Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(C)=CC=CC=1C.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C@H:22]([OH:40])[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:12][CH:11]=1.FC(F)(F)S(O[Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])(=O)=O>C(Cl)Cl>[Si:47]([O:40][C@@H:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=2)[CH2:25][CH2:24]1)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1ccc(N2CCC([C@@H](O[Si](C)(C)C(C)(C)C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
2,6-Lutidine (1.128 ml, 9.68 mmol) was added to a solution of (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11A (First Eluting Compound), 1.74 g, 3.87 mmol) in DCM (10 ml) at 0° C. tert-Butyldimethylsilyl trifluoromethanesulfonate (1.3 ml, 5.81 mmol) was added dropwise via syringe at 0° C. and the resulting mixture was allowed to warm up to room temperature for 10 minutes. Evaporation of the volatiles under reduced pressure gave a residue, which was purified by column chromatography (ISCO, 80 g silicon column, eluting with 0→10% EtOAc/hexanes) to give the title product (2.1 g, yield: almost quantitative).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[CH2:20]([O:19][C:17]1[CH:16]=[CH:15][C:14]([S:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1ccnc2ncccc12
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (100 mg, 0.559 mmol) was reacted with 4-(2-amino-4-benzyloxy-phenylsulfanyl)-phenol (224 mg, 0.559 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (mg, %). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.14 (s, 2 H), 6.31 (d, J=6.99 Hz, 1 H), 6.61-6.69 (m, 2 H), 7.08-7.23 (m, 5 H), 7.32-7.46 (m, 5 H), 7.92 (dd, J=8.46, 4.41 Hz, 1 H), 8.47 (d, J=6.99 Hz, 1 H), 9.10-9.21 (m, 2 H), 9.77 (s, 1 H), 11.14 (s, 1 H); MS (ESI+) m/z 452 (M+H−TFA)+; (ESI−) m/z 450 (M−H−TFA)−.
Reaction SMILES: [C:1]1([S:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(C)[CH:20]=[O:21]>O1CCCC1>[C:1]1([S:7][C:8]2[S:9][C:10]([CH:20]=[O:21])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: c1ccc(Sc2cccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2ccccc2)s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of 2-phenylthiothiophene (3.87 g) in dry tetrahydrofuran (50 ml) at -30° C. under N2, was added dropwise, n-butyllithium (8.0 ml, 2.5M) and the solution left to stir at -30° C. for 2 hours. Dry dimethylformamide (2.32 ml) was then added and the solution allowed to stir at -30° C. for a further hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with 2N HCl (50 ml), extracted with ether (2×50 ml), dried over MgSO4 and evaporated under reduced pressure to give an orange oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using 20% ether-hexane to give a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:13]1([CH2:12][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-1H-inden-1-one (1.0 g, 6.2 mmol), benzyl alcohol (0.65 g, 5.6 mol) and tributylphosphine (1.7 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azocarbonyl)dipiperidine (2.1 g, 8.4 mmol), and the mixture was stirred at room temperature for 16 hours. Insolubles were filtered off, and then the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=10:1) to give the title compound (1.3 g, yield 97%) as powders.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11](O)=[O:12])=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:63]([NH:66][NH2:67])(=[O:65])[CH3:64]>C(OCC)(=O)C.CC(N(C)C)=O>[C:63]([NH:66][NH:67][C:11]([C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]1)[N:6]=[CH:5][N:4]=2)=[O:12])(=[O:65])[CH3:64]
Reactant: CC(=O)NN
Reactant: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)NNC(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
In a 10 mL round bottomed flask, 9-Methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid (185 mg, 0.51 mmol, 1 equiv) and HATU (290 mg, 0.76 mmol, 1.5 equiv) were suspended anhydrous DMA (2 mL). Diisopropylethylamine (175 μL, 1.0 mmol, 2 equiv) followed by acetic hydrazide (45 mg, 0.61 mmol, 1.2 equiv) were added and the reaction stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL), and the extracted with water (20 mL), and aqueous hydrochloric acid solution (0.1 M, 40 mL). The combined aqueous layers were then neutralized to pH=7 with saturated aqueous sodium bicarbonate. The resulting precipitate was filtered off, washed with water (2 mL) and acetonitrile (1 mL) and air dried yielding 135 mg of N′-acetyl-9-methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carbohydrazide in 59% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.91 (s, 1H), 8.29 (s, 1H), 7.18-7.08 (m, 1H), 6.87 (dt, 3H), 4.52 (t, 1H), 3.92 (d, 3H), 2.31 (s, 2H), 1.86 (s, 3H), 1.79 (d, 2H). MS (EI) for C21H23N9O3: 450 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:8]1=2)[CH3:2].CO.[ClH:28]>CO>[ClH:28].[ClH:28].[NH2:10][C:9]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:8]=1[CH:7]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:18])[N:6]1[CH2:5][CH2:4][N:3]([CH2:24][CH3:25])[CH2:1][CH3:2]
Reactant: CCN(CC)CCNC1c2ccccc2C(=O)Nc2c(C)cccc21
Agent: Cl
Solvent: CO
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1cccc(C)c1N
Temperature: 25 °C

