Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17]Br)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (5.0 g) in N,N-dimethylformamide (100 mL) were added tert-butyl(2-bromoethyl)carbamate (12 g) and cesium carbonate (19 g), and the mixture was stirred overnight at 40° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:30][CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](Cl)=[O:42])=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][N:30]([C:41](=[O:42])[CH2:40][O:39][C:38]2[CH:44]=[CH:45][C:35]([Cl:34])=[CH:36][CH:37]=2)[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)COc2ccc(Cl)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17].[OH-].[Na+].Cl>C1OCCOC1>[CH2:19]([O:18][C:16]([NH:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:17])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)COC(=O)Cl
Reactant: NC1(C(=O)O)CCc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)COC(=O)NC1(C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice cooled solution of amino acid from Example 53B (248 mg, 1.3 mmol) and anhydrousl, 4-dioxane (6 mL) was added isobutyl chloroformate (0.23 mL, 1.69 mmol). The solution's pH was maintained at 11 using 2M NaOH. The reaction was allowed to warm to room temperature. After 1 hour the reaction was complete. The pH was adjusted to 2 with 2 M HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the titled compound as a sticky white solid (341 mg, 90%). 1H (δ, DMSO-d6): 12.45 (br s, 1H), 7.39 (s, 1H), 7.03–7.15 (m, 4H), 3.6–3.8 (m, 2H), 3.1–3.2 (m, 2H), 3.07 (d, 1H), 2.71 (br s, 1H), 2.25 (br s, 1H), 1.9–2.0 (m, 1H), 1.77–1.9 (m, 1H). MS (DCI/NH3): 292.1 (M+1), 309.2 (M+H+NH4+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH:36]2[CH3:42].C([O-])(O)=O.[Na+]>>[CH3:42][CH:36]1[C:35]2[C:39](=[C:31]([NH:30][C:2]3[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)[CH:32]=[CH:33][CH:34]=2)[C:38](=[O:40])[N:37]1[CH3:41]
Reactant: CC1c2cccc(N)c2C(=O)N1C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4C)n2)c(OC)c1)OCC
Yield: 34.3 %

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (230.1 mg, 0.5071 mmol) and 7-amino-2,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 157A, 95.1 mg, 0.540 mmol) in TFE (5 mL). The reaction mixture poured into a separatory funnel containing saturated NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled solid loading cartridge [RediSepRf 2.5 gram] and purified using an ISCO Combiflash unit [RediSepRf 4 gram silica], eluting first with 40-100% EtOAc:Heptane and then 0-15% MeOH:CH2Cl2. The product was purified again by MDP [under basic conditions; ammonium bicarbonate buffer (pH 9)] to afford title product as a white solid (103.1 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 9.13 (s, 1H), 8.39 (s, 1H), 7.64-8.90 (m, 1H), 7.41 (br s, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.05 (s, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.55 (q, J=6.5 Hz, 1H), 3.91-4.06 (m, 4H), 3.74 (s, 3H), 3.29 (d, J=22.5 Hz, 2H), 2.99 (s, 3H), 1.40 (d, J=6.6 Hz, 3H), 1.20 (t, J=7.1 Hz, 6H). MS (ES+): m/z 594.17 (100) [MH+]. HPLC: tR=1.59 min (TOF, polar—3 min).
