Solvent: CCO
Product: c1cn2ccnc2cn1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of aminopyrazine (1 g, 10.5 mmol) and chloroacetaldehyde (50% wt in H2O; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated at 90° C. in a sealed tube for 5 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and diluted with dichloromethane (DCM). The organic layer washed with saturated aqueous NaHCO3 then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 10% MeOH/DCM) to provide 0.8 g of product.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2/[CH:13]=C/C.[O:16]=[O+][O-].CSC>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[O:16]
Reactant: C/C=C/c1cccc2c(=O)cc(C)oc12
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(=O)c2cccc(C=O)c2o1
Temperature: -60 °C

Procedure:
18.5 g (62.8 mmol) of 2-methyl-8-[(1E)-prop-1-en-1-yl]-4H-chromen-4-one are dissolved in 400 ml of dichloromethane and cooled to −60° C. Ozone is passed into the reaction solution for 30 min. Dimethyl sulfide is then added to the reaction mixture. After warming to room temperature, the solvent is removed in vacuo, and the residue is slurried in a little methanol. The solid remaining after filtration is recrystallized from diethyl ether. 9.1 g (77.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[C:29]1([S:35]([O:38][C:39]2[CH:40]=[CH:41][C:42]([CH2:45]Br)=[N:43][CH:44]=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:9]([CH2:45][C:42]2[CH:41]=[CH:40][C:39]([O:38][S:35]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:37])=[O:36])=[CH:44][N:43]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Oc1ccc(CBr)nc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)c2ccccc2)cn1)N=C(c1ccccc1)c1ccccc1
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of ethyl N-(diphenylmethylene)glycinate (1.71 g, 6.40 mmol) in dry THF (10 ml) was added to a stirred solution of LDA (2M in heptane/THF/ethylbenzene, 3.20 ml, 6.40 mmol) in dry THF (10 ml) at −70° under nitrogen. After stirring at this temperature for 0.75 h, a solution of 5-benzenesulphonyloxy-2-bromomethyl-pyridine [2.00 g, 6.01 mmol; prepared as described by Myers et al, J.Org.Chem. (1996), 61, 813] in dry THF (10 ml) was added. The reaction mixture was stirred at −70° for 1 h then at room temperature for 18 h. The reaction was quenched with water (10 ml) then partitioned between EtOAc (70 ml) and brine (30 ml). The phases were separated and the aqueous phase re-extracted with EtOAc (2×40 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford the crude product as a dark oil. Purification by flash chromatography (silica, 60% to 75% Et2O/hexane; applied as DCM solution) afforded the title compound as a tan-coloured solid (2.25 g, 72%). δH (CDCl3) 8.02 (1H, d, J 2.8 Hz, pyr-H(6), 7.72 (2H, d, J˜8 Hz, ortho-Ar—H), 7.59 (1H, t, J˜8 Hz, para-Ar—H), 7.50 (2H, dd, J 8.4, 1.4 Hz, phenyl-H), 7.40-7.27 (8H, ms, Ar and phenyl-H), 7.19 (1H, dd, J 8.5, 2.8 Hz, pyr-H(4), 7.11 (1H, d, J 8.5 Hz, pyr-H(3), 6.67 (2H, br d, J˜8 Hz, phenyl-H), 4.50 (1H, dd, J 9, 4.6 Hz, CH-α), 4.24-4.10 (2H, sym.m. CH2CH3), 3.50-3.33 (2H, m, pyr-CH2), 1.24 (3H, t, J 7.2 Hz, CH2CH3); m/z (ESI) 515 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1F>CN(C=O)C.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:18]=1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: c1c[nH]cn1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Br)c(-n2ccnc2)c1
Temperature: 150 °C
Yield: 60 %

