Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[ClH:15].C(N(CC)CC)C.[CH:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43](=O)[NH:42][N:41]=2)=[CH:35][CH:34]=1>O>[ClH:15].[ClH:15].[CH:23]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]2[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]([CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)=[N:41][N:42]=2)=[CH:28][CH:27]=1)([CH3:25])[CH3:24]
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 210 °C
Reaction time: 4 h

Procedure:
In the manner described in Example 45, a mixture of 1.80 g (12.68 mmol) phosphorus pentoxide, 1.73 g (12.6 mmol) triethylamine hydrochloride, 1.8 ml (12.74 mmol) 4-isopropylaniline, and 1 g (4.2 mmol) 4-(4-pyridylmethyl)-1 (2H)-phthalazinone is stirred for 4 h at 210° C. The frozen melt is then suspended in water using an ultrasonic bath, filtered, and the filtrate evaporated in the RE. The oil-like residue is distributed between dichloromethane and a mixture of 20 ml water and 5 ml conc. ammonia, and the organic phase dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue is then stirred with acetonitrile, filtered off from some non-transformed 4-(4-pyridylmethyl)-1 (2H)-phthalazinone, and the filtrate evaporated under vacuum. Flash chromatography of the residue on silica gel with a particle size of 0.04-0.06 mm using acetate/methanol mixtures (20:1 and 10:1) yields a resin (free base of the title compound), which is dissolved in a mixture of 4 ml methanol and 1.5 ml of 3N methanolic HCl. After evaporation under vacuum, recrystallization of the residue from methanol/ether, drying under HV (8 h, 120° C.), and equilibration for 16 h at 20° C. and in room atmosphere, title compound is obtained with a water content of 9.4%; m.p. >250° C.; ESI-MS: (M+H)+=355.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:27]1([C:33]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](B(O)O)=[C:39]3[C:34]=2[CH:35]=[CH:36][CH:37]=[CH:38]3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:56]1([CH3:62])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>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.CO.O.C(O)C>[C:27]1([C:33]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:9]=[CH:10][C:11]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)=[N:12][C:13]=4[C:14]4[CH:19]=[CH:18][C:17]([C:57]5[C:56]6[C:61]([C:60]([C:7]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)=[C:59]7[C:58]=5[CH:9]=[CH:8][CH:13]=[CH:14]7)=[CH:10][CH:11]=[CH:21][CH:62]=6)=[CH:16][CH:15]=4)=[CH:4][CH:3]=3)=[C:39]3[C:34]=2[CH:35]=[CH:36][CH:37]=[CH:38]3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc(-c2ccc(-c3ccccn3)nc2-c2ccc(Br)cc2)cc1
Reactant: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
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: CCO
Solvent: O
Solvent: CO
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-c4ccc(-c5ccccn5)nc4-c4ccc(-c5c6ccccc6c(-c6ccccc6)c6ccccc56)cc4)cc3)c3ccccc23)cc1
Temperature: 120 °C
Yield: 43 %

Procedure:
In a 100-mL three-neck flask were put 0.74 g (1.6 mmol) of 5,6-bis(4-bromophenyl)-2,2′-bipyridine, 1.1 g (3.7 mmol) of 10-phenylanthracene-9-boronic acid, 0.79 g (7.4 mmol) of sodium carbonate, 20 mL of toluene, 5 mL of ethanol, and 5 mL of water. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To this mixture was added 74 mg (0.14 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was refluxed at 120° C. under a nitrogen stream for ten hours. After a predetermined time, water was added to this mixture to separate an aqueous layer and an organic layer, and then an organic substance was extracted with toluene from the aqueous layer. The obtained extracted solution and the organic layer were combined and washed with saturated saline, the aqueous layer and the organic layer are separated, and the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was concentrated to give an oily substance. The obtained oily substance was purified by silica gel column chromatography (toluene), so that a solid was obtained. A methanol suspension of the obtained solid was irradiated with ultrasonic waves, and a solid was collected by suction filtration. The obtained solid was recrystallized with toluene to give 0.56 g of light yellow powder, which was the objective substance, in a yield of 43%. The synthesis scheme of this reaction is shown below.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[IH:12].[PH2](O)=O.[OH-].[Na+]>O>[I:12][CH:8]1[CH2:7][CH2:6][NH:5][CH:4]([C:3]([OH:2])=[O:11])[CH2:9]1
Reactant: I
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: O=[PH2]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(I)CCN1
Temperature: 85 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57% hydroiodic acid (13.3 mL) and 50% aqueous hypophosphorous acid (0.66 mL) was stirred at 85° C. for 2 h and then was stirred at 107° C. overnight. The mixture was cooled to 95° C. At this temperature over 30 minutes 10 M sodium hydroxide aqueous solution (4.2 mL) was added, followed by the addition of water (15.2 mL). The mixture was cooled to rt and stirred at rt for 1 h. The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give 4-iodopipecolinic acid 13a (3.5 g, 66%): 1H NMR (300 MHz, DMSO d6) δ 8.39 (d, J=5.1, 1), 8.35 (d, J=1.8, 1), 8.07 (dd, J=1.7, 5.2, 1); MS (ESPOS): 250.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Reactant: CCCCN
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1OC
Temperature: 90 °C
Reaction time: 70 h

