Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH2:11])=[O:10])[C:4]1=[O:12])C.[CH:13]([N:16]([CH3:20])[CH2:17][CH2:18]N)([CH3:15])[CH3:14]>>[CH3:20][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18][NH:11][C:9](=[O:10])[CH2:8][N:5]1[CH2:6][CH2:7][CH2:3][C:4]1=[O:12]
Reactant: CC(C)N(C)CCN
Reactant: CCC1CCN(CC(N)=O)C1=O
Product: CC(C)N(C)CCNC(=O)CN1CCCC1=O

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetamide and 11.6 g. of N-isopropyl-N-methylethylenediamine, following the procedure of Example 1, there is obtained N-[2-[methyl(1-methylethyl)amino]ethyl]-2-oxo-1-pyrrolidineacetamide; b.p. 152° C./0.07 mm.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[CH2:3][CH2:4][C@@H:5]([C:21](=[O:47])[NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:24]1)[C@H:6]([CH2:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:48][C:2]([F:1])([F:49])[CH2:3][CH2:4][C@@H:5]([C:21](=[O:47])[NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:24]1)[C@H:6]([CH2:14][CH2:15][CH2:16][C:17]([F:20])([F:18])[F:19])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@@H](CCCC(F)(F)F)[C@@H](CCC(F)(F)F)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H](CCCC(F)(F)F)[C@@H](CCC(F)(F)F)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 117.3 %

Procedure:
A solution of Intermediate 1C (62 mg, 0.090 mmol) in DCM (1 mL) was treated with TFA (1 mL). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated to dryness to afford Intermediate 1D (67 mg, 100%). HPLC: RT=3.011 min (CHROMOLITH® ODS 4.6×50 mm (3 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=634 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:19]4)=[N:16][CH:15]=[N:14][C:10]=3[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].C(Cl)Cl>CO>[C:29]([O:28][C:26]([NH:25][CH2:24][CH:20]1[O:21][CH2:22][CH2:23][N:18]([C:17]2[C:9]3[C:8]4[C:12](=[CH:13][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=4)[NH:11][C:10]=3[N:14]=[CH:15][N:16]=2)[CH2:19]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1ncnc(N3CCOC(CNC(=O)OC(C)(C)C)C3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4cc(C(=O)O)ccc4c23)CCO1
Reaction time: 8 h

Procedure:
A suspension of 4-[2-(tert-Butoxycarbonylamino-methyl)-morpholin-4-yl]9H-pyrimido[4,5-b]indole-7-carboxylic acid methyl ester (35 mg, 0.079 mmol) in methanol (2 mL) was treated with NaOH (1 mL, 4 M in dioxane, 4 mmol) and left overnight at room temperature. DCM (5 mL) was added to the reaction mixture. The aqueous layer was collected and acidified with 1M HCl, evaporated to dryness and suspended in water. The resulting precipitate was collected by filtration as a white solid (12 mg, 0.028 mmol). LC-MS (1) Rt 1.17 min; m/z (ES−) 426.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]=[CH:9][CH:10]2[CH2:14][CH2:13][O:12][C:11]2=O)[CH:3]=1.P(Br)(Br)([Br:18])=O>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:11](=[O:12])[C:10]([CH2:14][CH2:13][Br:18])=[CH:9][N:8]=[C:4]2[CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=C1OCCC1C=Nc1cc(Br)ccn1
Product: O=c1c(CCBr)cnc2cc(Br)ccn12
Temperature: 0 °C
Yield: 86.2 %

Procedure:
3-((4-bromopyridin-2-ylimino)methyl)dihydrofuran-2(3H)-one (800 mg, 2.97 mmol) and POBr3 (4 g, 13.9 mmol) was stirred at 80° C. for 1.5 hr. After the suspension was poured into ice water, the solution was adjusted to pH 8 and extracted with DCM (3×100 mL). The combined organic layers were washed with brine and concentrated to give 850 mg crude product, which was directly used for the next step without further purification. MS (ESI): 330, 332, 334 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[C:7]([S:10][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Product: CCCCc1nnc(SCc2ccc(OC)cc2)n1Cc1ccc(O)cc1
Yield: 70 %

Procedure:
Reaction of 5-butyl-2,4-dihydro-4-(4-hydroxybenzyl)-3H-1,2,4-triazole-3-thione (from Example 1, Step D) with 4-methoxybenzyl chloride according to the procedure of Example 5, Step A, gave a 70% yield of the title compound as a solid, mp 130°-131° C.; homogeneous by TLC in 95:5 CH2Cl2 -MeOH.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[NH:1]([C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1)[C:19]([CH3:20])=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(Cc2ccc(N)cc2)cn1
Product: COC(=O)c1ccc(Cc2ccc(NC(C)=O)cc2)cn1

