Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH2:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[F:16][C:17]1[CH:40]=[CH:39][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:31][C:30]([C:32](OCC)=O)=[C:29]([CH3:37])[CH:28]=3)[C:23]2=[O:38])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:7]([CH:8]1[CH2:9][NH:10][C:32]([C:30]2[S:31][C:27]([N:24]3[CH2:25][CH2:26][N:22]([CH2:21][C:20]4[CH:39]=[CH:40][C:17]([F:16])=[CH:18][CH:19]=4)[C:23]3=[O:38])=[CH:28][C:29]=2[CH3:37])=[N:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)cc1C
Reactant: NC[C@@H](N)Cc1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C1=NC(Cc2ccccc2)CN1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a stirred solution of (S)-3-phenylpropane-1,2-diamine (0.37 g, 2.48 mmol) in toluene (20 mL) at 0° C. under nitrogen atmosphere was added dropwise trimethylaluminum (1.24 mL of 2.0 M solution in toluene, 2.48 mmol). When the fuming ceased, ethyl 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate (0.60 g, 1.66 mmol) in toluene (5 mL) was added slowly. The resulting mixture was stirred at reflux for 18 h, cooled to ambient temperature and partitioned between ethyl acetate (75 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (3×75 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with dichloromethane/methanol/triethyl amine (9/1/0.1) to afford the title compound as brown viscous oil in 29% yield (0.06 g): MS (ES+) m/z 449.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:35][CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: NC1CCOCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCOCC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with tetrahydro-2H-pyran-4-amine via General Procedure E to give 8.6 mg of 288 following reverse phase purification. MS (Q1) 463.2 (M)+
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(Cl)Cl.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
1-Isopropylpiperazine (1.8 mL, 12.7 mmol, 2 equiv) was added to a cold (5° C.) solution of 2-chloro-5-nitropyrimidine (1 g, 6.3 mmol,) in DCM (5 mL). The reaction mixture was stirred for 20 min at 5° C. and then diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to provide 1.41 g of the title compound as a beige solid: ESI-MS: 252.2 [M+H]+; tR=1.89 min.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[C:20](Cl)(=[O:22])[CH3:21]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:20](=[O:22])[CH3:21])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: CC(=O)Cl
Product: CCc1noc(-c2sc(NC(C)=O)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and acetyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:6][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:15][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[CH2:30][C:31]1[CH:39]=[CH:38][C:34]2=[N:35][O:36][N:37]=[C:33]2[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:35]1[O:36][N:37]=[C:33]2[CH:32]=[C:31]([CH2:30][N:11]3[C:10]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:9]=4[N:8]=[C:7]3[CH2:6][C:2]([CH3:28])([CH3:1])[C:3]([OH:5])=[O:4])[CH:39]=[CH:38][C:34]=12
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1)C(=O)O
Reactant: BrCc1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc2nonc2c1)C(=O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A suspension of 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)propanoic acid (300 mg, 0.75 mmol), 5-(bromomethyl)benzo[c][1,2,5]oxadiazole (168 mg, 0.75 mmol) and potassium carbonate (310 mg, 2.25 mmol) in DMF (20 mL) was heated to 70° C. for 18 h. The mixture was cooled to RT and concentrated to dryness. The residue was dissolved in THF/MeOH (18 mL, 1:1) and treated with 5% aq. NaOH (2 mL). The mixture was stirred at 40° C. for 16 h. The reaction was allowed to cool to RT and then concentrated to dryness. The residue was diluted with water (30 mL), washed with EtOAc (20 mL), and then treated with 6N aq. HCl to ˜pH 6. The aqueous was then extracted with DCM (2×30 mL). The organics were combined, dried with Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C29H26N6O4, 507.19; m/z found, 507.9 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=8.6, 1H), 8.11-7.98 (m, 3H), 7.85-7.77 (m, 1H), 7.71 (d, J=8.5, 1H), 7.68-7.61 (m, 2H), 7.58-7.52 (m, 1H), 3.35-3.33 (m, 2H), 7.50-7.43 (m, 1H), 7.38-7.33 (m, 1H), 7.21-7.12 (m, 1H), 5.84 (s, 2H), 5.47 (s, 2H), 1.30 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:11][N:12]=[C:4]2[CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:34][NH2:35]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=2)[N:12]2[N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:5]=[C:4]2[CH:3]=1
Reactant: CSc1nc(Cl)cc2nnc(-c3ccco3)n12
Reactant: COc1ccc(CN)cc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(Cl)cc3nc(-c4ccco4)nn23)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
Into 600 mL of THF, 50.0 g (188 mmol) of Compound B was dissolved, and 42.0 mL (280 mmol) of DBU was added thereto, followed by stirring at room temperature for about 30 minutes. During the period, crystals were precipitated from the reaction solution. Next, 94 g (563 mmol) of 3,4-dimethoxybenzylamine was added thereto, followed by stirring at 60° C. for about 2 hours. After completion of the reaction, the solvent was evaporated, the residue was diluted with chloroform and washed with water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was triturated with ethyl acetate to obtain 53.2 g of Compound D as a white solid (yield: 74%). The residue obtained by concentrating the solution part present after trituration was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to additionally recover Compound D in about 10% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:35])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CO)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 89.8 %

