Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]3)=[O:10])[CH2:5]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:46][C:47]1([F:53])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:46][C:47]1([F:53])[CH2:52][CH2:51][N:50]([C:20]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([C:9]([N:6]2[CH2:7][CH2:8][CH:4]([N:3]([CH3:23])[CH3:2])[CH2:5]2)=[O:10])=[CH:19][CH:18]=3)=[O:21])[CH2:49][CH2:48]1
Reactant: FC1(F)CCNCC1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1

Procedure:
The title compound was synthesized in analogy to example 1, from (RS)-5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, as a colorless solid (77%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:19]([NH:21][NH:22][S:23]([NH:26][CH2:27][C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl.O1CCC[CH2:41]1>CO.O>[CH3:41][CH:27]([NH:26][S:23]([NH:22][NH:21][C:19](=[O:20])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:32][CH:33]([CH3:34])[CH3:35])(=[O:24])=[O:25])[C:28]([OH:30])=[O:29]
Reactant: C1CCOC1
Reactant: COC(=O)CNS(=O)(=O)NNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NNS(=O)(=O)NC(C)C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 0.431 g of methyl(E)-2-[[2-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]hydrazino]sulphonamido]acetate in 10 ml of tetrahydrofuran and 5 ml of methanol was treated with 0.040 g of lithium hydroxide monohydrate and the mixture was left to stir overnight. A further 0.020 g of lithium hydroxide monohydrate was added and stirring continued for 4 hours. The mixture was then diluted with water, acidified using 2M aqueous hydrogen chloride, and extracted with ethyl acetate. The ethyl acetate fraction was dried over anhydrous magnesium sulphate and evaporated to give 0.462 g of methyl(E)-2-[[2-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]hydrazino]sulphonamido]acetic acid as an oil.
Reaction SMILES: [CH3:1][NH2:2].C(O)(=O)C.[Br:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][CH:13]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:14]([NH:16][CH2:17][C:18](=O)[CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=O)=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[Br:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][CH:13]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:14]2[N:2]([CH3:1])[C:18]([CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=[CH:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Reactant: CN
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Methylamine (2 M in tetrahydrofuran) (1.2 mL, 24 mmol) followed by acetic acid (1.2 mL) were added to an ambient temperature solution of benzyl {1-(4-bromobenzyl)-2-[(4,4-dimethyl-2-oxohexyl)amino]-2-oxoethyl}carbamate (for synthesis see Example 37) (600 mg, 1.2 mmol) in xylene (10 mL). After stirring at 150° C. for 2 h, the reaction mixture was concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}carbamate.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].O1CCCC1>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C1=Cc2ccccc2C1

Procedure:
Alternatively, the keto group in the indanone may simply be reduced under standard conditions (e.g. sodium borohydride in methanol and/or tetrahydrofuran (THF)) followed by dehydration to form the desired indene or indene skeleton-containing compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccncc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(-c2n[nH]c3ccncc23)c1
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
To a solution of 12 mg of 3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine in 2 mL of dichloromethane was added 1 mL of trifluoroacetic acid at room temperature and stirred at this temperature for 10 minutes. The reaction solution was poured into aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:3), to afford 4 mg of the title compound as colorless crystals.
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:12]1([CH2:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]3=[C:9]([C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:19]([CH3:20])[N:2]3[CH2:3][CH2:4]2)[CH:8]=1
Reactant: NN1CCc2cc(Cl)ccc21
Reactant: CC(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)c2cc(Cl)cc3c2n1CC3

Procedure:
A mixture of 13 g. (0.077 mole) of 1-amino-5-chloroindoline, 10 g. (0.073 mole) of phenylacetone and 10 g. of sodium acetate in 120 ml. of glacial acetic acid was heated on a steam bath for 1 hour. The mixture was cooled, filtered and the solid material washed with acetic acid and water. The product was recrystallized from benzene-isooctane; yield 12.7 g. (65%); m.p. 202°-204°C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:29][C:28]1[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: COc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@H]2CC[C@]3(C)C2(C)C)cc1
Temperature: 80 °C
Yield: 77.9 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 150 mg, 0.49 mmol), tetrabutylammonium iodide (181 mg, 0.49 mmol) and 4-methoxybenzyl bromide (280 μL, 1.94 mmol) in dimethylformamide (3 mL) was heated at 80° C. overnight. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 60-75% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-(4-methoxy-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (162 mg, 78%). APCI(+)-MS (M+H) 425.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19]Cl.O.[SH:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19][S:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1-c1ccccc1
Yield: 84.1 %