Procedure:
A microwave vial charged with a solution of potassium tert-butoxide (0.462 g, 4.12 mmol), imidazole (0.280 g, 4.12 mmol), and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.000 g, 4.12 mmol) in 2 mL DMF was heated to 150° C. in an oil bath overnight. The reaction mixture was diluted with DCM, filtered through a syringe filter, and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 1-(2-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (0.720 g, 2.474 mmol). [M+H]+=291.0
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:22]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[CH:21][N:20]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37].O1CCOCC1>O1CCOCC1.CCOCC>[ClH:37].[ClH:37].[C:31]1([S:28]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:15]=3[C:22]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:21]2)(=[O:30])=[O:29])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(-c2cccs2)cn3S(=O)(=O)c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)n1cc(-c2cccs2)c2c(N3CCNCC3)ncnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 4-(7-Benzenesulfonyl-5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.23 mmol) in 2 mL dioxane was added 1.5 mL 4M HCl/dioxane. The reaction mixture was stirred at room temperature 6 hours, after which it was diluted with ether, and the solids were isolated by filtration through a fritted funnel with nitrogen pressure, rinsed with ether, and dried in vacuo to give 7-Benzenesulfonyl-4-piperazin-1-yl-5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (110 mg, 95%) as a yellow powder. LCMS (APCI+) m/z 426 [M+H]+; Rt: 1.95 min.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
In analogy with Example 1j), 28.8 g (54.8 mmol) of 5(S)-(Boc-amino)4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl]hexanoic acid in 288 ml of DMF, are converted into the title compound with 35.8 g (237.6 mmol) of tert-butyldimethylchlorosilane and 30 g (440 mmol) of imidazole. The title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4:1 to 1:1); TLC Rf (E)=0.34; tRet (gradient from 75 to 100% (a) in (b) over 20 min)=25.06 min; FAB-MS (M+H+)=526.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>ClCCl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])[CH:37]=[CH:38][CH:39]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cl)c1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-chloro-phenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3-chloro-phenyl)-amide as a white solid. (Yield 32 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20]([CH2:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([O:29]C(=O)C)[CH2:25][CH2:24]1)=[O:21].C(O[C@@H]1CC[C@H](CC(NC2SC3C(N4CCOCC4)=CC=C(OC)C=3N=2)=O)C1)(=O)C>>[OH:29][C@@H:26]1[CH2:27][CH2:28][C@H:23]([CH2:22][C:20]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:21])[CH2:24][CH2:25]1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CC(=O)O[C@H]1CC[C@@H](CC(=O)Cl)CC1
Agent: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](OC(C)=O)C3)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](O)CC3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and (cis)-acetic acid 4-chlorocarbonylmethyl-cyclohexyl ester, the tide compound was synthesized in exact the same manner as (cis)-2-(3-acetoxy-cyclopentyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide and obtained as light yellow crystals (33% yield). MS: m/e=406(M+H+), mp 212-216° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[Cl-].[Na+]>CN1CCCC1=O>[CH:25]1([NH:28][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Reactant: NC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 100 °C

Procedure:
7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (1.0 wt, prepared as outlined above in Example 66 of WO 2006/070195) and 1-methyl-2-pyrrolidinone (3.0 vol) are charged to a suitably sized flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) is added at 15 to 30° C. under nitrogen. The contents are then heated to 95 to 105° C. and stirred at this temperature until the reaction is judged complete by 1H NMR analysis. Once complete, the reaction mixture is cooled to 16 to 25° C. and added slowly (approximately 2 to 3 hours) to stirred ca. 13% w/w sodium chloride solution (11.5 vol) whilst maintaining the mixture at 16 to 25° C. A precipitate is formed. The transfer of the reaction mixture is completed with a 1-methyl-2-pyrrolidinone (0.5 vol) rinse at 16 to 25° C. The precipitated solid is collected by filtration, washed with water (0.5 vol) and pulled dry on the filter until deemed suitable for handling. The solid is suspended in ethyl acetate (5.0 vol) and water (6.0 vol) and stirred at 16 to 25° C. for 60 to 70 minutes. The solid is collected by filtration, sequentially washed with ethyl acetate (1.0 vol) and mixed heptanes (2×2.0 vol) and dried on the filter until deemed suitable for handling. The solid is suspended in ethyl acetate (4.0 vol) and stirred at 15 to 25° C. for at least 60 minutes. The solid is collected by filtration, washed with ethyl acetate (1.0 vol) and pulled dry on the filter to yield crude 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea (60 to 80% w/w) as a dark brown/red solid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.[CH2:9]([N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14](OC)=[O:15])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1.C1COCC1>[CH2:9]([N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14]([N:3]([CH3:4])[CH3:2])=[O:15])[CH:10]=[CH2:11]
Reactant: C=CCN(CC(=O)OC)Cc1ccccc1
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCN(CC(=O)N(C)C)Cc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of dimethylamine hydrochloride (2.08 g, 25.5 mmol, 8.0 eq) in anhydrous toluene (10 mL) at 5° C. under N2 was added trimethyl aluminum (1.0M in toluene, 25.5 mL, 25.5 mmol, 8.0 eq) dropwise over 1 h. The reaction mixture was heated to 20° C. and stirred for another 2 h. To a mixture of methyl 2-(allyl(benzyl)amino)acetate (0.70 g, 3.19 mmol, 1.0 eq) in anhydrous toluene (50 mL) and THF (15 mL) at 5° C. was added the above reaction mixture and the reaction mixture was heated at 70° C. for 48 h. Then the mixture was cooled to 0° C. and quenched with a small amount of water. The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and filtrated. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (50:1 (v/v) CH2Cl2/CH3OH) to afford the title compound as colorless oil (0.62 g, 77%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 233.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.86 (3H, s), 2.94 (3H, s), 3.16 (2H, d, J=6.8 Hz), 3.24 (2H, s), 5.16 (2H, m), 5.86 (1H, m), 7.18-7.27 (5H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1>[O:17]=[C:16]1[CH2:15][CH2:14][CH2:13][N:1]1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(C(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Sodium 4-aminobenzoate (42.5 g,0.267 mol) was suspended in 250 ml benzene. To this solution, upon vigorous stirring, 4-chlorobutyryl chloride (29 ml, 0.248 mol) was added slowly. The temperature of the reaction mixture was heated to 60° C. It is at 60° C. that the reaction was continued for another 20 hours. Na2CO3 solution (20%, 600 ml) was then added and the benzene layer was separated. The aqueous layer was acidified and the white precipitate was filtrated and recrystallized from methanol to form colorless crystal of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid. Mass Spectra: m/e (relative intensity) 205(M+, 44.23).