Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cccc(N)c2)CC1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To 10% palladium-carbon (30 mg), a solution of tert-butyl 4-((3-nitrophenyl)amino)azepane-1-carboxylate (C25, 78 mg) in tetrahydrofuran (2 mL) and methanol (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 4-((3-aminophenyl)amino)azepane-1-carboxylate (C26, 64 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+:11].CC(C)=O.[C:16](Cl)(=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[C:16]([NH:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5])(=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[Na+:11].[Na+:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a one L three-necked flask were placed 31.9 g (0.24 mol) of L-aspartic acid and an aqueous solution of 19.2 g (0.48 mol) of sodium hydroxide in 150 mL of water under stirring. After the L-aspartic acid was dissolved, 120 mL of acetone was added to the mixture in the flask. Then, to the resultant reaction liquid which had been cooled to 0° C. were added dropwise over a period of 30 minutes, 52.2 g (0.2 mol) of pentadecanoyl chloride and an aqueous solution of 0.2N sodium hydroxide in 30 mL of water simultaneously therewith, while maintaining the reaction temperature at 0 to 5° C. and pH at 11 to 12. Thereafter, by gradually raising the temperature of the reaction liquid to room temperature (25° C) under stirring over a period of 2 hours, a solution of disodium pentadecanoyl-L-aspartate was obtained. To the resultant solution was added 140 mL of 5N hydrochloric acid to lower the pH of the solution to 1. The crystal thus precipitated was separated from the solution by means of vacuum filtration, washed with water and dried under reduced pressure. The resultant crystal was washed with 500 mL of hexane, dried and recrystallized from a mixed solvent of ethanol/water (1:1 v/v). As a result 39.8 g (0.11 mol) of N-pentadecanoyl-L-aspartic acid was obtained in a yield of 55.6% based on the fed pentadecanoyl chloride. The physical properties of the objective N-pentadecanoyl-L-aspartic acid were as follows.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.COC1C=CC(C[N:30]2[CH2:35][CH2:34][N:33]3[N:36]=[C:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH:38]=[C:32]3[C:31]2=[O:44])=CC=1>O.C(#N)C>[O:44]=[C:31]1[NH:30][CH2:35][CH2:34][N:33]2[N:36]=[C:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH:38]=[C:32]12
Reactant: COc1ccc(CN2CCn3nc(COC(C)=O)cc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1cc2n(n1)CCNC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
A solution of ammonium cerium (IV) nitrate (0.7 g, 1.29 mmol) in water (1.1 mL) was added to a stirred solution of acetic acid 5-(4-methoxy-benzyl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester (142 mg, 0.43 mmol) in ACN (4.3 mL). The mixture was stirred at room temperature for 30 minutes and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 7 N solution of ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield acetic acid 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester (56 mg, 62% yield) as a white solid.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.C[Si]([N:39]=[C:40]=[O:41])(C)C>C(Cl)Cl>[S:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:27]=[C:19]1[O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([CH2:8][N:2]3[CH2:7][CH2:6][N:5]([C:40]([NH2:39])=[O:41])[CH2:4][CH2:3]3)=[CH:10][O:11][C:12]=2[CH:17]=1
Reactant: c1cnc2nc(Oc3ccc4c(CN5CCNCC5)coc4c3)sc2c1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)N1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
To a suspension of 2-(3-piperazin-1-ylmethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (122 mg, 0.30 mmol) in DCM (3 mL) was added Et3N (0.21 mL, 1.51 mmol) and the reaction mixture was stirred (rt, 15 min). The resulting solution was treated with trimethylsilyl isocyanate (0.14 mL, 0.91 mmol) and stirred (rt, 4 h). The reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse phase HPLC to afford the title compound as a white solid (55 mg, 44%). MS (ESI): mass calcd. for C20H19N5O3S, 409.47; m/z found, 410.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.02 (dd, J=7.9, 1.6, 1H), 7.77 (d, J=8.5, 1H), 7.59 (d, J=1.9, 2H), 7.29 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 4.43 (s, 2H), 3.66 (d, J=0.7, 2H), 3.47-3.36 (m, 4H), 2.55-2.46 (m, 4H).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.B(O)(O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH2:44])=[O:43])[CH:37]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:36]2[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=2)[C:42]([NH2:44])=[O:43])=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C(N)=O)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and (3-aminocarbonyl)phenylboronic acid (58 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 100%).
