Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8]>C(O)C.[C].[Pd]>[CH2:3]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])[CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)=Cc1cccc(CN)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
3-(2-Methylpropenyl)-benzylamine described in Preparation Example 137 (100 mg, 0.621 mmol) was dissolved in ethanol (5 mL), 10% palladium-carbon (50% water wet, 20 mg) was added thereto, and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. The catalyst was filtered, then, the solvent was evaporated, and the title compound (58 mg, 56.6%) was obtained as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.[C:20]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:20][O:18][C:17]([C:7]1([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1)=[O:19]
Reactant: O=C(O)C1(c2ncccn2)CCC2(CC1)OCCO2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
To a solution of crude 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carboxylic acid and K2CO3 (227 mg, 1.64 mmol) in DMF (5 mL) was added MeI (76.7 μl, 1.23 mmol) at 25° C. After being stirred at 25° C. for 15 h, DMF was removed under reduced pressure and the residue was diluted (H2O), extracted (2×EtOAc), and washed (2× brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 40-50% EtOAc/Hexanes, gradient elution) gave 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carboxylic acid methyl ester (170 mg, 0.611 mmol, 74%) as a colorless liquid.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:16]([O:18]C)=[O:17])=[N:10][C:11]=2[O:12][CH2:13][CH2:14][F:15])[CH2:3]1.O.[OH-].[Li+]>O1CCCC1.O>[F:20][C:2]1([F:1])[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:16]([OH:18])=[O:17])=[N:10][C:11]=2[O:12][CH2:13][CH2:14][F:15])[CH2:3]1
Reactant: COC(=O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1

Procedure:
A solution of methyl 5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carboxylate (Example 147 b, 73 mg, 252 μmol) and lithium hydroxide hydrate (12.7 mg, 302 μmol) in tetrahydrofuran (500 μL) and water (50.0 μL) was stirred for 12 h at ambient temperature. The reaction mixture was poured onto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (25 mL), dried over Na2SO4, filtered and evaporated to dryness to give the target compound (69 mg, quant.) as off-white solid, MS (ESI) m/e=277.1 [MH+].
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>O>[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([N:20]([C:18]([C:15]2[NH:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=2)=[O:19])[NH2:21])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCc1c[nH]c(C(=O)NN)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCc1c[nH]c(C(=O)N(N)S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Into a mixture of 3.29 g (11 mmol) of 4-dodecylpyrrole-2-carboxylic acid hydrazide obtained in Synthesis Example 9 and 35 ml of pyridine, was added little by little 2.23 g (12 mmol) of p-toluenesulfonyl chloride under stirring and cooling with ice. The reaction was carried out for 1.5 hours at room temperature, and the reaction mixture was added to an iced water containing 70 ml of 6N hydrochloric acid. The crystals precipitated by stirring were collected by filtration, washed with water and recrystallized from a mixed solvent of ethanol/water (10/1) to obtain 4.55 g of 4-dodecylpyrrole-2-carboxylic acid p-toluenesulfonylhydrazide as white crystals. The yield was 91% and the melting point was 134.5° to 135.5° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1C=CC=[CH:5][CH:4]=1.OOS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CC[O:23][C:24]([CH3:26])=[O:25]>CN(C=O)C.O=[Os](=O)(=O)=O>[C:24]([OH:23])(=[O:25])[C:26]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CCOC(C)=O
Reactant: C=Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
Styrene (100 mg) was dissolved in DMF (10 mL), and OsO4 (0.12 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (2.36 g) was added in one portion and the reaction had a final volume (13 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (600 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (50 mL×3) and brine (50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. Benzoic acid was obtained in 94% yield without the need for further purification.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:30][C:31]([CH2:33]Cl)=[CH2:32]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:33][C:31](=[CH2:30])[CH2:32]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(CCl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in example 9, step 1) in dry DMF (0.06 M) was added NaH (2.5 eq., 60% suspension in mineral oil). After 30 min, 3-chloro-2-(chloromethyl)prop-1-ene (1.2 eq.) was added dropwise via syringe and the solution stirred at RT for 60 min. The reaction mixture was diluted with EtOAc and washed with 1N aqueous HCl and with brine, dried (Na2SO4) and evaporated. The crude residue was purified by flash chromatography (10:1 PE/EtOAc), affording the pure methyl 14-cyclohexyl-7-methylene-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (70%) as light yellow foam; MS (ES+) m/z 402 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=2)[N:4]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[OH-].[Li+]>CO.O.O>[C:22]([O:21][C:19]([N:4]1[C@@H:3]([C@H:2]([OH:1])[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:7][CH2:6][C@H:5]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a stirred solution of the title compound from Step A (8.51 g, 20.0 mmol) in methanol/water=4:1 (50 mL) was added lithium hydroxide (2.39 g, 100 mmol). The resulting mixture was stirred at RT overnight. The mixture was diluted with water and extracted with ether. The aqueous layer was acidified with 1N citric acid to PH 4.5, and then extracted with ethyl acetate. The organic layer was separated and washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by SFC (using an AD column 35% MeOH/65% CO2, 150 ml/min 100 bar) to afford 6.90 g (84%) of the title compound (i-4) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 2H), 8.00 (d, J=7.7 Hz, 2H), 7.77 (d, J=6.4 Hz, 1H), 7.32-7.29 (m, 1H), 7.21 (d, J=8.0 Hz, 2H), 5.22 (s, 1H), 4.51 (d, J=8.4 Hz, 1H), 4.13-4.11 (m, 1H), 4.09-4.01 (m, 1H), 3.07-3.04 (m, 1H), 2.58-2.56 (m, 1H), 1.68-1.51 (m, 2H), 1.42 (s, 9H). MS: m/z (ESI) 413 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][CH:14]=[CH2:15]>>[CH2:15]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=C1COc2ccccc2N1
Product: C=CCN1C(=O)COc2ccccc21