Reaction SMILES: N#N.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:22][B-:23]([F:26])([F:25])[F:24].[H+]>CO.O>[F:22][B-:23]([F:26])([F:25])[F:24].[C:16]1([PH+:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: F[B-](F)(F)F
Agent: N#N
Agent: [H+]
Solvent: O
Solvent: CO
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Temperature: 10 °C

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and cooled to 10° C. by a ice-bath. 250.8 g (1.1 mol) of fluoroboric acid aqueous solution (40 wt %) was then added dropwise under strong stirring. After one hour of reaction, the reaction temperature was increased to about 50° C., and the unreacted materials as well as the solvents, including water and methanol, were removed by distillation under vacuum to obtain triphenylphosphonium tetrafluoroborate. The phosphonium salt was then transferred to an autoclave, and 202.0 g (2.2 mol) of dimethyl carbonate was also introduced. After 6 hours of reaction at temperature of 160° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 375.0 g of methyl triphenyl phosphonium tetrafluoroborate was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:21]3[CH2:24][CH2:23][CH2:22]3)=[N:9][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])=O)[CH:5]=[CH:6][N:7]=1>C(O)(=O)C>[NH:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:11]1[C:10]1[N:9]=[C:8]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=12
Reactant: Nc1ccccc1NC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Solvent: CC(=O)O
Product: Nc1nccn2c(C3CCC3)nc(-c3nc4ccccc4[nH]3)c12

Procedure:
A solution of 8-amino-N-(2-aminophenyl)-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxamide (40.0 mg, 0.124 mmol) in acetic acid (1.2 mL) was microwaved at 120° C. for 10 min (300W). The resulting solution was purified mass directed preparative HPLC to afford 1-(1H-benzimidazol-2-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92-2.05 (m, 1 H) 2.07-2.21 (m, 1 H) 2.53-2.59 (m, 4 H) 3.91-4.06 (m, 1 H) 7.08 (d, J=4.80 Hz, 1 H) 7.16-7.26 (m, 2 H) 7.38 (d, J=4.80 Hz, 1 H) 7.44 (br. s., 1 H) 7.55 (d, J=8.08 Hz, 1 H) 7.62 (d, J=6.82 Hz, 1 H) 10.49 (br. s., 1 H) 12.76 (s, 1 H); MS (ES+): m/z 305.15 [MH+].
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[H][H]>[Pd].C(OCC)(=O)C>[CH2:6]([CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[C:5]1[CH:10]=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: O=C1CC=Cc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CCC1Cc1ccccc1
Yield: 114.7 %

Procedure:
A Parr® hydrogenation bottle was charged with naphthalen-1-one (15 gm), ethyl acetate (150 mL) and 1 g of 10% palladium on charcoal. The mixture was hydrogenated on a Parr® shaker for about 15 hrs under 20 psi of hydrogen. The resulting mixture was filtered through a pad of Celite® and concentrated in vacuo to afford a red oil which was purified by flash chromatography (3:1 hexane/diethyl ether) to afford 14.1 gm of benzyltetralone, mp 50-51° C. Analysis calculated for C18H18O2 : 266.1302. Found: 266.1308.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14]OCC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:35]([C:37]1[CH:38]=[N:39][C:40]([OH:43])=[CH:41][CH:42]=1)#[N:36].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:14][O:43][C:40]3[CH:41]=[CH:42][C:37]([C:35]#[N:36])=[CH:38][N:39]=3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: N#Cc1ccc(O)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: N#Cc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 3-cyano-6-hydroxy-pyridine and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate and a reaction time of 18 h. Light yellow solid (41%). MS (Turbo Spray): m/z=493.2 [M+H].
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=O.[Na+].O.[C:15]([O:18]CC)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([O:18][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8])(=[O:17])[CH3:16]
Reactant: CCOC(C)=O
Reactant: CSCC[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSCC[C@@H](OC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
D-Methionine (14.9 g, 0.10 mol) was stirred in 300 ml of acetic acid. Sodium nitrite (13.8 g, 0.2 mol) was added portionwise over 45 minutes while maintaining the temperature in the range 20°-30° C. After stirring for an additional 90 minutes at room temperature, the resulting yellow solution was stripped in vacuo to solids which were distributed between 300 ml each of water and ethyl acetate. The organic layer was separated, washed with saturated NaCl, dried over MgSO4 and stripped to yield 7.0 g of title product as a yellow oil, used directly in the next step; tlc Rf 0.08 (3:1 hexane:ethyl acetate).
