Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:16].[K+].[K+]>C(#N)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]([C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)=[O:16]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: COC(=O)CCOc1ccc(C)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CCOc1ccc(C=O)cc1
Reaction time: 3.5 h
Yield: 92.5 %

Procedure:
A solution of methyl 3-(4-methylphenoxy)-propanoate, (15.0 g, 0.077 moles) in acetonitrile, (270 ml), was added to a solution of potassium peroxydisulphate, (41.60 g, 0.154 moles) and copper (II) sulphate (3.85 g, 0.015 moles) in water, (270 ml). The resulting mixture was stirred at 65°-70° C. for 3.5 h, then cooled and extracted with diethyl ether. The organic extract was washed with water, saturated brine and dried, (MgSO4). Evaporation of the solvent gave 14.83 g of an orange oil which was distilled at 0.1 mm/Hg to yield 7.40 g (47%) of the title compound as an oil which crystallized, mp 48°-50° C., υmax (mull) 1735, 1680, (shoulder at 1685), 1605, 1580, 1515 cm-1 δ(CDCl3) 2.81 (2H, t, J 6 Hz, CH2CO2) 3.72 (3H, S, CH3) 4.30 (2H, t, J6 Hz OCH2) 7.39 (4H, ABq, Δυ75 Hz, J9 Hz C6H4) 9.90 (1H, s, CHO).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)([CH3:20])[CH3:19]>CN1CCCC1=O.O>[CH:18]([C:21]1[N:22]=[CH:23][C:24]([CH2:27][CH2:28][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:25][CH:26]=1)([CH3:20])[CH3:19]
Reactant: C=Cc1ccc(C(C)C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(C)C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.4 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.5 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.140 g, 2.5 mmol) and allowed to stir for 10 min at RT. 2-Isopropyl-5-vinyl-pyridine (0.185 g, 1.25 mol) was added and stirred for further 4 h at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.025 g, 14% yield). 5-[2-(6-Isopropyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.00007 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0095 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.024 g, 77% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][O:19][CH:20]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]2)[CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:31][CH:28]1[CH2:27][CH2:26][CH:25]([N:22]2[CH2:23][CH2:24][CH:20]([O:19][CH3:18])[CH2:21]2)[CH2:30][CH2:29]1
Reactant: COC1CCN(C2CCC(N)CC2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: COC1CCN(C2CCC(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Yield: 44.5 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 4-(3-methoxypyrrolidin-1-yl)cyclohexanamine (297 mg, 1.5 mmol) to afford the desired product (210 mg, 45%) as a yellow solid: ESI MS m/z 472 [C24H30BrN3O2+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]4[NH:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][C:21]=5[C:27](O)=[O:28])[CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.C1N=C[N:32](C(N2C=NC=C2)=O)C=1.CN(C)C=O.N>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]4[NH:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][C:21]=5[C:27]([NH2:32])=[O:28])[CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(Nc2cc(-c3cc4cccc(C(=O)O)c4[nH]3)c3[nH]ncc3c2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2cc(-c3cc(Nc4ccnc(N)n4)cc4cn[nH]c34)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
A solution of 2-[5-(2-amino-pyrimidin-4-ylamino)-1H-indazol-7-yl]-1H-indole-7-carboxylic acid (Example #F.5.11, 0.100 g, 0.000259 mol) and N,N-carbonyldiimidazole (0.0842 g, 0.000519 mol) in N,N-dimethylformamide (2.5 mL, 0.032 mol) was heated at about 55° C. for about 45 min. The mixture was cooled with an ice bath and treated with ammonia gas for about 15 min at about 0° C. The mixture was sealed and allowed to warm to ambient temperature. After about 1 hour the mixture was opened to atmosphere, and a 1.2 mL portion of the mixture was purified by reverse phase preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min) then filtered to remove the remaining acid. The filtrate was then lyophilized to yield 2-[5-(2-amino-pyrimidin-4-ylamino)-1H-indazol-7-yl]-1H-indole-7-carboxylic acid amide (2 mg, 2% yield): LC/MS Rt (Method e) 0.7 min; m/z (M+H)+ 385.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[N:3]=1.[NH3:27]>O1CCCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=3)[N:3]=[C:2]([NH2:27])[N:7]=2)[CH:13]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CN(C)C)cc2)n1
Reactant: N
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(CN(C)C)cc2)n1
Temperature: -78 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
A pressure bottle was charged with [4-chloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]-triazin-2-yl]-(4-dimethylaminomethyl-phenyl)-amine (0.305 g, 0.79 mmol) and tetrahydrofuran (20 ml) and cooled to −78° C. A slow stream of ammonia gas was passed into the solution for 2 minutes and the bottle was sealed. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to provide the title compound (0.148 g, 49% yield). 1H NMR (CDCl3) δ 7.9 (s, 1H), 7.2-7.6 (m, 6H), 3.25 (d, 6H) 2.5 (s, 3H).
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:27])[O:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2[O:25][CH3:26])[CH:16]=1)=O)C1C=CC=CC=1>[Pd]>[NH2:11][CH:12]([CH2:16][CH2:15][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=1[O:25][CH3:26])[C:13]([OH:27])=[O:14]
Reactant: COc1cccc(C2C=C(NC(=O)OCc3ccccc3)C(=O)O2)c1OC
Agent: [Pd]
Product: COc1cccc(CCC(N)C(=O)O)c1OC