Procedure:
To a solution of 1.35 g of 11-(2-diethylaminoethylamino)-4-methyl-5, 11-dihydro-6H-dibenz[b,e]azepin-6 -one in 50 ml of methyl alcohol was added 5 ml of 3N-hydrogen chloride methyl alcohol solution. After stirring at room temperature for an hour, the reaction mixture was concentrated to dryness under reduced pressure. The obtained solid was tritylated with isopropyl ether and then separated by filtration to give 1.91 g of 3-(2-amino-3-methylphenyl)-2-(2-diethylaminoethyl)isoindolin-1one dihydrochloride 0.6 hydrate (Compound 25').
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][C:17]([O:19]CC)=[O:18])[C:10]=3[N:9]([CH:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:23][CH2:24][CH3:25])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][C:17]([OH:19])=[O:18])[C:10]=3[N:9]([CH:22]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)[CH2:23][CH2:24][CH3:25])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(c1ccc(C(F)(F)F)cc1)n1cc(-c2ccccc2)c2c1C(CC(=O)OCC)CCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(c1ccc(C(F)(F)F)cc1)n1cc(-c2ccccc2)c2c1C(CC(=O)O)CCC2
Yield: 5.5 %

Procedure:
To a stirred solution of ethyl (3-phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetate (107 mg, 2.2 mmol) in dioxane (5 ml) and water (0.5 ml) was added lithium hydroxide (900 mg, 22.0 mmol) and the reaction heated to reflux for 16 h. After cooling, the reaction was diluted with ethyl acetate and acidified with 2N HCl. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers dried over sodium sulfate and concentrated in vacuo. The product was purified by mass directed HPLC to give (3-phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid (55.1 mg, 55%), a colourless foam as a 1:1 mixture of diastereomers A and B; 1H NMR δ (ppm) (CDCl3): 7.59 (2 H, d, J=8.2 Hz, A/B), 7.53 (2 H, d, J=8.1 Hz, A/B), 7.47 (2 H, d, J=8.1 Hz, A/B), 7.35 (4 H, t, J=7.3 Hz A+B), 7.21-7.13 (4 H, m, A+B), 7.06 (1 H, s, A), 6.95 (1 H, s, B), 5.19-5.11 (2 H, m, A+B), 3.39 (1 H, d, J=9.0 Hz, B), 3.06 (1 H, s, A), 2.79-2.65 (5 H, m, A+B), 2.37-2.19 (2 H, m, A+B), 2.14-2.08 (4 H, m, A+B), 2.00 (1 H, s, A/B), 1.90-1.78 (6 H, t, J=13.5 Hz, A+B), 1.74-1.70 (4 H, m, A+B), 1.42 (1 H, t, J=6.1 Hz, A/B), 1.38-1.30 (1 H, m A/B), 1.03 (3 H, t, J=7.3 Hz, A/B), 0.95 (3 H, t, J=7.3 Hz, A/B); m/z (ES−) 454 (M−H+).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=[N:11][C:10]=2[C:30]([OH:32])=O)=[CH:5][CH:4]=1.[CH2:35]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[CH2:45][NH2:46])[CH:36]([CH3:38])[CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:35]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[CH2:45][NH:46][C:30]([C:10]1[N:11]=[C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[C:25]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)[NH:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:33])[F:34])=[CH:4][CH:5]=1)=[O:32])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)CN1CCCCC1CN
Reactant: O=C(O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN1CCCCC1CNC(=O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-imidazole-4-carboxylic acid from step (d) above (50. mg, 0.103 mmol), (1-isobutylpiperidin-2-yl)methanamine (26 mg, 0.15 mmol, Example 29(c)), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (68 mg, 0.154 mmol, Aldrich), and DIEA (0.053 mL, 0.975 mmol, Aldrich) in DCM (0.6 mL) reacted under the condition of Example 16(f) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 638 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14](Cl)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8].[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C(C)=CC=CC=1C>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([C:14](=[P:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8]
Reactant: COCCOCC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COCCOCC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 43.2 %