Procedure:
In analogy to Example 64, step 1, 2H-1,4-benzoxazin-3(4H)-one (15 g) was reacted with 3-bromo-propene to give the title compound (17.4 g) as a colorless oil. MS (m/e)=190.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1/[C:35](/[NH:38]O)=[N:36]/[H])[NH:31][CH:30]=[C:29]2[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:36]=[C:35]([C:34]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:30][NH:31]4)=[CH:27][C:26]=3[F:25])[N:38]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: [H]/N=C(\NO)c1cc2[nH]cc(CCC(=O)OCC)c2cc1F
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)cc12
Temperature: 120 °C
Yield: 60.8 %

Procedure:
To a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (210 mg) in tetrahydrofuran (THF) (10 mL) was added EDC (373 mg) and HOBt (298 mg). The mixture was stirred for half an hour. Ethyl 3-{5-fluoro-6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D155) (286 mg) was then added and the resulting mixture was stirred further for 1 hour. Finally, TBAF (1019 mg) was added to the solution and the reaction vessel was sealed and heated in microwave at 120° C. for two hours. After cooling the reaction, the solution was diluted with ethyl acetate (80 mL) and washed with water (2×60 mL). The organic layer was then concentrated under vacuo and the residue was chromatographed on silica gel to give the designed product ethyl 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D158) (280 mg). MS (ES): C23H22ClFN4O4 requires 472.1; found 473.2 (M+H+).
Reaction SMILES: [N:1]1[C:6]([OH:7])=[CH:5][C:4]([OH:8])=[N:3][CH:2]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:8][C:4]2[N:3]=[CH:2][NH:1][C:6](=[O:7])[CH:5]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Oc1cc(O)ncn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=c1cc(OCc2ccc(Cl)cc2)nc[nH]1
Temperature: 25 °C
Yield: 9.5 %

Procedure:
To a stirred solution of pyrimidine-4,6-diol (2.5 g) in THF (25 ml) was added silver carbonate (15.3 g) at room temperature followed by dropwise addition of 4-chlorobenzyl bromide (4.58 g), and the resultant mixture was heated at reflux for 2 h. The reaction mixture was then cooled to room temperature, filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (500 mg) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6](Cl)=[O:7])[CH2:3][CH2:2]1.[CH:9]([C:12]1[C:13]([NH2:21])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:4][CH2:5][C:6]([NH:21][C:13]2[C:12]([CH:9]([CH3:11])[CH3:10])=[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CCC1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1c(NC(=O)CCC2CC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the product from Example 114D (100 mg, 0.754 mmol) in CH2Cl2 (0.5 mL) was added to a stirring solution of the product from Example 112C (109 mg, 0.62 mmol) in pyridine (1.0 mL) at room temperature. The solution was stirred at room temperature for 2 hours, and then quenched by addition of methanol (0.5 mL). After 30 minutes, the solution was concentrated under vacuum, and the residue was purified by flash chromatography (silica gel, eluted with EtOAc), followed by crystallization from 80% EtOH-water to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 0.07-0.18 (m, 2H) 0.40-0.53 (m, 2H) 0.71-0.89 (m, 1H) 1.41 (d, J=7.1 Hz, 6H) 1.63 (q, J=7.2 Hz, 2H) 2.55 (t, J=7.5 Hz, 2H) 3.14 (hept, J=7.1 Hz, 1H) 6.91 (dd, J=7.0, 4.2 Hz, 1H) 8.42 (dd, J=4.1, 1.7 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H) MS (ESI) m/z 273 (M+H)+; Anal. Calculated for C15H20N4O: C, 66.15; H, 7.40; N, 20.57. Found: C, 66.39; H, 7.28; N, 20.26.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:5])C.[OH-].[Na+]>CO>[C:23]([CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:4]([OH:5])=[O:3])=[CH:13][CH:12]=2)([CH3:16])[CH3:15])=[CH:29][CH:28]=1)([OH:25])=[O:24]
Reactant: CCOC(=O)COc1ccc(C(C)(C)c2ccc(OCC(=O)OCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(c1ccc(OCC(=O)O)cc1)c1ccc(OCC(=O)O)cc1