Procedure:
A stirred mixture of the product from step (i) (8 g) and butylamine (7.40 ml) in dioxane (100 ml) was heated at 90° C. for 72 h. More butylamine (7.40 ml) was added and the reaction mixture stirred for a further 70 hrs. The solvent was evaporated and the crude product was purified by chromatography (5% MeOHiDCM) to afford the subtitle compound as a tan solid, 4.5 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=O)[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[C:19]([NH:32][NH2:33])(=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CO>[CH3:18][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([NH:33][NH:32][C:19](=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:12])[CH2:5][C:4]([CH3:16])([CH3:17])[NH:3]1
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CCCCCCCCCCCC(=O)NNC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1

Procedure:
Into a 3-necked 300 ml flask was introduced a 60.9% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol (21.0 g, 0.05 mole), lauric acid hydrazide (13.5 g) and 150 ml of anhydrous methanol. The flask was equipped with a thermometer, a magnetic stirrer and a Dean Stark trap with a reflux condenser. The reaction mixture was heated to reflux and the methanol was slowly distilled off through the Dean Stark trap. The disappearance of the starting materials and the formation of the products were monitored by liquid chromatography. After 6 hours at reflux and the removal of 110 ml of methanol, the liquid chromatograph scans indicated the reaction was essentially complete. The reaction mixture was filtered hot and the filtrate was stripped to dryness on a rotating evaporator under reduced pressure. The residue was a white powder weighing 16.6 g and had a melting range of 80°-84° C. An infrared scan (nujol mull) of the product contained strong carbonyl bands at 1655, 1580 and 1490 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:19])[CH3:1])[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C(C)(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C(C)(C)C
Yield: 61.4 %

Procedure:
Following general N—C coupling procedure 1, 7-tert-Butyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.534 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (178 mg, 0.534 mmol, 1.0 eq) which gave 3-[6-(7-tert-Butyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (189 mg) in 61% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 10H) 1.59 (br. s., 2H) 1.74-1.84 (m, 12H) 3.00 (d, J=2.53 Hz, 7H) 4.14 (br. s., 2H) 6.48 (s, 1H) 7.85 (dd, J=8.84, 2.27 Hz, 1H) 8.28-8.39 (m, 2H) 8.80 (s, 1H) 9.89 (s, 1H). MS m/z 577.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:21])=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[N:10]2)=[CH:5][CH:4]=1.C([O:24][C:25]([C:27]12[CH2:44][CH:43]1[CH:42]=[CH:41][CH2:40][CH2:39][CH2:38][CH2:37][N:36]([CH3:45])[C:35](=[O:46])[N:34]1[CH:30]([CH2:31][CH:32](O)[CH2:33]1)[C:29](=[O:48])[NH:28]2)=[O:26])C>>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:21][CH:32]3[CH2:31][CH:30]4[N:34]([C:35](=[O:46])[N:36]([CH3:45])[CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH:43]5[C:27]([C:25]([OH:26])=[O:24])([NH:28][C:29]4=[O:48])[CH2:44]5)[CH2:33]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(O)nc(-c3cccc(C)n3)nc2c1C
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3cccc(C)n3)nc2c1C
Yield: 11.6 %

