Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)(=[O:3])[NH2:2].Cl.[Cl:11][CH2:12][C:13](=[NH:16])OC>CO>[ClH:11].[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:13](=[NH:16])[CH2:12][Cl:11])[CH2:5]1)(=[O:3])[NH2:2]
Reactant: NC(=O)C1CCCNC1
Reactant: COC(=N)CCl
Agent: Cl
Solvent: CO
Product: N=C(CCl)N1CCCC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.9 %

Procedure:
1.28 g of (3RS)-3-carbamoylpiperidine were added to a solution of 1.44 g of methyl 2-chloroacetimidate hydrochloride in 5 ml of anhydrous methanol, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then worked up in the same manner as in Example 3(1), giving 2.34 g of 2-[(3RS)-3-carbamoylpiperidin-1-yl]-2-iminoethylchloride hydrochloride.
Reaction SMILES: [C:1]1(=[O:8])O[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(OO)(=O)C.C(OO)(=O)C.CC(C)=O.C1(=O)NCCCCC1>C(O)(=O)C.CC(C)=O>[C:1]1(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCCO1
Agent: CC(=O)OO
Agent: O=C1CCCCCN1
Solvent: O=C1CCCCC1
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: Oc1ccccc1

Procedure:
The epsilon caprolactone employed in accordance with the invention is available commercially so that neither the compound per se nor the method by which it is obtained constitutes any portion of the invention. According to one method, epsilon caprolactone is prepared by oxidizing cyclohexanone with an anhydrous solution of peracetic acid and acetone. The product thus obtained comprises acetic acid and epsilon caprolactone. When this method is used, it is desirable to add the peracetic acid-acetone solution to an excess of the cyclohexanone, e.g., 5 to 1 molar ratio of cyclohexanone to peracetic acid, in a vessel maintained under reflux. The epsilon caprolactone is recovered from the vessel by conventional distillation. The cyclohexanone used in the preparation of epsilon caprolactone is an intermediate product in the preparation of caprolactam. Cyclohexanone can be obtained either by the hydrogenation of phenol or the oxidation of cyclohexane. If a commercially available epsilon caprolactone is used in accordance with the invention, I prefer to purify the material by vacuum distillation. According to a typical purification procedure, epsilon caprolactone is subjected to distillation in a vacuum distillation column, separately collecting that portion boiling at 56° to 57° C./0.4 torr. Epsilon caprolactone is water-white with a single gas-chromatography peak.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:26])[C:19](=[O:25])[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:10]2.[Cl-].[NH4+].CCOCC>C1COCC1.N#N>[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:26])[C:19]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)([OH:25])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10]2
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Phenylmagnesium bromide, 0.0057 mol (5.7 ml of a solution 1M in THF), was added to a solution of 1.3 g (0.0052 mol) of oxofuran-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e-) dissolved in 15 ml of THF, at −701 C in N2 atmosphere. The mixture was stirred at this temperature for 10 minuts, and then warmed to room temperature. After 1 hour, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate The organic phases were combined, washed with water and dried over Na2SO4. After removal of the solvent, the solid obtained was treated with ether and filtered to yield 0.67 g (40%) of a product whose structure was confirmed by 1H-NMR. This compound was also prepared as is described in Example I-1a (Method c). The diastereomers were separated by crystallization from acetonitrile and distinguished by 1H-NMR.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][C:12]=1[CH3:21])=[O:10])C1C=CC=CC=1.[C:22]([O-])([O-])=O.[K+].[K+].[CH3:28][C:29]([CH3:31])=[O:30]>>[CH3:21][C:12]1[NH:13][C:14]2[C:19]([C:11]=1[C:9]([OH:8])=[O:10])=[CH:18][C:17]([O:20][CH:28]([CH3:22])[C:29](=[O:30])[CH3:31])=[CH:16][CH:15]=2