Procedure:
6.7 g of ethyl 4-[1-(4-ethoxycarbonylmethoxyphenyl)-1-methylethyl]phenoxyacetate are dissolved in 20 ml of methanol, and 16.7 g of 10% strength sodium hydroxide solution are added. The mixture is heated to boiling under reflux for 3 hours, after which it is cooled down and the methanol is then distilled off on a rotary evaporator. The residue is diluted with water and acidified to pH 2 with 2 N HCl; the colorless precipitate is then filtered off with suction, washed with water and dried in vacuo over calcium chloride. 5.5 g of the title compound, having a m.p. of 177-179° C., are obtained.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH3:5][CH:6]=[C:7](N1CCCC1)[CH2:8][CH3:9]>C1C=CC=CC=1>[CH3:4][C:3]1[C:1](=[O:2])[CH:6]([CH3:5])[CH2:7][CH2:8][CH:9]=1
Reactant: CC=C(CC)N1CCCC1
Reactant: C=CC=O
Solvent: c1ccccc1
Product: CC1=CCCC(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
19.6 g (0.35 mole) of freshly distilled acrolein is added dropwise at a maximum of 50° C., with ice-cooling, to a solution of 27.8 g (0.2 mole) of N-(3-pent-2-enyl)-pyrrolidine in 50 ml of benzene. After completion of the addition, the mixture is stirred overnight at room temperature; it is subsequently heated for 2 hours at 50°-55° C. and then concentrated by evaporation. The oil remaining is dissolved in 250 ml of 20% hydrochloric acid and the solution is stirred overnight. Extraction is then performed five times with ether; the combined extracts are dried over magnesium sulphate and the ether is distilled off. The crude 2,6-dimethyl-cyclohex-2-en-1-one remaining is purified by vacuum distillation. There is obtained 14.8 g (60% of theory) of 2,6-dimethyl-cyclohex-2-en-1-one, b.p. 62°-64° C./ 10 Torr.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNC1CCCCC1NC>O1CCOCC1.[Cu](I)I>[Br:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:11]2=[O:15])[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc2c(c1)CCNC2=O
Agent: I[Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cccc1N1CCc2cc(C(C)(C)C)ccc2C1=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 6.1 %

Procedure:
6-tert-Butyl-3,4-dihydro-2H-isoquinolin-1-one (4 g, 19.67 mmol), Acetic acid 2,6-dibromo-benzyl ester (12.1 g, 2 eq), potassium phosphate tribasic (8.35 g, 2 eq) and copper iodide (787 mg, 0.2 eq) were taken up in dioxane (40 mL). Finally added N,N′-Dimethyl-cyclohexane-1,2-diamine (1.24 mL, 0.4 eq) and the resulting mixture was heated to reflux for 24 hours, after which time more copper iodide (394 mg, 0.1 eq) and N,N′-Dimethyl-cyclohexane-1,2-diamine (0.62 mL, 0.2 eq) were added. Stirred an additional 64 hours and then added more copper iodide (400 mg, 0.1 eq). Continued to stir at reflux for a total of 168 hours. Cooled to room temperature and then added ethylacetate (300 mL) and water (100 mL), partitioned and separated the layers. Washed with further water (2×100 mL) and then finally washed with brine (1×100 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to give 4.45 g of crude product. Purification on a 240 g Analogix column afforded the title compound as a white foamy solid (516 mg) ((M+H)+=431) and recovered 6-tert-Butyl-3,4-dihydro-2H-isoquinolin-1-one (2.188 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1.[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][NH:28][CH3:29]>CC(C)=O>[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][N:28]([CH3:29])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CNCCCN(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN1CCCC1=O
Product: CN(C)CCCN(C)c1ccc(C=O)cc1
Temperature: 50 °C