Procedure:
Quinazolinol derivative (117) (198 mg, 0.7 mmol) was coupled to compound 51 (268 mg, 0.7 mmol) followed by hydrolysis of the ethyl ester as described in example 52 which gave the title compound (50 mg, 10%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)=[O:19]>CN(C)C=O>[CH2:1]([S:8][C:16]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Cn1ccnc1C(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
Benzylmercaptan (4.3 g) and potassium carbonate (4.8 g) were added to a solution of 2-(2'-chloro-3'-nitro-benzoyl)-1-methyl-imidazole (9.2 g) in 150 ml of N,N-dimethylformamide. The reaction mixture was stirred at 80° C. for 5 hours. Then, the reaction mixture was poured onto ice water, and the resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water and then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting solvent:hexane/ethyl acetate=95:5 v/v). 2-(2'-Benzylthio-3'-nitrobenzoyl)-1-methylimidazole (8.7 g) was obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][S@@](C(C)(C)C)=O)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.Cl>CO.O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[C:18]([F:26])[CH:17]=2)([NH2:27])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.33 h

Procedure:
(R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.765 g, 1.53 mmol) was dissolved in anhydrous MeOH (4 mL). At RT, 4.0M HCl in dioxane (1.5 mL) was added and the reaction mixture stirred for 20 min. The reaction mixture was diluted with EtOAc (50 mL), transferred to a separation funnel and washed with 1.0M NaOH (ca. 20 mL). The organic portion was dried over anhydrous Na2SO4, decanted and concentrated yielding (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine as a pale yellow oil, (0.745 g, crude quantitative yield). LCMS: 1.51 min [M+1] 395.2 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:20][C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][N:17]=1.Cl>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[S:20][C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][N:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1nnc(N)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76 %

Procedure:
To a solution of p-acetamidobenzenesulfonyl chloride (275 mg, 1.18 mmol) in pyridine (5 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (200 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 156-157° C., in 76% yield (312 mg, 0.81 mmol); 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, 3H, J=7.0 Hz), 2.07 (s, 3H), 4.06 (s, 2H), 4.15 (q, 2H, J=7.0 Hz), 7.72 (m, 4H), 10.29 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 24.1, 35.7, 61.3, 118.6, 127.0, 135.5, 142.9, 151.6, 167.8, 168.1, 169.0; MS (LCQ, ESI+) Calcd for C14H17N4O5S2 385.1. found 385.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C14H17N4O5S2 385.0640. found 385.0638 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1)[C:13]([C:27]([OH:29])=[O:28])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([C@H:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P([N:53]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C>>[C:27]([OH:29])(=[O:28])[CH3:13].[C:30]1([C@H:36]([NH:38][C:27]([C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[NH:26])[NH2:53])[CH:20]=3)[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=3)=[O:29])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: N#Cc1cccc(Cn2c(C(=O)O)cc3cc(OCc4ccccc4)ccc32)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O
Product: C[C@@H](NC(=O)c1cc2cc(OCc3ccccc3)ccc2n1Cc1cccc(C(=N)N)c1)c1ccccc1
Yield: 73 %