Procedure:
One gram of methyl 5-(4-aminobenzyl)picolinate were heated together with 10 ml. of acetic anhydride under reflux for two hours. The reaction mixture was concentrated under reduced pressure. The residue was added with n-hexane to form crystals. The crystals were then recrystallized from a solvent comprising a mixture of chloroform/n-hexane to obtain 0.8 g of methyl 5-(4-acetaminobenzyl)-picolinate of a melting point of 175°-177° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:16])[C:12]([CH2:14][OH:15])=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:16])[C:12]([CH2:14][O:15][C:18]3[CH:50]=[CH:49][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:24]4=[O:48])=[CH:20][CH:19]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2nc(CO)n(C)c2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Yield: 85.8 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.33 g 5-isopropoxy-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 102), 0.69 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.37 ml of tributylphosphine, 0.38 g of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.85 g of the title compound, melting at 90-100° C. (softening).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][C@@H:41]([CH2:45][CH3:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH:41]([CH2:45][CH3:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: CCC1CN(C(=O)OC(C)(C)C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (3S)-3-Ethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:33])[C:9]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:10][O:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([N:8]([CH3:33])[C:9]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:10][O:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C(=NOCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C(=O)OC(C)(C)C)C(=NOCCN)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 2-(benzyloxycarbonylamino)ethoxy-N-methylguanidine (700 mg, 1.5 mmol), as prepared in the preceding step, 10% Pd/C (70 mg) in methanol (20 mL) and chloroform (5 mL) was hydrogenated under hydrogen (balloon) for 1 h. The catalyst was removed by filtration through Celite, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless foam (250 mg, 50%). 1H-NMR (300 MHz, CDCl3) δ 4.14 (t, J=5.0 Hz, 2H), 3.09 (s, 3H), 3.06 (q, J=5.0 Hz, 2H), 1.50 (s, 9H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[O-]CC.[Na+].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[N:38][CH:39]=1>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([NH:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:41]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][N:38]=1)=[O:49])=[O:9]
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: COCOc1cc(C(C)C)ccc1C(=O)O
Agent: CC[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCOc1cc(C(C)C)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 0.25 h

Procedure:
To a stirring solution of 2-methoxymethyloxy-4-isopropylbenzoic acid (3.0 g, 13.4 mmol) in THF (50 mL) was added sodium ethoxide (0.91 g, 13.4 mmol). After 15 min, the solvent was removed in vacuo and the residue was suspended in dichloromethane (50 mL). To this mixture was added a couple drops of DMF followed by oxalyl chloride (1.7 g, 13.4 mmol). After another 30 min, the solvent was removed in vacuo and the residue was again suspended in dichloromethane (150 mL). To this mixture was added pyridine (2.9 g, 36.5 mmol), followed by N-(5-chloropyridin-2-yl)-2-aminobenzamide (3.02 g, 12.2 mmol). After stirring for 2 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (400 mL) and water (200 mL). The organic phase was washed twice with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate and once with brine. The organic phase was then dried with MgSO4 and filtered. To this solution was added silica gel (about 10 g) and the solvent was removed in vacuo. The resulting dry pack was loaded onto the top of a silica gel column loaded with 10% ethyl acetate in hexanes and eluted with a gradient of 10% ethyl acetate in hexanes through 30% ethyl acetate in hexanes. The clean product containing fractions were combined and concentrated in vacuo to give 2.18 g (39%) of off white solid. Another set of fractions which contained a small amount of impurity were combined and concentrated in vacuo to give 2.09 g (about 38%) of an off white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](N2CCOCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1NC2N(CC3C=CC=CC=3[Cl:48])N=NC=2C(=O)N=1)(C)(C)C.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)Cl>>[C:1]([C:5]1[N:6]=[C:7]([Cl:48])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3Cl)c2[nH]1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: CCN(CC)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
5-tert-Butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine A mixture of 5-tert-butyl-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (12.3 mg, 38.7 μmol) and N,N-diethylaniline (12.3 μL, 77.4 μmol) in POCl3 (250 μL, 2.73 mmol) was refluxed for 3 h under N2 atmosphere. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with cold H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C@H:45]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:46](O)=[O:47])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([C@@H:45]([C@@H:41]2[CH2:42][CH2:43][CH2:44][N:40]2[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:46](=[O:47])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (d 0.742; 0.0410 mL, 0.235 mmol) was added to a solution of 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.0311 g, 0.0883 mmol, See Example 1), (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.020 g, 0.0589 mmol, see Example C) and TBTU (0.0227 g, 0.0706 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-carboxylate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (0.008 g, 24%). MS APCI (+) m/z 501.3 detected.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH2:4][CH2:3]1.[Br:17]Br>C(O)(=O)C>[Br:17][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:9][C:10]=1[N+:14]([O-:16])=[O:15]
Reactant: BrBr
Reactant: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Br)c([N+](=O)[O-])c2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-methyl-4-(3-nitrophenyl)piperazine (EP0533267A) (1.0 g; 4.5 mmol) in glacial acetic acid (25 ml) was treated with bromine (0.23 ml; 1 equivalent). The reaction mixture was stirred at 75° overnight, then cooled, filtered, and the yellow sticky solid was partitioned between potassium carbonate (aq) and 2% methanol in dichloromethane. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to leave the title compound (D26) as a viscous orange oil (928 mg, 68%) MH+=300/302.
Reaction SMILES: [OH-].[K+].[SH2:3].Cl[C:5]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[N:6][N:7]=[CH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1>C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:5]2[S:3][CH:8]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:7][N:6]=2)[CH:16]=1
Reactant: ClC(=NN=Cc1cccnc1)c1cccnc1
Reactant: S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1cncc(C2=NNC(c3cccnc3)S2)c1