Procedure:
To a suspension of 6-benzyloxy-4-(4-chlorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (4.25 g, 9.5 mmol) in toluene (50 ml) was added thionyl chloride (1.4 ml, 19 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.98 g, 89.8%) as an oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].O>C(#N)C>[C:32]([O:31][C:29]([C:28]1[CH:27]=[C:26]([CH:38]=[CH:37][CH:36]=1)[CH2:25][NH:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1cccc(CN[C@@H](Cc2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of tert-butyl L-phenylalaninate hydrochloride (456 mg) in acetonitrile (8.00 mL) were added potassium carbonate (510 mg) and tert-butyl 3-(bromomethyl)benzoate (400 mg), followed by stirring at room temperature overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[3-(tert-butoxycarbonyl)benzyl]-L-phenylalaninate (340 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[SH:27]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: Sc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3cc(Cl)c(Cl)cc3Cl)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and 2,4,5-trichloro-thiophenol.
Reaction SMILES: [CH2:1]([C:8]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[S:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:8]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[S:12][C:11](=[O:13])[N:10]([CH2:27][C:28]([OH:30])=[O:29])[C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)NC2=O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)N(CC(=O)O)C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-Benzyl-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione (Example 6) (0.740 g, 1.96 mmol) in 34.5 mL of acetone was added t-butyl bromoacetate (4.227 g, 21.67 mmol) and potassium carbonate (2.75 g, 19.90 mmol) and the mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. The mixture was filtered and concentrated in vacuo. Column chromatography provided the t-butyl ester of the title compound as a viscous yellow oil. This material was dissolved in 96 mL of dichloromethane and 17.8 mL of trifluroacetic acid was added and the mixture was stirred 2.5 h at room temperature under a nitrogen atmosphere. The mixture was concentrated in vacuo, triturated with hexane, and filtered. The solid was redissolved in dichloromethane and again concentrated in vacuo to give 0.720 g of the title compound as a beige solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH3:21])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1n[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]nc(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (180 mg, 0.61 mmol) in 1,4-dioxane (1 mL) was added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (440 mg, crude), K3PO4 (360 mg, 1.71 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 4 h at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.5% methanol in dichloromethane to afford methyl 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (85 mg, 35%).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33]([CH2:35][NH2:36])=[O:34])=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:36][CH2:35][C:33]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)=[O:34])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
BOC-Ala-OH (94.6 g.), H-Gly-OBzl.TosOH (168.8 g.) and HOBT (67.6 g.) were dissolved in THF (450 ml.) and WSC (91.5 ml.) was added thereto, then stirred for 1 hour at 0° C. and overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (800 ml.). 1 N HCl (500 ml.) was added, the precipitate was removed by filtration, and the ethyl acetate layer was washed with 1 N HCl (400 ml.), and twice with 5% sodium bicarbonate solution and water in this order, and, after drying with anhydrous magnesium sulfate, concentrated in vacuo. The residue was treated with n-hexane to obtain crude material (152.5 g.) Recrystallization was carried out twice by ethyl acetate - n-hexane to obtain BOC-Ala-Gly-OBzl (144 g., Yield: 85.7%, m.p.: 87° - 88.5° C., TLC: one spot, RF1 = 0.59).
Reaction SMILES: [H-].[Na+].C[C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CCS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:11][CH2:4][O:5][CH2:6][CH:7]([OH:8])[CH2:9][OH:10]
Reactant: CC1(C)OCC(CO)O1
Reactant: COCCOCCOCCCCCCCCS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCCCCCCCCOCC(O)CO
Reaction time: 48 h
Yield: 42 %