Procedure:
A mixture of p-nitrobenzyl 2-[4-(2-methoxyethoxyacetylthio)-2-oxo-1-azetidinyl]-2-chloroacetate (761 mg.), triphenylphosphine (524 mg.; 2.00 mmoles) and 2,6-lutidine (0.235 ml.; 214 mg.; 2.00 mmoles) in tetrahydrofuran (7 ml.) was stirred under N2 atmosphere at room temperature for 50 hours. After filtration of the precipitate, the filtrate was evaporated to yield 1.39 g. of a crude oil. This oil was purified by columm chromatography (SiO2 ; 30 g.; eluant-ethyl acetate) yielding title product (494 mg.; 0.736 mmole; yield 42.3% based on starting ester) as a brownish oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7]C2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].C[C:36]1[N:41]=[C:40]([CH:42]=O)[CH:39]=[CH:38][CH:37]=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([CH3:42])[N:41]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1cccc(C=O)n1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1cccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)n1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 6-methylpicolinaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 4.83-4.77 (m, 1H), 4.13-4.08 (m, 2H), 3.99-3.95 (m, 1H), 3.72-3.69 (m, 1H), 3.62-3.54 (m, 2H), 3.42 (t, J=8.3 Hz, 1H), 3.06 (d, J=9.9 Hz, 1H), 2.85-2.83 (m, 1H), 2.64-2.57 (m, 1H), 2.55 (s, 3H), 2.44-2.29 (m, 3H), 2.08-2.03 (m, 1H), 1.91-1.82 (m, 2H), 1.20 (t, J=7.1 Hz, 3H). MS: (M+H m/z 409.1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4].[H-].[Na+].[CH3:16]N(C=O)C>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C@H:8]([O:10][CH3:16])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1C[C@H](N=[N+]=[N-])[C@@H](OC)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) solution of (1R,3S,4S)-3-azido-4-hydroxy-cyclopentanecarboxylic acid methyl ester (300 mg; CAS 213742-85-9) in DMF (5 ml) under an argon atmosphere was added NaH (78 mg; 55% dispersion in mineral oil). The ice bath was removed and stirring at r.t. was continued for 1 h. The mixture was cooled again and methyl iodide (0.3 ml) was added in one portion. The mixture (slowly warming up to r.t.) was then stirred for 18 h. More methyl iodide (0.3 ml) was added and the mixture (orange slurry) was stirred at r.t. for another 7 h. More methyl iodide (0.3 ml) was added and stirring was continued for another 17 h. The mixture was diluted with EtOAc and washed with H2O (10 ml). The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give (3S,4S)-3-azido-4-methoxy-cyclopentanecarboxylic acid methyl ester (215 mg, epimeric mixture) as light yellow oil. MS: 200.3 ([M+H]+).
Reaction SMILES: [N+](C1C=CC(COC(N2C[C@@H](S)C[C@H]2C(N2CCN(C(=O)CSC[C@H](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)NC(OCC3C=CC([N+]([O-])=O)=CC=3)=O)CC2)=O)=O)=CC=1)([O-])=O.Cl.[NH2:62][C@@H:63]([C:66]([OH:68])=[O:67])[CH2:64][SH:65].[CH3:69][O:70][C:71]1[CH:78]=[CH:77][C:74]([CH2:75]Cl)=[CH:73][CH:72]=1>[OH-].[Na+]>[CH3:69][O:70][C:71]1[CH:78]=[CH:77][C:74]([CH2:75][S:65][CH2:64][C@H:63]([C:66]([OH:68])=[O:67])[NH2:62])=[CH:73][CH:72]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C(N[C@H](CSCC(=O)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Product: COc1ccc(CSC[C@@H](N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(4-(2-((2S)-2-(p-nitrobenzyloxycarbonyl) -2-(p-nitrobenzyloxycarbonylamino) ethylthio)acetyl)piperazine-1-yl)carbonyl-4-mercaptopyrrolidine ##STR13## 1) To 5.05 g of D-cysteine hydrochloride dissolved in 4N sodium hydroxide and cooled on an ice bath was added dropwise 9.39 ml of p-methoxybenzyl chloride, followed by 2 hours of stirring at room temperature. The resulting reaction solution was washed with ether and acidified with concentrated hydrochloric acid, and a crystal was collected by filtration to yield 7.78 g of S-p-methoxybenzyl-D-cysteine in the form of pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].C[O-].[Na+].CN(C)C=O.Br[CH2:32][C:33]([O:35][CH2:36][CH2:37][CH3:38])=[O:34]>O.C1(C)C=CC=CC=1>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:13]1[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][C:8]=2[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[N:10][CH2:11][C:12]1=[O:14])[CH2:37][CH3:38]
Reactant: CCCOC(=O)CBr
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCOC(=O)CN1C(=O)CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Reaction time: 6 h