Procedure:
Prepared according to Procedure C using Intermediate 2i (400 mg, 1.05 mmol), 6-mercaptopurine monohydrate (196 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was chromatographed in MeOH/CH2Cl2 and subsequently recrystallized from EtOH to provide 439 mg of a pale yellow crystalline solid (84%), mp 222.0-222.5° C. (dec). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.55 (s, 1H); 8.45 (s, 1H); 7.73 (t, J=8.0 Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.50-7.59 (m, 4H); 7.41-7.48 (m, 1H); 7.25-7.38 (m, 5H); 4.41 (d, J=16 Hz, 1H); 4.16 (d, J=16 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 157.0, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134.1, 133.3, 131.5, 130.5, 130.3, 130.1, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ES): m/z 497.0 (M+). Anal. calcd. for C26H17ClN6OS: C, 62.84; H, 3.45; Cl, 7.13; N, 16.91; S, 6.45. Found: C, 62.60; H, 3.47; Cl, 7.15; N, 16.65; S, 6.41.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(O)(C)C>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)O
Product: COc1ccc2c(c1)NC(=O)CC2
Yield: 89.5 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3) (16.317 g, 100 mmol) in anhydrous isopropanol (200 mL) was added potassium carbonate (16.585 g, 120.0 mmol) with stirring under an atmosphere of dry N2. The reaction mixture was stirred at room temperature for 30 minutes, then iodomethane (10.0 mL, 161.3 mmol) was added slowly. The reaction was heated to reflux with stirring for 60 hours, cooled, and the solvent evaporated under reduced pressure. To this residue water (200 mL) was added, and the mixture stirred and sonicated, filtered, and the pale yellow solid was washed with water (1000 mL), and dried under rescued pressure. To the crude dry solid was added 15% ethyl acetate in n-hexane (150 mL), and the mixture sonicated, filtered, washed with n-hexane (50 mL), and dried under reduced pressure, to afford 7-methoxy-3,4-dihydroquinolin-2(1H)-one (15.865 g, 89.5 mmol, 90%), the compound of formula (4). LCMS mz 178.0 (M+H), 200.0 (M+Na), anal HPLC>95% in purity, 1H NMR (400 MHz; dmso-D6) δ 7.09 (d, J=8.2 Hz, 1H); 6.57 (dd, J=8.2 and 2.7 Hz, 1H); 6.48 (d, J=2.7 Hz, 1H); 3.78 (s, 2H); 2.90 (t, J=7.0 Hz, 2H); 2.57 (t, J=7.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc(Br)c3)n2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
3 g (0.01 mol) of 4-[3-(3-bromophenyl)-1H-pyrazol-4-yl]pyridine were dissolved in 50 ml of dry dimethylformamide and 3.9 g (0.012 mol) of cesium carbonate and 1.6 ml (0.012 mol) of p-methoxybenzyl chloride were added. The mixture was stirred at 70° C. for 2 hours and the solvent removed in vacuo. The residue was taken up with dichoromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated. Purification by column chromatography (dichloromethane-acetone 95/5) afforded 2 g (48% yield) of the title compound as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38](O)=[O:39])=[CH:35][C:34]=2[CH:41]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]([NH:1][C@@H:2]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:3]([NH:5][CH2:6][C:7]([N:9]3[CH2:10][CH2:11][N:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[CH2:13][CH2:14]3)=[O:8])=[O:4])=[O:39])=[CH:35][C:34]=2[CH:41]=1
Reactant: N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1)c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.5 %

Procedure:
To a suspension of (2S)-2-amino-N-[2-[4-(4-chlorophenyl)-1-piperazinyl]-2-oxoethyl]-3-(2-pyridyl)propanamide (18 g) and 5-chloro-1-benzofuran-2-carboxylic acid (8.8 g) in N,N-dimethyl-formamide (180 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (9.44 g) and N-hydroxybenzotriazole (6.66 g) at 0° C. The mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution and the resulting solid was collected by filtration. The solid was washed successively with saturated aqueous sodium hydrogencarbonate solution and water. The solid was crystallized from water:ethanol (1:9 (v/v)) to give the title compound (23 g) as crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(NC(C)C)(C)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])([CH3:21])[CH3:20]
Reactant: NC(=O)c1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(C(N)=O)c1
Temperature: 120 °C
Yield: 64.6 %