Procedure:
To a solution of 6.7 g (0.1 mole) of 85 % potassium hydroxide in 190 ml of ethanol which has been freshly saturated with hydrogen sulfide are added 24.3 g (0.1 mole) of 1-chloro-1,4-bis(pyrid-3-yl)-2,3-diazabutadiene at low temperature. After 2 hours the solvent is removed by evaporation under vacuum and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and with a saturated solution of sodium chloride, then dried over sodium sulfate, filtered, and the filtrate is concentrated by evaporation. The residue is stirred in hexane/ether, filtered, washed and dried, affording 2,5-bis(pyrid-3-yl)-4,5-dihydro-1,3,4-thiadiazole of formula ##STR11## with a melting point of 77°-78° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:14]=2)[C:6](=[O:34])[CH2:5]1)[CH2:2][CH3:3]>CC(O)=O.O>[NH:13]1[CH:14]=[C:10]([CH2:9][N:7]2[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]2=[O:34])[N:11]=[CH:12]1
Reactant: CCCC1CC(=O)N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Solvent: O
Solvent: CC(=O)O
Product: CCCC1CC(=O)N(Cc2c[nH]cn2)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 88 %

Procedure:
In a 50 ml reaction flask fitted with a magnetic stirrer, 4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x45 (1.8 g, 4 mmol) is dissolved in a 1/1 mixture of CH3CO2H/H2O (30 ml) and the solution is stirred for 36 h at room temperature. Most of the solvents are removed under vacuum and the residue is dissolved in 1N HCl and diluted with CH2Cl2. The first organic phase is removed and pH of the aqueous phase is adjusted to 9 by addition of solid Na2CO3. Then CH2Cl2 is added and the second organic phase is separated, dried over MgSO4 and concentrated to dryness, affording 730 mg of 1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one 110.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[CH:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([O:17][S:33]([CH3:32])(=[O:35])=[O:34])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)O)[C@H]2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e10) (80 mg) was treated with methanesulphonyl chloride and triethylamine in dichloromethane as described in Example 1. After work-up, evaporation of the dichloromethane solution afforded p-nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e11) as a pale-yellow foam (67 mg); νmax (CH2Cl2) 1780, 1700, 1675, 1425, 1245 and 1175 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:30][CH2:29][C:19]2([NH:23][C:22](=[O:24])[N:21]([CH2:25][CH2:26][CH3:27])[C:20]2=[O:28])[CH2:18][CH2:17]1.[H-].[Na+].[CH3:35]I>CN(C=O)C>[CH3:32][C:2]([CH3:31])([CH3:1])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:17][CH2:18][C:19]2([N:23]([CH3:35])[C:22](=[O:24])[N:21]([CH2:25][CH2:26][CH3:27])[C:20]2=[O:28])[CH2:29][CH2:30]1
Reactant: CCCN1C(=O)NC2(CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(C)C2(CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a solution of 7-(2,2-dimethyl-propyl)-6-(2,4-dioxo-3-propyl-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.2 g, 0.48 mmol) in DMF (2 ml), NaH (22 mg, 0.55 mmol) and MeI (50 □1, 0.55 mmol) are added at 0° C. The reaction mixture is stirred at ambient temperature for 4 h, quenched with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and filtrated The combined extracts are concentrated and the residue is purified by column chromatography on silica gel using CH2Cl2:MeOH=25:1 (v/v) and CH2Cl2:MeOH=15:1 (v/v) to give 71 mg of desired product in 34% yield.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[S:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:15]2[S:16][CH:17]=[C:13]([CH2:12][C:11](=[O:28])[N:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:6][CH2:7]3)[N:14]=2)=[O:27])=[CH:21][CH:22]=1
Reactant: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CBr)CC2)cs1)c1ccc(Cl)cc1
Reactant: C1CCNC1
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CN3CCCC3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 55.2, N-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamide was reacted with pyrrolidine to give 4-chloro-N-(4-{2-oxo-2-[4-(2-pyrrolidin-1-yl-acetyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide. Off-white amorphous solid. MS 476.0 ([M+H]+)