Reaction SMILES: C[O:2][C:3]([CH:5](C1C=CC(Br)=CC=1)[CH:6]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O.COC([C@@H](C1C=CC=CC=1)[C@@H]1NCCCC1)=O>>[N:11]12[C:3](=[O:2])[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]2
Reactant: COC(=O)C(c1ccc(Br)cc1)C1CCCCN1
Agent: COC(=O)[C@@H](c1ccccc1)[C@H]1CCCCN1
Product: O=C1CC2CCCCN12

Procedure:
Pan et al., Eur. J. Pharmacol., 264:177-182 (1994) (“Pan”) describes the synthesis of bromine-substituted methylphenidate analogs. In particular, Pan describes the synthesis of the o-bromo, m-bromo and p-bromo methylphenidate (bromo substitutents on the phenyl ring). The Panizzon synthesis of methylphenidate was modified to prepare p-bromomethylphenidate. Briefly, methylphenidate's molecular skeleton was prepared by base catalyzed reaction of p-bromophenylacetonitrile with o-chloropyridine. Following hydrolysis of the nitrile group to an amide, the pyridine ring was reduced to produce a 4:1 mixture of the erythro and threo isomers of ritalinic acid amide. Epimerization with NaOH, acid hydrolysis of the amide, and treatment with methanol/hydrogen chloride then gave dl-threo-p-bromo-methylphenidate hydrochloride in about 10% overall yield. An early batch used in in vivo experiments was about 85% pure due to the presence of erythro isomers of p-bromomethylphenidate and a trace of dl-threo-methylphenidate. These impurities were removed by several recrystallizations from methanol/ether before in vitro binding experiments were performed. Nuclear magnetic resonance (NMR) spectroscopic data were consistent with the assigned structure (δ3.26 doublet for the benzylic hydrogen showing the threo configuration; δ7.18 and 7.44 doublets for the aromatic protons) and a purity of >98%. Chiral high performance liquid chromatography (HPLC) using a Daicel 250×10 mm column eluted with hexane-isopropanol-diethylamine (98:2:0.1, v/v at 4 ml/min) showed two peaks of equal area at 10 and 12 minutes. The analogous o- and m-bromo derivatives were also prepared from the corresponding o- and m-bromophenylacetonitriles, and shown by NMR and chiral HPLC to be >95% pure.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:19])=[O:17])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of 2-amino-5-chlorobenzophenone (500 mg, 2.16 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C. was added dropwise (CF3SO2)2O (545 μL, 3.24 mmol) in anhydrous CH2Cl2 (10 mL) over 10 min and the reaction allowed to warm to RT over 15 hours. The reaction mixture was washed with water, dried over MgSO4 and concentrated under vacuum. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 7:3) to afford N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (710 mg, 90%), as a pale yellow solid. 1H n.m.r. (200 MHz, CDCl3) δ 7.80-7.69, m, 3H, 7.66-7.51, m, 5H. HRMS (M+) 362.9928.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([O:25][CH2:26][CH:27]([OH:29])[CH3:28])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.C(OC)(C)(C)C>C1COCC1.O>[CH3:1][S:2]([O:29][CH:27]([CH3:28])[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:31][CH:30]=1)(=[O:4])=[O:3]
Reactant: CC(O)COc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)OS(C)(=O)=O
Reaction time: 3 h

Procedure:
0.35 mL (4.50 mmol) methanesulphonic acid chloride are added at RT to a solution of 1.50 g (4.12 mmol) 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-propan-2-ol and 1.14 mL (8.20 mmol) triethylamine in 80 mL THF and the reaction is stirred for 3 h at this temperature. The solvent is eliminated i.vac. and the residue is combined with 40 mL tert-butylmethylether and 60 mL water. The precipitate is suction filtered and further purification is carried out by column chromatography on silica gel (EtOAc).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.C(O)(=O)C.[ClH:42].O>O1CCOCC1>[ClH:42].[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C

Procedure:
The title compound was prepared using the previously described procedure and the following reagants: t-butyl oxycarbonyl-methionyl-valyl-tryptophan (4.61 grams), 32 milliliters of glacial acetic acid and 17.5 ml (106.2 mmoles) 6.07 N hydrochloric acid in dioxane. Yield is 3.2 grams. Analysis calculated for C21H30N4O4S.HCL.H2O: C, 51.57; H, 6.80; N, 11.46. Found: C, 51.29; H, 6.59; N,-11.72.