Reaction SMILES: [CH3:1][O:2][B:3](OC)OC.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([B:3]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: COB(OC)OC
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COB(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Trimethylborate (2.2 ml, 1.92×10−2 mol) is added dropwise to a freshly prepared solution of p-chlorophenyl magnesium bromide (40.4 ml, 1 M, 4.04×10−2 mol) in tetrahydrofuran (60 ml) under argon at −78° C. The mixture is warmed to room temperature and stirred overnight. The solution is cooled to −78° C. and excess grignard reagent is destroyed by the dropwise addition of methanol until no more effervescence is observed. The solvents are removed in vacuo and the residue dissolved in diethyl ether and washed with water. The organic layer is dried (MgSO4), filtered and the solvents removed in vacuo to give methyl di(p-chlorophenyl)borinate (4.60 g, 92%) as a solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][CH2:10][OH:11])=[N:6][C:5]([S:12][CH3:13])=[CH:4][N:3]=1.O>CN(C)C=O.[Cu]I>[CH3:13][S:12][C:5]1[N:6]=[C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CSc1cnc(N)c(C#CCO)n1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cnc2[nH]c(CO)cc2n1
Temperature: 150 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of the compound obtained in Example 34 (3) (381 mg) in N,N-dimethylformamide (10 ml), copper(I) iodide (111 mg) was added and the mixture was stirred at 150° C. for 2 hours. The reaction solution was poured into water, and the mixture was extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol=20:1) to obtain 155 mg (40.7%) of the desired product as a yellow powder.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH:9]([CH3:11])[CH3:10])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.ClCCl>[C:12]([O:7][CH2:6]/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:8]/[CH:9]([CH3:10])[CH3:11])(=[O:14])[CH3:13]
Reactant: CCC(/C=C/CO)=C\C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(/C=C/COC(C)=O)=C\C(C)C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a solution of (E,E)-4-ethyl-6-methyl-2,4-heptadien-1-ol (23.8 g) in pyridine (61.4 g) at 0° C. was added dropwise acetic anhydride (50.9 g). After two hours, the reaction mixture was diluted with dichloromethane. The solution was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3% ethyl acetate-hexane) to give (E,E)-1-acetoxy-4-ethyl-6-methyl-2,4-heptadiene (24.11 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:32](OCC)(OCC)OCC>O>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]3[C:15]([N:24]4[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]4)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)=[O:11])=[CH:3][C:2]=2[N:1]=[CH:32]1
Reactant: CCOC(OCC)OCC
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(N)c(N)c2)CC1
Solvent: O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc3[nH]cnc3c2)CC1
Temperature: 25 °C

Procedure:
2-(3,4-diaminophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)-propionamide (48 mg, 0.110 mmol) was combined at RT with triethyl orthoformate (2 ml). The reaction mixture was heated to reflux for 2 h and cooled to RT. The reaction mixture was combined with water and repeatedly extracted with DCM. The combined organic phases were dried over MgSO4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (DCM/MeOH=10:1).
Reaction SMILES: [Si]([C:5]1[N:6]=NN[CH:9]=1)(C)(C)C.[N:10]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](Cl)=[O:13]>S1(CCCC1)(=O)=O.[Cl-].[Na+].O>[CH2:21]([O:20][C:18]([N:10]1[CH2:17][CH2:16][CH2:15][CH:11]1[C:12]1[O:13][CH:9]=[CH:5][N:6]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)c1c[nH]nn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C(OCc1ccccc1)N1CCCC1c1ncco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of TMS-triazole (14.17 g, 100.3 mmol, 1 equiv.) in sulfolane (290 mL) at rt under nitrogen, is added dropwise Z-L-Pro-Cl (26.85 g, 100.3 mmol, 1 equiv.) in sulfolane (70 mL). The resulting mixture is stirred at rt for 30 minutes, then the temperature is elevated to 140° C. for 3 hours. After the reaction mixture is cooled to rt, poured into excess brine and extracted with diethyl ether. The diethyl ether extracts are washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue is purified by flash chromatography (DCM:acetone=9:1) to give the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[CH:18](=[N+:25]([CH3:27])[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:18]([N:25]([CH3:27])[CH3:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(-c2ccc(Cl)cc2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-chlorophenyl)-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(CCN1C(=O)c2ccccc2C1=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid (40 g, 182.49 mmol, 1.00 equiv) in water (250 mL). This was followed by the addition of aniline (17 g, 182.55 mmol, 1.00 equiv). To this was added sodium carbonate (9.6 g, 90.57 mmol, 0.50 equiv). The resulting solution was stirred for 3 h at 25° C. The pH value of the solution was adjusted to 5-6 with hydrochloric acid (1 mol/L). The solids were collected by filtration. The filter cake was washed with 1×200 mL of water. This resulted in 40 g (74%) of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-phenylpropanamide as a white solid. MS (ESI) m/z 295 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([NH:17][NH2:18])(=O)[CH:13]([CH3:15])[CH3:14]>O=P(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:3]([C:4]2[O:6][C:12]([CH:13]([CH3:15])[CH3:14])=[N:17][N:18]=2)[C:2]([NH2:1])=[N:10][CH:9]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CC(C)C(=O)NN
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc(-c2cc(Br)cnc2N)o1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-bromo-nicotinic acid (1.0 g, 4.60 mmol) in POCl3 (20 mL) was added isobutyric acid hydrazide (705 mg, 6.912 mmol) at RT. The reaction temperature was slowly heated to 100° C. and stirred for 18 h. The solvent was evaporated under reduced pressure, the residue was basified with saturated cold sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3×50 mL), organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 40% EtOAc in petroleum ether to afford the title compound as a yellow solid.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.NC1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[NH:17][N:16]=1>C(O)(=O)C>[CH2:23]([O:22][C:20]([C:19]1[C:18]([CH3:25])=[N:17][N:16]2[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:13]=12)=[O:21])[CH3:24]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: CCOC(=O)c1c(N)n[nH]c1C
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 9.09 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 2.54 g. of ethyl 3-amino-5-methylpyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 16 hours. The solvent is removed and the residue in dichloromethane is washed with saturated sodium bicarbonate solution. The dichloromethane solution is passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give 3.1 g. of the product of the example, m.p. 145°-146° C.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][S-:18].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:17][S:18][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To 1,1-dimethylethyl 4-(2-iodoethyl)-1-piperidinecarboxylate (3.13 g, 9.23 mmol) in DMF (50 mL) was added sodium thiomethoxide (661 mg, 10.4 mmol) in one portion. The reaction was stirred for 3 days. Upon completion by TLC, the reaction was diluted with EtOAc (250 mL), washed with H2O (4 times), dried (MgSO4) and concentrated to provide the title compound of step B (2.37 g, 9.20 mmol, 99%, approximately 93% pure, used without further purification). 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.13 (m, 2H), 1.42 (s, 9H), 1.48-1.55 (m, 3H), 1.63 (d, J=12.5 Hz, 2H), 2.07 (s, 3H), 2.45-2.53 (m, 2H), 2.65 (td, J=12.8, 2.6 Hz, 2H), 4.02-4.09 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH:15]=[CH:14][N:13](C(=O)C(C)(C)C)[CH:12]=[C:11]1[CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCC1C1=CN(C(=O)C(C)(C)C)C=CC1COCc1ccccc1
Agent: [S]
Solvent: Cc1ccccc1
Product: CN1CCCC1c1cnccc1COCc1ccccc1
Yield: 59 %

Procedure:
A solution of 1-[4-benzyloxymethyl-3-(1-methylpyrrolidin-2-yl)-4H-pyridin-1-yl]-2,2-dimethyl-propan-1-one (0.176 g, 0.48 mmol), sulfur (0.015 g, 0.48 mmol) and toluene (5 mL) was refluxed for 3 days. After filtration of the mixture through a pad of Celite and evaporation of the solvent under reduced pressure, the crude material was purified by radial PLC (hexanes) to afford 0.08 g (60%) of 4-benzyloxymethyl-3-(1-methylpyrrolidin-2-yl)-pyridine as a yellow oil. IR (thin film, neat, NaCl) 3436, 1637, 1090 cm−1; 1H NMR (CDCl3, 300 MHz) δ 8.74 (s, 1H), 8.47 (d, 1H, J=4.8 Hz), 7.40-7.27 (m, 6H), 4.62 (d, 2H, J=13.2 Hz), 3.34-3.18 (m, 2H), 2.28-2.18 (m, 2H), 2.15 (s, 3H), 2.11-1.09 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 149.31, 148.37, 145.16, 137.86, 128.67, 128.06, 127.98, 122.14, 72.92, 68.19, 65.88, 57.07, 40.75, 34.28, 27.83, 22.91; HRMS Calcd for C18H22N2O: 283.1810 [M+H]+. Found: 283.1800 [M+H]+. [α]D24−75.9 (c 2.5, CH2Cl2).