Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[NH2:19][CH:20]([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1)[CH2:21][C:22]([OH:24])=O.[C:33](O)([C:35]([F:38])([F:37])[F:36])=[O:34].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:32][C:27]1[CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]2[C:26]=1[C:22](=[O:24])[CH2:21][CH:20]2[NH:19][C:33](=[O:34])[C:35]([F:38])([F:37])[F:36]
Reactant: Cc1cc(C)cc(C(N)CC(=O)O)c1
Reactant: O=C(O)C(F)(F)F
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C)c2c(c1)C(NC(=O)C(F)(F)F)CC2=O
Temperature: 25 °C
Yield: 71 %

Procedure:
Step BM (1). A solution of 3-amino-3-(3,5-dimethylphenyl)propanoic acid (18 g, 0.078 mol) and TFA (72 mL) was stirred at rt for 30 min. Trifluoroacetic anhydride (72 mL) was added and the resulting mixture was heated at reflux for 2 h. After cooling to rt, the reaction was concentrated in vacuo. The crude residue was dissolved in EtOAc and sequentially washed with 1 N NaOH and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford 15 g (71% yield) of N-(4,6-dimethyl-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide as a white solid. LC-MS (M+H)+=272.09; 1H NMR (500 MHz, CDCl3) δ ppm 7.17 (s, 1H) 7.04 (s, 1H) 6.91 (d, J=6.71 Hz, 1H) 5.52-5.59 (m, 1H) 3.15 (dd, J=18.92, 7.93 Hz, 1H) 2.50 (s, 3H) 2.46 (d, J=3.36 Hz, 1H) 2.40 (s, 3H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=O)=[CH:23][CH:22]=1.Cl>CCOCC>[N:15]1([CH2:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([OH:20])=[CH:22][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: Oc1ccc(CN2CCCC2)c2ccccc12
Yield: 112.2 %

Procedure:
NaB(OAc)3H (6.4 g, 0.030 mol) was added in portions for 15 min to a mixture of pyrrolidine (2.1 mL, 0.025 mol) and 4-hydroxynaphthalene-1-carbaldehyde (3.40 g, 0.020 mol) in (C2H5)2O (80 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (18 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 9 (30 mL) and extracted with (2×100 mL) (C2H5)2O. The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.1 g, 75%) was obtained as white crystals. LCMS-data: 228.1 and 229.1 (M+H)+, (calculated for C15H17NO 227.13). 1H NMR (400 MHz)-data (DMSO-d6, J, Hz): 9.18 (br s, 1H, OH); 6.83 (s, 2H, ArH); 3.79 (s, 3H, CH3); 3.44 (s, 2H, CH2Ar); 2.36-2.44 (m, 4H, CH2CH2CH2CH2,); 1.65-1.72 (m, 4H, CH2CH2CH2CH2,).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([Cl:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:26][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][CH:23]=1
Reactant: Clc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 3-bromochlorobenzene (1.76 mL, 15 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.06 g (91%) of the product 4-(3-chloro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [C:1]([CH:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])C(OCC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].B(O)(O)O.C(O)C>CCCCCC>[O:5]=[C:1]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCCC(=O)C(CC(=O)OCC)C(=O)OCC
Agent: OB(O)O
Solvent: CCCCCC
Solvent: CCO
Product: CCCC(=O)CCC(=O)OCC
Temperature: 175 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
92.8 g of diethyl 2-butyrylsuccinate and 23.5 g of boric acid were heated to 150° C. in a round flask with distillation head piece, whereby ethanol distilled off. The mixture was subsequently heated to 175° C. and stirred at this temperature for 4 hours (evolution of carbon dioxide). After completion of the reaction, the mixture was cooled to room temperature, taken up in 500 ml of hexane and washed with 150 ml of 5% (wt./vol.) sodium hydrogen carbonate solution and 100 ml of water. The aqueous phases were back-extracted with 50 ml of hexane. The combined organic phases were dried over sodium sulphate and freed from solvent on a rotary evaporator. Distillation of the resulting crude product in a high vacuum over a Vigreux column gave in the main run 58.6 g (89.6%) of ethyl 4-oxoheptanoate as a colourless liquid; b.p. 50°-56° C./0.2 Torr.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].CCN(CC)CC.[C:16](Cl)(=[O:24])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20]>O.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:16](=[O:24])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)C(C)N
Reactant: CCCC(CCC)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)N[C@@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A solution of DL-alanine methyl ester hydrochloride (13.7 g, 98 mmole) and Et3N (20.2 g, 200 mmole) in water (50 ml) was added dropwise to an ice-cooled solution of valproyl chloride (15.0 g, 92 mmole) in CH2Cl2 (150 ml). After completion of addition the reaction mixture was stirred for 4 hrs. at RT. The layers were then separated and the aqueous layer extracted with CH2Cl2. The combined organic phases were washed successively with water, satd. NaHCO3, 0.1N HCl and satd. NaCl, dried and evaporated to dryness. The residue was treated with hexane (60 ml), and the resultant solid was collected by filtration, washed with hexane and dried to give 14.2 g (62 mmole, 63%) of the title compound as a white solid, mp 72°-3° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Br[CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: OCCBr
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OCCO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromo-ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O.Cl>[OH-].[Na+].CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCBr
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C2
Temperature: 80 °C