Reaction SMILES: [Br:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13]
Reactant: O=CC1=C(Br)CCc2ccccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: O=Cc1c(Br)ccc2ccccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
2-Bromo-6,7-dimethoxy-1-napthaldehyde (10). Dimethylformamide (3.0 g, 41 mmol) was added dropwise to solution of phosphorus tribromide (3.3 mL, 35 mmol) in dry chloroform (50 mL) at 0° C. The mixture was stirred at 0° C. for 1 h to give pale yellow suspension. A solution of compound 8 (2.0 g, 9.7 mmol) in chloroform was added to the yellow suspension and the mixture was heated at reflux for 1 h. The reaction mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution was added dropwise until no effervescence was obtained. The resulting mixture was extracted with dichloromethane, dried (Na2SO4) and evaporated to provide the respective 2-bromo-3,4-dihydro-1-napthaldehyde derivatives as yellow solids. Each of the 2-bromo-3,4-dihydro-1-napthaldehyde derivatives were chromatographed on silica gel using a 3:1 mixture of hexanes:ethyl acetate as the eluent to give the 2-bromo-3,4-dihydro-1-napthaldehydes in an 87% yield. The 2-bromo-3,4-dihydro-1-napthaldehyde (2.4 g, 8.1 mmol) and DDQ (2.2 g, 97 mmol) was refluxed in toluene (50 mL) for 15 h. After cooling to room temperature, the mixture was subjected to filtration through a celite bed and the filtrate was evaporated to dryness. The residue obtained was chromatographed on 75 g silica gel using a 3:1 mixture of hexanes:ethyl acetate as eluent to give the 2-bromo-1-napthaldehyde in a 95% yield; 1H NMR δ 4.00 (3H, s), 4.05 (3H, s), 7.07 (1H, s), 7.54 (1H, d, J=8.5), 7.79 (1H, d, J=8.5), 8.71 (1H, s), 10.74 (1H, s); 13C NMR δ 56.3, 56.6, 104.2, 107.0, 126.5, 128.8, 129.4, 129.8, 129.9, 134.3, 150.4, 153.1, 195.9; HRMS calcd for C,3H11O3Br: 293.9891; found: 293.9896.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[C:5]([C:14](Cl)=[O:15])[CH:4]=[CH:3]1.[OH:17][CH:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1>N1C=CC=CC=1>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[CH:18]([O:17][C:14]([C:5]1[CH:4]=[CH:3][C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=1)=[O:15])[CH2:19]2
Reactant: O=C(Cl)c1ccc(=O)n(-c2ccccc2)c1
Reactant: OC1CN2CCC1CC2
Solvent: c1ccncc1
Product: O=C(OC1CN2CCC1CC2)c1ccc(=O)n(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
After dissolution of the mixed solution of 6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carbonyl chloride obtained in Example 115-1 in 5 mL of pyridine, 231 mg (1.82 mmol) of 3-hydroxyquinuclidine was added thereto. Afterward, the resulting reaction solution was stirred at room temperature for about 3 days. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo. Without an additional purification process, the resulting compound was extracted three times with water and chloroform, and the organic phase was purified using liquid chromatography (chloroform:methanol: ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 65 mg, Percent yield: 20%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]([CH3:34])[CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([N:25]([CH3:34])[CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:23][N:24]=3)[CH:21]=2)[CH2:4][CH2:3]1
Reactant: CN(CCN1CCOCC1)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 7 h
Yield: 51.1 %

Procedure:
To a solution of Intermediate A (225 mg, 1.38 mmol) in DMF (3 mL) was added NaH (60% in oil, 150 mg, 3.75 mmol) and the mixture stirred at RT for 20 min, before Intermediate 45c (350 mg, 1.25 mmol) was added. This mixture was stirred at 60° C. for 7 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-20% [2M NH3 in MeOH] in DCM, gave the title compound as an orange oil (270 mg, 51%). LCMS (Method 4): Rt 0.22 min, m/z 423 [MH+].