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)C(C)Oc1ccc2[nH]c(C)c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.0 g, 3.56 mmol), 2-bromobut-2-one (0.806 g, 5.33 mmol) and K2CO3 (1.47 g, 10.7 mmol) were mixed together in acetone (30 mL) and stirred at room temperature for 4 hours. The mixture was then filtered, concentrated under reduced pressure and redissolved in ethyl acetate. The resulting solution was washed with deionized water twice and dried over anhydrous Na2SO4. The crude was chromatographed (5% EtOAc/CH2Cl2) to give 0.97 g (77%) of 2-methyl-5-(1-methyl-2-oxo-propoxy)-1H-indole-3-carboxylic acid as a viscous oil. 1HNMR (400 MHz, DMSO): δ 1.36 (d, J=6.75 Hz, 3H), 2.06 (s, 3H, CH3CO), 2.59 (s, ArCH3), 4.67 (q, J=6.75 Hz, 1H), 5.28 (s, 2H), 6.73 (d, J=8.44 Hz, 1H), 7.23 (d, J=8.64 Hz, 1H), 7.29-7.46 (m, 6H), 11.76 (s, 1H, NH). MS (APCI+). Anal. Calcd for C21H21N1O4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.46: H, 6.04: N, 3.76. IR (KBr): 3276, 1715, 1659, 1458, 1168, 1078 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ccccn3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3ccccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyridin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H), 7.86 (m, 4H), 7.77-7.51 (m, 5H), 7.24 (m, 1H), 7.11 (m, 3H), 6.76 (dd, 1H), 6.64 (d, 1H), 6.59 (d, 1H), 4.38 (s, 2H), 4.35 (s, 2H), 4.30 (s, 2H), 1.48 (s, 9H); MS 545 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:31]2[O:32][CH:33]=[C:34]([C:36]([OH:38])=O)[N:35]=2)=[C:8]2[C:26](=[O:27])[N:25]3[CH2:28][CH2:29][CH2:30][N:24]3[C:9]2=[N:10][C:11]=1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:5])[CH3:2].CCN=C=[N:43][CH2:44][CH2:45][CH2:46]N(C)C.[CH:50]1[CH:51]=[CH:52][C:53]2N(O)N=N[C:54]=2[CH:55]=1.Cl>C(Cl)Cl>[C@H:44]1([NH:43][C:36]([C:34]2[N:35]=[C:31]([C:7]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH2:12][CH2:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=4)[N:10]=[C:9]4[N:24]5[CH2:30][CH2:29][CH2:28][N:25]5[C:26](=[O:27])[C:8]=34)[O:32][CH:33]=2)=[O:38])[C:54]2[C:53](=[CH:52][CH:51]=[CH:50][CH:55]=2)[CH2:46][CH2:45]1
Reactant: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1nc(C(=O)O)co1)c(=O)n1n2CCC1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1nc(C(=O)N[C@@H]3CCc4ccccc43)co1)c(=O)n1n2CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
2-(3-(ethoxycarbonyl)-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-8,9-dihydro-5H,7H-pyrazolo[1′,2′:1,2]pyrazolo[3,4-b]pyridin-4-yl)-1,3-oxazole-4-carboxylic acid (0.076 g, 0.143 mmol) was dissolved in CH2Cl2 (2 mL). R-(−)-1-aminoindane (0.018 mL, 0.215 mmol) was added followed by EDCI (0.033 g, 0.172 mmol) and HOBt (0.023 g, 0.172 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a yellow residue. Chromatography on silica gel using 9:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.046 g, 0.0.071 mmol, 50% yield): 1H NMR (CDCl3, 400 MHz) 8.44 (s, 1H), 7.49 (d, J=7.9 Hz, 2H), 7.29–7.12 (m, 6H), 5.64 (dd, J=15.7, 7.6 Hz, 1H), 4.58 (d J=5.9 Hz, 2H), 4.07 (dd, J=14.3, 7.0 Hz, 2H), 3.99–3.91 (m, 4H), 3.24–3.10 (m, 4H), 3.04–2.97 (m, 1H), 2.92–2.84 (m, 1H), 1.93–1.87 (m, 1H), 1.04 (t, J=7.1 Hz, 3H); ESMS m/z 646 (M+H)+, 644 (M−H)+ Anal. Calcd. For C34H30F3N5O5.½H2O: C, 62.38; H, 4.77; N, 10.70; found: C, 62.59; H, 4.74; N, 10.58.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[C:28]2[CH2:33][CH2:32][C:31]3([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:30][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[CH:28]2[CH2:29][CH2:30][C:31]3([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:32][CH2:33]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3=CCC4(CCCCC4)CC3)c2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3CCC4(CCCCC4)CC3)c2)CC1
Yield: 98.3 %