Procedure:
2nd step--The step consists in the catalytic hydrogenation of 3-benzyloxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one, for example with palladium on carbon as catalyst in alcoholic medium, thus obtaining directly in a single step the deprotected 2-amino-4-(2,3-dimethoxyphenyl)butyric acid. The reaction takes place in nearly quantitative yields. The reaction, as already discussed in the above process, can be carried out under enantioselectivity conditions, to obtain 2-amino-4-(2,3-dimethoxyphenyl)butyric acid in an optically active form.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([N:34](CC)C(C)C)(C)[CH3:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N)C>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([NH:34][CH2:31][CH3:32])=[O:30])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3ccccc3)n12
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2ccccc2)n1
Reaction time: 0.03 h

Procedure:
To a solution of 3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]propanoic acid (8.0 mg, 0.020 mmol, prepared as in Example 95, Step 1) in DMF (0.40 mL) was added N,N-diisopropylethylamine (14 μL, 0.080 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (14 mg, 0.036 mmol, Aldrich). After stirring for 2 minutes, ethylamine (11 μL, 0.20 mmol, neat, Aldrich) was introduced, and the reaction was stirred for 15 minutes. The reaction was diluted with MeOH, and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.3 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:13]=1>N1C2C(=CC=CC=2)C=CC=1.C(OCC)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: Clc1ccc2ccsc2c1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of the above 6-chlorobenzo[b]thiophen-2-ylcarboxylic acid (3.0 g) and copper powder (1.2 g) in quinoline (20 ml) was stirred at 210° C. for 40 minutes. The mixture was cooled to room temperature and diluted with diethyl ether, and insoluble materials were filtered off. The filtrate was washed successively with 10% aqueous hydrochloric acid solution and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 6-chlorobenzo[b]thiophene (1.79 g) as colorless crystals. (3) The above 6-chlorobenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give 5-bromo-2-chloro-1-(6-chlorobenzo[b]thiophen-2-ylmethyl)benzene as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ncc(C(=O)O)s1
Yield: 66.2 %