Procedure:
This compound was prepared from 5-benzyloxy-1-(3-cyano-benzyl)-1H-indole-2-carboxylic acid and (R)-1-phenyl-ethyl-amine by using diphenylphosphoryl azide and diisopropylethylamine as described in example 3/1. The crude material was purified by flash chromatography on silica gel with dichloromethane to give the desired product in 73% yield. M.p. 169-170° C. MS: 486.3 (M+H+).
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:18]1(/[CH:22]=[CH:23]/[C:24](OCC)=[O:25])[CH2:21][CH2:20][CH2:19]1>ClCCl.O>[CH2:2]([N:9]1[CH:22]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH2:23][C:24](=[O:25])[O:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)/C=C/C1CCC1
Reactant: ONCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC(C2CCC2)N(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
N-benzylhydroxylamine hydrochloride (0.77 g, 4.82 mmol) and triethylamine (0.76 mL, 5.45 mmol) were successively added to a solution of (E)-ethyl 3-cyclobutylacrylate, 46a, (0.65 g, 4.19 mmol) in dry dichloromethane (23.5 mL). The reaction mixture was allowed to stir at room temperature under an atmosphere of nitrogen for 3 days. The mixture was diluted with 75 mL of water and the layers were separated. The aqueous phase was reextracted twice more with dichloromethane (50 mL). The combined organic phases were dried over MgSO4, filtered and evaporated to dryness. The residue was purified via silica gel chromatography (0-100% EtOAc/Hexanes gradient) to afford 834 mg (86%) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m, 5H), 4.64 (s, 1H), 3.82 (q, J=13.5 Hz, 2H), 3.37-3.18 (m, 1H), 2.80-2.52 (m, 2H), 2.33 (dd, J=14.5, 5.1 Hz, 1H), 2.22-2.09 (m, 1H), 2.01-1.68 (m, 5H).
Reaction SMILES: [CH3:1][I:2].[C:3]1([CH2:9][CH2:10][CH2:11][S:12][C:13]2[C:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:16][O:15][N:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(C)=O>[I-:2].[C:3]1([CH2:9][CH2:10][CH2:11][S:12][C:13]2[C:17]([C:18]3[CH:19]=[N+:20]([CH3:1])[CH:21]=[CH:22][CH:23]=3)=[N:16][O:15][N:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(CCCSc2nonc2-c2cccnc2)cc1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2nonc2SCCCc2ccccc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl iodide (1 ml, 15 mmol) was added to a solution of 3-(3-(3-phenylpropylthio)-1,2,5-oxadiazol-4-yl)pyridine (7 mmol) in acetone and the reaction mixture was stirred at room temperature for 20 h.and evaporated.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(OCC)C>C(#N)C>[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]([C:5]3[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(COc1ccc(C(=O)CBr)cc1)NCc1ccccc1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)NCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 2-[4-(bromoacetyl)phenoxy]-N-(phenylmethyl)acetamide (1.40 g) (preparation described in EPO 052442) in acetonitrile (5 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (1.14 g) in acetonitrile (20 ml). After stirring overnight the liquors were decanted from the residual gum, then concentrated in vacuo. Purification by flash chromatography on silica, eluting with 2 to 5% v/v methanol/dichloromethane, gave a solid. Trituration of this solid with diethyl ether gave the title compound, 95 mg: m.p. 150°-151° C.; NMR (d6DMSO) δ 8.67 (1H, bt), 8.15 (2H, d), 8.00 (2H, d), 7.26 (5H, m), 7.06 (2H, d), 6.81 (2H, d), 4.66 (2H, s), 4.34 (2H, d), 3.84 (2H, s), 3.33 (4H, t), 2.54 (4H, t); m/e 445 (M+H)+ ; calculated for C26H28N4O3. 0.25H2O: C, 69.5; H, 6.4; 12.5. found: C, 69.6; H, 6.4; N, 12.3%.
Reaction SMILES: N[C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[CH2:3]1.[CH2:14]=O.S([O-])([O-])(=O)=O.[Mg+2].[C:22]([BH3-])#[N:23].[Na+]>O.C(O)(=O)C.CO>[CH3:14][N:23]([CH3:22])[C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[CH2:3]1
Reactant: C=O
Reactant: CCCCOC(=O)N1CC[C@H](N)C1
Reactant: [BH3-]C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCCOC(=O)N1CC[C@H](N(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 186.7 %

Procedure:
To a dried 100 mL single-mouth round bottom flask were added absolute methanol (40 mL), and then the starting materials (S)-butyl 3-aminopyrrolidine-1-carboxylate (1.86 g, 10 mmol), paraformaldehyde (3 g), anhydrous magnesium sulfate (2.5 g), acetic acid (1.2 g) and sodium cyanoborohydride (2.5 g, 39.8 mmol). The mixture was stirred at room temperature for 24 hr. The reaction system was poured into water to quench, concentrated under reduced pressure. The residue was extracted with ethyl acetate, the combined organic layer was concentrated under reduced pressure to obtain a crude yellow viscous product (4.0 g).