Procedure:
10 g of 4-fluorobenzaldehyde, 12 g of K2CO3 and 20 ml of NMP are stirred and heated at 50° C. 13 ml of N,N,N′-trimethyl-1,3-propanediamine are added dropwise to the medium kept stirring and heated at 80° C. for 10 h. After the reaction medium has been cooled to ambient temperature, 100 ml of acetone are added. The precipitate obtained is filtered off, and the filtrate is evaporated to dryness and then dried. 21.85 g of powder are recovered. The analyses indicate that the product is in conformity.
Reaction SMILES: Cl.NO.[OH-].[K+].[CH3:6][O:7][C:8]([C:10]1[N:11]([CH3:22])[N:12]=[C:13]([N:15]2C(C)=CC=C2C)[CH:14]=1)=[O:9]>C(O)C.O>[CH3:6][O:7][C:8]([C:10]1[N:11]([CH3:22])[N:12]=[C:13]([NH2:15])[CH:14]=1)=[O:9]
Reactant: COC(=O)c1cc(-n2c(C)ccc2C)nn1C
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(N)nn1C
Temperature: 105 °C
Yield: 16.1 %

Procedure:
A mixture of hydroxylamine hydrochloride (453 mg, 6.52 mmol) in ethanol (4.85 mL) was treated with a solution of potassium hydroxide (197.5 mg, 3.52 mmol) in water (2.93 mL) and ethanol (2.93 mL) followed by addition of 5-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (0.32 g, 1.40 mmol). The resulting reaction mixture was heated in a sealed tube at 105° C. for 3 d. After this time, the reaction was cooled to 25° C. and then concentrated in vacuo. The residue was then partitioned between water (150 mL) and diethyl ether (3×75 mL). The combined organics were washed with a saturated aqueous sodium bicarbonate solution (2×150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 10-100% ethyl acetate/hexanes) afforded 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (34.9 mg, 16%) as an orange-brown solid; ES+-HRMS m/e calcd for C6H9N3O2 [M+H+] 156.0768, found 156.0767.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13](I)[CH:14]=[CH2:15]>CS(C)=O.O>[CH2:15]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH:14]=[CH2:13]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCn1ccc2cc(Br)ccc21
Yield: 60.6 %

Procedure:
To a stirred mixture of NaOH (204 mg., 5.1 mmol., 1 eq.) in DMSO (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for three hours upon complete dissolution of the NaOH (approximately 1 h.). To this solution was added allyl iodide (0.466 mL., 5.1 mmol., 1 eq.) via syringe. After 2 h. the mixture was diluted with water and extracted 2× with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The product was purified by flash column chromatography on silica gel (4:1 hexanes/acetone) affording 730 mg 1-allyl-5-bromoindole.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([C:18]1[CH2:24][C@H:23]2[N:20]([C:21](=[O:35])[C@@H:22]2[C@H:25]([O:27][Si](C(C)(C)C)(C)C)[CH3:26])[C:19]=1[C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[CH2:10][NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.O>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([C:18]1[CH2:24][C@H:23]2[N:20]([C:21](=[O:35])[C@@H:22]2[C@H:25]([OH:27])[CH3:26])[C:19]=1[C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[CH2:10][NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C1=C(C(=O)OCC=C)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C1=C(C(=O)OCC=C)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.6 %

Procedure:
To a solution of 1.74 g of allyl (5R,6S)-3-[2-allyloxycarbonylamino-1-(N-allyloxycarbonylaminomethyl)ethyl]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and 0.54 ml of acetic acid in 9 ml of tetrahydrofuran was added dropwise 3.29 g of 70 % tetrabutylammonium fluoride at room temperature. The mixture was stirred for 20 hours at room temperature. 60 ml of Ethyl acetate and 45 ml of water were added to the reaction mixture and the aqueous layer was extracted three times with ethyl acetate. The extracts were combined, washed in turn with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was chromatographed on silica gel to give 766 mg of allyl (5R,6S)-3-[2-allyloxycarbonylamino-1-(N-allyloxycarbonylaminomethyl)ethyl]-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.