Procedure:
4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl]piperazine-1-carboxylic acid t-butyl ester (524 mg, 1.0 mmol) prepared in Example (39f) was used as the starting material. A mixed solution of methanol, tetrahydrofuran and ethyl acetate was used instead of a mixed solvent of methanol and tetrahydrofuran for reaction in a manner similar to Example (8a) and treated in a similar manner, to give 517 mg of the title compound as a colorless solid.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[N:13][CH:12]=2)[CH2:10][CH2:9]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]([O:4][CH2:5][CH2:6][NH:7][C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)=[N:13][CH:12]=[C:11]([CH:8]2[CH2:10][CH2:9]2)[N:16]=1)=[O:18])=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)OCCN
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)OCCNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reaction time: 24 h
Yield: 80.4 %

Procedure:
To a stirred mixture of 2-aminoethyl isopropyl ether (25 mg, 242 μmol) and 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (101 mg, 267 μmol) at rt in THF (5 ml) under an argon atmosphere were added 4-methylmorpholine (123 mg, 134 μl, 1.21 mmol) and HATU (184 mg, 485 μmol). The mixture was heated to reflux and stirring was continued for 1 day. The reaction mixture was concentrated. The crude product was purified by silica gel chromatography using an EtOAc/MeOH gradient as eluent. After trituration with MeOH, the title compound (90 mg, 80%) was obtained as yellow solid.
Reaction SMILES: C(O)=O.FC(F)(F)C(O)=O.Cl.[NH2:12][C:13]1[S:17][N:16]=[C:15]([C:18](=[N:49][O:50][CH2:51][C:52]([OH:54])=[O:53])[C:19]([NH:21][C@@H:22]2[C:47](=[O:48])[N:24]3[C:25]([C:44]([O-:46])=[O:45])=[C:26]([CH2:29][N+:30]4([CH3:43])[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:14]=1>C(OCC)(=O)C>[NH2:12][C:13]1[S:17][N:16]=[C:15]([C:18](=[N:49][O:50][CH2:51][C:52]([OH:54])=[O:53])[C:19]([NH:21][C@@H:22]2[C:47](=[O:48])[N:24]3[C:25]([C:44]([O-:46])=[O:45])=[C:26]([CH2:29][N+:30]4([CH3:43])[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[N+](C)(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCNCC1
Reaction time: 1.5 h
Yield: 33 %

Procedure:
To a mixture of formic acid (10 ml) and trifluoroacetic acid (5 ml) was added 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-4-tert-butoxycarbonyl-1-piperazinio)methyl-3-cephem-4-carboxylate hydrochloride (syn isomer) (5.7 g) at 20° C. under stirring. The stirring was continued for 1.5 hours at the same temperature. The reaction mixture was poured into ethyl acetate (200 ml). The resulting precipietes were collected by filtration, added to water. The mixture was adjusted to pH 2.0 with a saturated aqueous solution of sodium bicarbonate and filtered. The filtrate was subjected to column chromatography on Diaion HP-20 using 10% aqueous isopropanol as an eluent. The eluate was evaporated in vacuo to remove isopropanol and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (1.50 g).
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS([CH2-])=O.[PH5].[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CS(C)=O.O.C1COCC1>[CH2:3]([OH:2])[CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCC=O
Reactant: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [CH2-]S(C)=O
Agent: [PH5]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC/C=C\CCCCCO
Reaction time: 0.33 h