Procedure:
To a suspension of 9.01 g of unwashed 50% sodium hydride in 100 ml of dimethyformamide was added, dropwise over one hour, 22.06 g of solketal. After cooling in an ice bath a solution of 42 g of 1-[[8-[2-(2-methoxyethoxy)-ethoxy]octyl]sulfonyl]-4-methylbenzene in 25 ml of dimethylformamide was added. This mixture was stirred for 2 days, then water was added and the mixture extracted with ether. The ether extract was dried and the solvent removed. The residue was refluxed for one hour in a mixture of 175 ml of methanol, 25 ml of water and 1.25 ml of concentrated sulfuric acid. The methanol was removed, saturated aqueous sodium chloride added and the mixture extracted with ethyl acetate. The organic extract was dried, the solvent removed and the residue purified by HPLC, eluting with ethyl acetate, giving 14.7 g of the desired compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:12][N:11]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)OCc1ccccc1)[C@H]1CCNC1
Reaction time: 0.5 h
Yield: 115.1 %

Procedure:
A solution of tert-butyl (S)-3-(N-benzyloxycarbonyl-N-methylamino)pyrrolidine-1-carboxylate (Intermediate 130, 1.81 g) in trifluoroacetic acid (8 mL) and DCM (8 mL) was left to stand at room temperature for 30 minutes. The resultant mixture was concentrated in vacuo and the residue was dissolved in DCM and brine, basified with 2M sodium hydroxide and filtered through a phase separator. The filtrate was concentrated in vacuo to give benzyl N-methyl-(S)-pyrrolidin-3-ylcarbamate (1.46 g) as a light coloured oil.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[N:14]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)=[N+:15]=[N-:16].N1C=CC=CC=1C1C=CC=CN=1>CN(C=O)C.CCOC(C)=O>[OH:23][C:19]1[CH:18]=[C:17]([N:14]2[CH:3]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=3)[N:16]=[N:15]2)[CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)C#Cc1cccc(O)c1
Reactant: [N-]=[N+]=Nc1cccc(O)c1
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Oc1cccc(-c2cn(-c3cccc(O)c3)nn2)c1
Temperature: 80 °C
Yield: 69.5 %

Procedure:
To 3-TMSE-phenol (4.0 g, 21.02 mmol) in 35 mL of DMF were added 3-azidophenol (3.41 g, 25.2 mmol), CuBr (153 mg, 1.05 mmol), and 2,2′-bipyridyl (328 mg, 2.10 mmol). The mixture was heated at 80° C. for 24 h, cooled to room temperature, then diluted with 250 mL of EtOAc. The combined organic mixture washed with water, and dried over MgSO4. Solvents were removed by rotary evaporation, and the residue was recrystallized in acetic acid/water to give 3.70 g (70% yield) of a brown crystalline solid. 1H NMR (MeOD-d4, 300 MHz, ppm): 8.80 (s, 1H, triazol-H), 7.43-7.26 (m, 6H, Ar—H), 6.95-6.91 (m, 1H, Ar—H), 6.84-6.83 (m, 1H, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 158.6, 157.7, 148.1, 137.9, 131.1, 130.4, 129.7, 118.8, 116.7, 115.6, 115.1, 112.1, 110.7, 107.1.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2cc(F)ccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc(F)ccc2F)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.08 g), sodium hydrogen carbonate (1.53 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,5-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.88 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.38 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.67 g, 68%).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.BrC1C=C2C(=CC=1)C[C:37](=[O:42])CC2.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:37]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:42])[CH:13]=[CH:12][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: Brc1ccc2c(c1)CCC(NCc1ccccc1)C2
Solvent: NCc1ccccc1
Product: O=C(c1ccc2c(c1)CCC(NCc1ccccc1)C2)N1CCCC1CN1CCCC1

Procedure:
(6-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from benzyl-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner substantially analogous to Procedure A. (See herein Example 1). Starting material, benzyl-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine, can be prepared from 6-bromo-2-tetralone and benzylamine in a manner substantially analogous to Preparation 1. Mass spectrum (APCI) 418 (M++1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]1=[O:14])C.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][C:9]1[CH:10]=[C:11]([CH3:12])[N:6]([CH2:5][C:4]([NH:17][NH2:18])=[O:3])[C:7](=[O:14])[CH:8]=1
Reactant: NN
Reactant: CCOC(=O)Cn1c(C)cc(C)cc1=O
Solvent: CCO
Solvent: O
Product: Cc1cc(C)n(CC(=O)NN)c(=O)c1

Procedure:
As described for example 112a, (4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (Shusherina, N. P.; Slavyanova, O. V.; Petrova, L. K.; Levina, R. Ya. Zhurnal Organicheskoi Khimii (1972), 8(2), 387-9) in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 120 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the title compound was obtained as a white solid (yield. 90%). MS: m/e=218.2 [M+Na]+.