Procedure:
3-Iodobenzamide (I142) (1.00 g, 4.05 mmol), bis(triphenylphosphine)palladium(II) chloride (0.142 g, 5 mol %), copper(I) iodide (0.077 g, 10 mol %), DMF (4 mL) and diisopropylamine (12 mL) were loaded into a microwave tube. The mixture was degassed for ten minutes with nitrogen, then trimethylsilylacetylene (0.69 mL, 4.9 mmol) was added and the resulting mixture heated under microwave irradiation at 120° C. for 15 minutes. The volatiles were evaporated under reduced pressure and the residue chromatographed (Biotage Isolera, 40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I143) (0.569 g, 65% yield) as a brown solid; 1H NMR (400 MHz, CDCl3) δ 7.88 (td, J=1.8, 0.5 Hz, 1H), 7.78 (ddd, J=7.8, 1.8, 1.2 Hz, 1H), 7.63-7.59 (m, 1H), 7.40 (td, J=7.8, 0.5 Hz, 1H), 6.05 (br s, 1H), 5.67 (br s, 1H), 0.26 (s, 9H). LCMS Method C: it 5.94 min, m/z 218.2 [M+H]+.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>O1CCCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 6.3 g of Z-Thr(tBu)-OH and 2.34 ml of N-methylmorpholine in 100 ml of tetrahydrofuran are added at -17°C 3.0 ml of chloroformic acid-isobutylester, the batch stirred for 20 minutes at this temperature, then reacted with 6.7 g of H-Pro-OtBu in 100 ml of tetrahydrofuran. The batch is allowed to stand at room temperature overnight, then filtered, the filtrate evaporated to dryness under vacuum, the residue dissolved in ethyl acetate and extracted several times with dilute aqueous citric acid solution, dilute aqueous sodium carbonate solution, and saturated sodium chloride solution. The resulting oily compound shows in the thin-layer chromatogram on silica gel:
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[OH-].[K+].[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)([O-:15])=[O:14]>O.CO>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:4]1[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH:3]=1)([O-:15])=[O:14]
Reactant: O=C1CN2CCC1CC2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CN4CCC3CC4)c2c1
Reaction time: 48 h

Procedure:
44.8 mmol of 1-azabicyclo[2.2.2]octan-3-one hydrochloride (3-quinuclidinone hydrochloride) and 112 mmol of potassium hydroxide are added to a solution of 22.4 mmol of 5-nitro-1H-indole in 100 ml of water/methanol (1/1), and the mixture is stirred at the boiling point for 48 hours. The crystals which deposit on cooling of the reaction solution are filtered off, washed and dried, giving 3-(5-nitro-1H-indol-3-yl)-1-azabicyclo[2.2.2]-oct-2-ene.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[C:10](Cl)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11].O>O1CCOCC1>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: C1COCCO1
Product: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Yield: 34.3 %

Procedure:
D-Nle-OH (1.01 g) was dissolved in 30 ml of 10% NaCO3 and 10 ml of dioxan. While stirring, a solution of Fmoc-Cl (2.0 g) in 10 ml of dioxan was added to the solution. After stirring at room temperature for 2 hours, 400 ml of water was added to the mixture. The reaction mixture was extracted twice with 200 ml of ether to remove by-products. Ice was added to the aqueous phase and the mixture was neutralized with conc. hydrochloric acid. After extracting with ethyl acetate, the extract was washed with water. Crystallization from ether gave 933 mg of Fmoc-D-Nle-OH.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:20])[CH:3]=1.FC1C=C([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[F:20][C:4]1[CH:3]=[C:2]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[O:10][C:11]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=2[N:13]=1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: Cc1cc(C)c2oc(Nc3ccc(Br)cc3F)nc2c1
Product: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3F)nc2c1

Procedure:
N2-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromo-2-fluorophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (6.500 g, 19.39 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as a pink solid (3.549 g, 48%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt=15.50 min, 78%; m/z 383 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:23])[CH2:14][O:15]CC2C=CC=CC=2)=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:23])[CH2:14][OH:15])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(NC(=O)CO)cc1
Reaction time: 5 h
Yield: 77 %

Procedure:
4-(2-Benzyloxyacetylamino)-phenoxyacetic acid methyl ester 66 (25 g, 76 mmol) was dissolved in methanol (450 ml) in a pressure vessel, palladium on carbon (5%, 10 g) added and the mixture stirred under a hydrogen atm. (2 Kg) for 5 hrs. Catalyst was removed by filtration and methanol distilled off. Crude 67 was recrystallised in chloroform:hexane (1:6) to give pure 67 (14 g) as a white powder. M.p: 147.5-150° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1)[CH3:18].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[C:22]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:21]=1)[CH3:18]
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cc(N2CCCC2)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc(N2CCCC2)c1
Temperature: 150 °C
Yield: 46.5 %

Procedure:
A microwave flask was charged with 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (48 mg, 0.17 mmol), 1-[3-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine (54 mg, 0.17 mmol), and K2CO3 (59 mg, 0.43 mmol). Dioxane (2.1 ml) and water (0.5 ml) were added, and the solution was vacuum degassed under argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (14 mg, 0.02 mmol) was added, and the reaction mixture was heated (150° C.) in a microwave reactor for 45 minutes. The reaction mixture was filtered through a plug of celite using ethyl acetate. The filtrate was transferred to a separatory funnel and shaken with water (20 ml). The organic phase was collected and the aqueous phase back extracted with ethyl acetate (2×15 ml). The organic phases were combined, dried (MgSO4), filtered and stripped to provide a viscous semi-solid. This material was purified by preparative TLC, eluting with 4.8% methanol in methylene chloride to afford 31 mg of 1-[2-(3-ethoxy-5-pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow powder. MP 236-237° C., M+H=393.