Procedure:
(6-Hydroxyhexyl)triphenylphosphonium bromide 6 (0.5 g, 1.13 mmol) in warm DMSO (3 ml) was added to THF solution of methylsulfinylmethanide ion (prepared from NaH (57 mg, 2.37 mmol) and DMSO (1 ml) under N2 at 70-75° C. for 80 min) with cooling in an ice-bath. The bright yellow solution of phosphorane was stirred at room temperature for 10 min, then treated with octanal (0.159 g, 1.25 mmol) at 0° C. After stirring for 20 min, the reaction mixture was poured into 5 ml H2O and extracted several times with ether. Drying with MgSO4 and concentration affords a residue which was purified by FCC (14% EtOAc in hexanes) to yield 7 (0.13 g, 54%, lit. 60%); δH(270 MHz, CDCl3) 0.86 (3H, t, J=6.5 Hz), 1.10-1.43 (16H, m), 1.55 (2H, m), 2.00 (4H, m), 3.6 (2H, t, J=6.5 Hz) and 5.3-5.4 (2H, m).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[NH2:20][CH:21]1[CH:26]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:25]2[CH2:34][CH2:35][CH:22]1[CH2:23][CH2:24]2.CN(C)C=O.C(O)(C)C>C(N(CC)CC)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:26]2[CH:21]([NH:20][C:2]3[C:3]4[N:4]=[CH:5][N:6]([C:7]=4[N:8]=[CH:9][N:10]=3)[C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:22]3[CH2:35][CH2:34][CH:25]2[CH2:24][CH2:23]3)=[CH:32][CH:31]=1
Reactant: NC1C2CCC(CC2)C1c1ccc(Cl)cc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4C5CCC(CC5)C4c4ccc(Cl)cc4)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 96 h

Procedure:
A mixture of 28.6 g of 6-chloro-9(β-D-ribofuranosyl)-purine, 23.6 g of 2-amino-3-p-chlorophenylbicyclo[2,2,2]octane, 450 ml of dimethylformamide, 450 ml of isopropanol and 50 ml of triethylamine is left to stand at 20° for 4 days. The mixture is evaporated, the residue is dissolved in chloroform, the chloroform solution is washed with 1% aqueous acetic acid and evaporated again and the residue is triturated with ether to give N6 -[2-(4-chlorophenyl)-bicyclo[2,2,2]oct-3-yl]-adenosine (Ia). M.p.: 145° (decomposition). Rf: 0.41 (silica gel; CH2Cl2 :CH3OH 9:1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CC(C)([O-])C.[K+].[C:12]([C:14]1([C:17]2([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][O:18]2)[CH2:16][CH2:15]1)#[N:13].CN(C=O)C>C(OCC)(=O)C>[C:12]([C:14]1([C:17]([OH:18])([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:15][CH2:16]1)#[N:13]
Reactant: N#CC1(C2(CCc3ccccc3)CO2)CC1
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC1(C(O)(CCc2ccccc2)Cn2cncn2)CC1
Yield: 26.6 %