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH2:15][CH3:16]>CN(C)C=O.CCOCC>[C:1]([N:8]([CH2:9][C:10]#[CH:11])[CH2:15][CH3:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Di-tert-butyl dicarbonate (42.8 g, 196 mmol) in dichloromethane (100 mL) was added dropwise to a solution of propargylamine (11.02 g, 200 mmol) in dichloromethane (200 mL) at room temperature with magnetic stirring. After 2 h, the reaction mixture was washed with aqueous 1N hydrochloric acid (300 mL) and saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layers were washed with dichloromethane (300 mL). The dichloromethane solutions were combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40S, EtOAc-hexanes V/V 1:9 as solvent) to give crude N-Boc-propargylamine. (32.32 g). The crude N-Boc-propargylamine (3.1 g, 20 mmol) was dissolved in dry dimethylformamide (20 mL) with magnetic stirring and cooled in an ice-water bath. Sodium hydride (0.61 g, 24 mmol) was added in small portions. After stirring for 15 min., iodoethane (3.74 g, 24 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. then diluted with ether and extracted with water and saturated brine. The aqueous layers were back washed with ether and the ether layers were combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40M, ethyl acetate-hexanes as solvent to give N-Boc-N-ethylpropargylamine. (Yield 3.19 g, 87%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1)=[O:5])#[N:2].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.C(OCC)(=O)C>COCCOCCO.O>[F:14][C:9]1[CH:8]=[C:7]([N:6]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: CO/C=C/C(C)=O
Reactant: N#CCC(=O)Nc1cc(F)cc(F)c1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: COCCOCCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(=O)n1-c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
A solution (30 mL) of 2-cyano-N-(3,5-difluorophenyl)acetamide (3.10 g, 16.0 mmol), (3E)-4-methoxybut-3-en-2-one (2.40 g, 24.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (2.70 g, 24.0 mmol) in 2-(2-methoxyethoxy)ethanol was stirred at 130° C. for 12 hr. After cooling to room temperature, the reaction solution was divided into two layers with ethyl acetate and water and subjected to extraction (3 times) with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (1.60 g, 40%) as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O>>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:14]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:17]=3)(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:14]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)cc2c1
Product: Cc1ccc2sc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)cc2c1
Yield: 24.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-methyl-benzothiophene-2-sulfonyl chloride (30 mg, 0.12 mmol) and 5-(3-aminophenyl)tetrazole (20 mg, 0.12 mmol) giving the title compound as a white solid (11 mg, 25%). 1H NMR (400 MHz, MeOH-d4) δ ppm 2.40 (s, 3 H) 7.25-7.30 (m, 1 H) 7.34-7.40 (m, 1 H) 7.45 (t, J=7.91 Hz, 1 H) 7.62-7.65 (m, 1 H) 7.68-7.74 (m, 2 H) 7.78 (s, 1 H) 7.94 (t, J=1.88 Hz, 1 H). MS (ESI+) calcd for C16 H13N5O2S2 371.051066, found 371.050166.
Reaction SMILES: N[C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].N([O-])=O.[Na+]>O.Cl>[O:9]=[C:8]1[O:10][C@@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CC[C@H](C(=O)O)O1
Yield: 57.1 %

Procedure:
To a mixture of D-glutamic acid (1, 25 g, 170 mmol) in water (67 mL) and conc. HCl (35 mL) at 0° C. with stirring was added a solution of NaNO2 (17.5 g, 253.6 mmol) in water (37.5 mL) over a period of 4 h, and then the resulting clear solution was stirred at room temperature overnight. After removal of the solvent by evaporation in vacuo, the residue was treated with EtOAC (80 mL) and filtered. The filtrate was dried over Na2SO4, and concentrated. The residue, after crystallization from EtOAc/benzene/hexane, afforded the title compound 2 as a white crystalline solid (12.63 g, 57%). M.P. 71-73° C.; 1H NMR (400 MHz, CD3OD) δ 4.20 (m, 1H, CHO), 1.8-2.3 (m, 4H, CH2CH2).