Procedure:
To a stirred solution of 2-methyl-thiazole-5-carboxylic acid ethyl ester (1.3 g, 8.0 mmol) in dioxane (12 mL) at room temperature was added NaOH (2N, 12 mL). After 1 h the reaction mixture was neutralized with HCl (1N, 12 mL), then filtered and the collected solid dried in vacuo to give the title compound (758 mg, 70%) as an off white solid. MS: m/e=142.0 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CS(O[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:35])=[C:24]([C:26]3[O:27][C:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=4[N:30]=3)[CH:25]=2)[CH:17]=[N:16]1)(=O)=O>CN(C=O)C>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[C:24]1[C:23]([NH2:35])=[N:22][CH:21]=[C:20]([C:18]2[CH:17]=[N:16][N:15]([CH2:14][CH2:13][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:19]=2)[CH:25]=1
Reactant: CS(=O)(=O)OCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(CCn2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 1-methylpiperazine (0.115 ml) was added to 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethyl methanesulphonate (138 mg) dissolved DMF (5 ml). The resulting solution was stirred at 100° C. for 1 hour. The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 2 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and the solid was triturated with hot acetonitrile to afford 3-(1,3-benzoxazol-2-yl)-5-[1-[2-(4-methylpiperazin-1-yl)ethyl]pyrazol-4-yl]pyridin-2-amine (109 mg) as a solid. NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 2.30 (bs, 4H), 2.44 (bs, 4H), 2.74 (t, 2H), 4.23 (s, 2H), 7.40-7.50 (m, 2H), 7.65 (bs, 2H), 7.77-7.82 (m, 1H), 7.82-7.87 (m, 1H), 7.90 (s, 1H), 8.24 (s, 1H), 8.40 (d, 1H), 8.51 (d, 1H); Mass spectrum: M+H+ 404.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:44])([CH3:43])[CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[O:31])=[CH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH3:45][C:46]1[CH:54]=[C:53]2[C:49]([C:50]([Sn](CCCC)(CCCC)CCCC)=[N:51][NH:52]2)=[CH:48][CH:47]=1>CN(C=O)C.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.[Cu]I>[Si:36]([O:35][CH2:34][C:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:50]3[C:49]4[C:53](=[CH:54][C:46]([CH3:45])=[CH:47][CH:48]=4)[NH:52][N:51]=3)=[CH:3][N:4]=[C:5]2[N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:9]=1)=[O:31])([CH3:43])[CH3:44])([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(C)ccc12
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]c2c1
Temperature: 90 °C
Yield: 65 %

Procedure:
A mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (1.73 g, 2.58 mmol), 6-methyl-3-(tributylstannyl)-1H-indazole (1.2 g, 2.84 mmol), Pd(PPh3)4 (298 mg, 0.258 mmol) and CuI (98 mg, 0.516 mmol) in dry DMF (20 mL) was heated to 90° C. for 4 hours. Product was extracted with ethyl acetate (200 mL), organic phase washed with water (2×50 mL) and brine (2×50 mL), then dried over Na2SO4, filtered and concentrated. The residue was triturated with petroleum ether (10 mL) then decanted and dried to afford N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (1.21 g, 65%) as a yellow solid. LCMS: (M+H)+=721.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([N:12]2[CH:13]=[N:14][N:15]=[CH:16]2)=[N:10]1)(=[O:19])[CH3:18]
Reactant: c1ccc(-c2cn[nH]c2-n2cnnc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1cc(-c2ccccc2)c(-n2cnnc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-(4-phenyl-5-pyrazolyl)-4H-1,2,4-triazole (1.0 g) in acetic anhydride is refluxed until a clear solution is obtained. The solution is poured into ice water and stirred for 1/2 hour. The yellowish solid is collected and recrystallized from a mixture of chloroform/hexane, giving a white powder, m.p. 165° C to 168° C. Similarly prepared is the propionyl derivative.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[CH2:36]([O:43][CH2:44][CH2:45]I)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:43][CH2:44][CH2:45][O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Reactant: ICCOCc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCCOCc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86 (eee)] with 2-(benzyloxy)-ethyl iodide [Helv.Chim.Acta Vol.71, (1988), 2039] there was obtained tert-butyl (1RS,2RS,3RS,5SR)-3-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless oil; MS: 625 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16]C=2)O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)C(O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(C(O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
4-nitrobenzoin (4.55 g, 20.1 mmol) was dissolved in 70 ml of anhydrous methanol cooled down to 0° C. in an ice bath, NaBH4 (0.915 g, 24.2 mmol) was then added under N2, the mixture was stirred at r.t., for overnight, quenched with NH4Cl sat'd aqueous solution, MeOH was evaporated and EtOAc was added, the mixture was washed with water, the organic layer was dried over MgSO4 and concentrated to give a solid as the desired product(˜4.58 g, ˜100% yield).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Brc1ccccn1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromopyridine
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH3:18])=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:62][C:63]([Si:66]([CH3:79])([CH3:78])[O:67][CH2:68][C:69]1[CH:70]=[C:71](B(O)O)[CH:72]=[CH:73][CH:74]=1)([CH3:65])[CH3:64]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:65][C:63]([Si:66]([CH3:79])([CH3:78])[O:67][CH2:68][C:69]1[CH:70]=[C:71]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=2[O:17][CH3:18])[CH:72]=[CH:73][CH:74]=1)([CH3:62])[CH3:64]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(B(O)O)c1
Reactant: COc1c(Br)cccc1CNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc2ccccc2c1-c1c(P(C2CCCCC2)C2CCCCC2)ccc2ccccc12
Solvent: C1COCCO1
Product: COc1c(CNC(=O)OC(C)(C)C)cccc1-c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 80 °C
Yield: 72 %