Procedure:
0.8 g (12 mmol) of 1,2,4-triazole, 0.1 g (1 mmol) of potassium tert.-butoxide and 0.8 g (4 mmol) of 2-(1-cyanocyclopropyl)-2-(2-phenylethyl)oxirane (IV-16, Example 34) are heated to 80° C. for 6 h in 10 ml of abs. DMF. The solvent is stripped off in vacuo, and the residue is taken up in ethyl acetate and washed with water. After drying over Na2SO4, the solvent is evaporated in vacuo and the residue is chromatographed on silica gel (CH2Cl3 containing 2% ethanol). 0.3 g (28% of theory) of 2-(1-cyanocyclopropyl)-4-phenyl-1-(1,2,4-triazol- 1-yl)butan-2-ol is obtained in the form of a colorless oil, 1H--NMR (CDCl3):
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.COCCOC.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:14]1[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1ccc(-c2cc3ccccc3s2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A two-necked 250 mL round-bottomed flask fitted with a reflux condenser (with gas inlet) and a rubber septum was flushed with argon before 2-bromopyridine (2.57 mL, 27 mmol) and ethyleneglycol dimethylether (80 mL, dry and degassed) were introduced. Tetrakis(triphenylphosphine)palladium (1.0 g, 0.87 mmol) was added and the solution stirred at room temperature for 10 minutes. Benzothiophene-2-boronic acid (5.0 g, 28.1 mmol) was then added, followed by anhydrous sodium bicarbonate (8.4 g. 100 mmol) and water (50 mL, degassed). The septum was replaced with a glass stopper and the reaction mixture was heated at 80° C. for 16 hours, cooled to room temperature and the volatiles removed in vacuo. Organics were extracted with ethyl acetate (3×100 mL), washed with brine and dried over magnesium sulfate. Removal of the organics yielded a pale yellow solid. Recrystallisation from ethanol yielded a colourless solid (3.9 g, 68%, two crops), m.p. 124-6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[CH2:31]([S:35](Cl)(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]>>[CH2:31]([S:35]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: CCCCS(=O)(=O)N1CC(C(=O)N2CCN(c3cc(C)ccc3C)CC2)N(c2ccccc2)C1=O

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 1-butanesulfonyl chloride to give the title compound as an off-white solid. MS: 499.0 ([M+H]+)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].Cl[C:10](=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](OCC)=O)[CH2:11][CH3:12].C(N(CC)CC)C.P(Cl)(Cl)([Cl:33])=O>C1(C)C=CC=CC=1>[Cl:33][C:14]1[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:10]([CH2:11][CH3:12])[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: CCn1nccc1N
Reactant: CCOC(=O)C(C(=O)OCC)=C(Cl)CC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Temperature: 110 °C
Yield: 93.3 %

Procedure:
To 1-ethyl-1H-pyrazol-5-amine (Aldrich, 1.52 g, 13.7 mmol) was added a solution of diethyl (1-chloropropylidene)propanedioate (3.21 g, 13.7 mmol) in toluene (40 mL) followed by triethylamine (3.78 mL, 27.3 mmol) and then heated at reflux for 6 h. The cooled mixture was evaporated to dryness and the resulting brown residue was treated with phosphorus oxychloride (25 mL, 0.274 mol) and heated to 110° C. for 17.5 h. The cooled mixture was evaporated to dryness and the residue was to water (caution, exotherm) and extracted with ethyl acetate. The aqueous phase was treated with aqueous sodium hydroxide (2M) to achieve pH 9 and extracted with additional ethyl acetate. The combined organics were washed with aqueous sodium bicarbonate, then brine, dried and evaporated to dryness to afford 3.6 g of a dark brown oil. The product was purified by flash chomatography on silica (150 mL), eluting with ethyl acetate/cyclohexane from 1:10 to 1:8 to afford 1.8 g of the title compound. LC-MS m/z 282 (M+H)+, 3.46 min (ret time).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:16]>CC(O)C>[CH:12]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:16])[C:3]3=[C:10]([I:11])[N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: N
Reactant: Clc1nccn2c(C3CCC3)nc(I)c12
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(I)c12
Temperature: 115 °C

Procedure:
A Parr bomb containing 8-chloro-3-cyclobutyl-1-iodoimidazo[1,5-α]pyrazine (759 mg, 2.3 mmol) in IPA (100 ml) was saturated with NH3(g) for 5 min at 0° C. then sealed and heated at 115° C. for 38 h. The reaction mixture was then concentrated under reduced pressure, partitioned between DCM (200 mL) and H2O (50 mL) and extracted with DCM (50 mL). Combined organic fractions were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J=4.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.63 (br, 2H), 3.73 (quintetd, J=0.8 Hz, 8.4 Hz, 1H), 2.60-2.38 (m, 4H), 2.20-1.90 (m, 2H); MS (ES+): m/z 315.9 (100) [MH+]; HPLC: tR=1.75 min (OpenLynx, polar-5 min).