Procedure:
A mixture of 0.1 mole of 7-nitro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° C. for about 20 minutes. To the mixture is added a solution of 0.11 mole of propyl bromoacetate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloride-methanol and the like to obtain 7-nitro-2,3-dihydro-2-oxo-5-(o-chlorophenyl)-1H-1,4-benzodiazepin-1-acetic acid propyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9]/[C:10]/2=[N:13]\[S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]([O:23][CH3:24])(=[O:22])[CH3:21]>>[CH3:24][O:23][C:20](=[O:22])[CH2:21][C@:10]1([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1
Reactant: COC(C)=O
Reactant: CC(C)(C)S(=O)/N=C1\CCc2ccc([N+](=O)[O-])cc21
Product: COC(=O)C[C@@]1(N[S@](=O)C(C)(C)C)CCc2ccc([N+](=O)[O-])cc21

Procedure:
Starting from 2-methyl-propane-2-sulfinic acid [6-nitro-indan-(1E)-ylidene]-amide and methyl acetate, the product [(S)-1-((R)-2-methyl-propane-2-sulfinylamino)-6-nitro-indan-1-yl]-acetic acid methyl ester was obtained as a black oil. MS (ESI): m/z=355.5 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]3[C:23]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=3[N:19]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:6])=[O:4].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39].C(=O)([O-])O.[Na+]>ClCCl>[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH2:2][C:3]([N:5]([CH2:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]3[C:23]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=3[N:19]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:6])=[O:4])[CH3:39]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CCl)cc3)nc12
Reactant: CNCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCN(C)CC(=O)N(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
4-[(Chloroacetyl-methyl-amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (100 mg, 205 mmol) are dissolved in N-(2-methoxyethyl)-methylamine (1.8 ml, 21 mmol) and the mixture stirred for 2 h at 55° C. Saturated aqueous sodium hydrogen carbonate is added (50 ml) and dichloromethane (50 ml) are added, the phases are separated and the aqueous phase extracted twice with 50 ml dichloromethane. The combined organic layers are dried with magnesium sulfate and evaporated. Flash chromatography (silica, dichloromethane containing 5% methanol) afforded the title compound as white crystals (74% yield), mp 171-173° C. MS: m/e=542 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=[CH2:13]>COC(C)(C)C>[CH3:13][CH:12]1[CH2:14][N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[NH:1][C:11]1=[O:15]
Reactant: C=C(C)C(=O)OCC
Reactant: Nc1nc2ccccc2[nH]1
Solvent: COC(C)(C)C
Product: CC1Cn2c(nc3ccccc32)NC1=O
Temperature: 130 °C
Reaction time: 7 h

Procedure:
5.326 g (40 mmol) 2-aminobenzimidazole and 4.56 g (40 mmol) ethyl methacrylate were dissolved in 25 ml Proglyde DMM. The reactionmixture is heated to 130° C. The reaction is allowed to continue for 7 hours at 130° C. The reactionmixture is allowed to cool down to room temperature and is added to 250 ml tert-butyl methyl ether. The precipitated 3,4-dihydro-3-methyl-pyrimidino[1,2-a]benzimidazol-2(1H)-one was isolated by filtration and recrystallized from 1-methoxy-2-propanol. 2.7 g (33%) of 3,4-dihydro-3-methyl-pyrimidino[1,2-a]benzimidazol-2(1H)-one was isolated (m.p. >260° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[CH:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[CH:16][CH:15]=1)=O.[O-]S([O-])(=O)=O.[Mg+2]>C(#N)C>[CH3:22][N:20]([CH3:21])[C:18](=[O:19])[C:17]1[CH:23]=[CH:24][C:14](/[CH:12]=[N:1]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][O:5][C:6]3=[O:11])=[CH:15][CH:16]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: CN(C)C(=O)c1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN(C)C(=O)c1ccc(/C=N/c2cccc3c2COC3=O)cc1
Yield: 80.5 %

Procedure:
4-Aminoisobenzofuran-1(3H)-one (2.10 g, 14.1 mmol), 4-formyl-N,N-dimethylbenzamide (2.50 g, 14.1 mmol) and dry MgSO4 (9.84 g, 82 mmol) were added to acetonitrile (170 mL) and stirred under reflux overnight. The mixture was filtered, and the solvent was evaporated under reduced pressure and the residue was re-crystallized to obtain 3.5 g of title compound as a pale solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.01 (s, 3H), 3.15 (s, 3H), 5.43 (s, 2H), 7.38-7.40 (d, J=7.6 Hz, 1H), 7.55-7.61 (m, 3H), 7.80-7.82 (d, J=7.6 Hz, 1H), 7.96-7.98 (d, J=8 Hz, 2H), 8.58 (s, 1H); LC-MS (ESI) m/z: 308 (M+1)+.