Procedure:
1,1-Dimethylethyl {[3-bromo-2-(methyloxy)phenyl]methyl}carbamate (5.2 g, 16.4 mmol), Pd(OAc)2 (110.4 mg, 0.49 mmol), dicyclohexyl[2′-(methyloxy)-1,1′-binaphthalen-2-yl]phosphane (317.2 mg, 0.66 mmol) and K3PO4 (4.2 g, 19.7 mmol) were dissolved in dioxane (60 mL). The mixture was heated at 80° C. for 30 min, and then [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (5.2 g, 19.7 mmol) was added. The mixture reaction was stirred at reflux overnight. The solvent was removed under reduced pressure, then the residue was diluted with CH2Cl2 (100 mL). The organic layer was washed with water (30 mL), brine (30 mL), and dried over Na2SO4. The product 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-(methyloxy)-3-biphenylyl]-methyl}carbamate (5.0 g) was purified by flash column chomatography (PE:EA=15:1) (yield: 72%). 1H NMR (400 MHz, CDCl3) δ 0.11 (s, 6H), 0.94 (s, 9H), 1.46 (s, 9H), 3.37 (s, 3H), 4.40 (d, J=6 Hz, 2H), 4.80 (s, 2H), 5.04 (s, 1H), 7.12-7.51 (m, 7H); 13C NMR (100 MHz, CDCl3) δ −5.2, 18.4, 25.9, 28.4, 40.3, 60.4, 65.0, 124.2, 125.0, 126.6, 127.5, 128.3, 128.4, 130.6, 132.3, 134.8, 138.2, 141.5, 155.8; HPLC: retention time: 4.348 min; purity: 99.9%; MS m/z 453 (M+), 344 (M+-TBS).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:5]([O:7][CH3:8])=[O:6].CCN(C(C)C)C(C)C.[CH2:33]([O:36][CH2:37][CH2:38]Br)[CH2:34]Br>C1(C)C=CC=CC=1>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[N:1]1[CH2:38][CH2:37][O:36][CH2:33][CH2:34]1)[CH:21]=[CH:20]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Reactant: BrCCOCCBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2)c(N2CCOCC2)c1
Temperature: 110 °C
Yield: 80.3 %

Procedure:
To a solution of methyl 3-amino-4-(6-methoxynaphthalen-2-yl)benzoate (1.00 g, 3.30 mmol) (see Step 1 of Example 5) and DIPEA (1.70 g, 13.2 mmol) in anhydrous toluene (20 mL) containing catalytic amount of KI (100 mg, 0.660 mmol) was added 2,2′-dibromodiethyl ether (1.50 g, 6.60 mmol). The mixture was heated to 110° C. for 3 days. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to give the product (1.00 g, yield 81%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:9]([NH:11][C@@H:12]([C:23]([NH:25][C@H:26]([C:39]([O:41][CH3:42])=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.[Pd]>[NH2:1][C@H:2]([C:9]([NH:11][C@@H:12]([C:23]([NH:25][C@H:26]([C:39]([O:41][CH3:42])=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)c1ccccc1

Procedure:
23.4 g (23.8 mmol) (Z-Phg-D-Trp-Lys(BOC)-OMe) are dissolved in 260 ml methanol, 2.6 g Pd/C 10% added and hydrogenated at RT and normal pressure. After 3 hours the catalyst is filtered off and the filtrate evaporated at 30°: white solid. HPLC 95.9% b.a. (17.6 min).