Procedure:
A solution of (S)-2-Tert-butoxycarbonyl-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (1 g) in a mixture of 10% NaOH aqueous solution (2.73 ml) and dimethylsulfoxide (11 ml) was stirred for half an hour at 80° C. Then, octyl bromide (0.589 ml) was added thereto, and stirred for 4 hours at 60° C. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 2.5 with conc. hydrochloric acid. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give (S)-2-Tert-butoxycarbonyl-1,2,3,4-tetrahydro-7-octyloxyisoquinoline-3-carboxylic acid (1.30 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[OH:6][C@@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[C:20](=O)[CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:27]([OH:29])=[O:28])[CH2:8]1.Cl>C(O)C.O>[OH:6][C@@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[C:20](=[N:2][OH:3])[CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:27]([OH:29])=[O:28])[CH2:8]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=NO)[C@@H]12
Yield: 63.8 %

Procedure:
Hydroxylamine hydrochloride (4 g) was added to a water cooled solution of sodium hydroxide (50%; 16 ml). This mixture was added to a solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (1.5 g) in ethanol (70 ml). The mixture was heated at reflux for 24 h, cooled and brought to pH 1 with concentrated HCl solution. Water (800 ml) was added and the precipitate (1.42 g) was collected by filtration, washed with water (2×300 ml) and dried. Crystallisation from ethyl acetate gave the title compound (1 g) m.p. 250°-253° C. (dec) [α]D +124° (EtOH C=1%).
Reaction SMILES: [Na:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][O:16]CC2C=CC=CC=2)=[C:5](Cl)[N:4]=1.O.[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Na:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:5]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:4]=1
Reactant: Nc1nc(Cl)c2ncn(COCCOCc3ccccc3)c2n1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2ncn(COCCO)c2n1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A solution of sodium benzylate in benzyl alcohol was prepared from sodium (2.58 g) and benzyl alcohol (28 ml). The solution was heated to 120° C. and 2-amino-6-chloro-9-(2-benzyloxyethoxymethyl)purine (3.47 g) was added over a 10 minute period. The reaction mixture was headed overnight with stirring at 120°-130° C. and then poured into a mixture of ice and water. The resulting mixture was extracted thoroughly with chloroform. The aqueous phase was neutralized with acetic acid, giving a white precipitate which was recrystallized from methanol and then from water to give analytically pure 2-amino-6-benzyloxy-9-(2-hydroxyethoxymethyl) purine, m.p. 291°-292° C. (dec.) in 50% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[CH2:6][C:7]1[C:11]2[C:12](=[O:26])[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[NH:9][N:8]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[CH2:6][C:7]1[C:11]2[C:12](=[O:26])[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[NH:9][N:8]=1
Reactant: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo [4,3-c][1,8]naphthyridin-4 (5H)-one (376 mg, 0.95 mmol, prepared in Example 26) in DMF (20 ml) and methanol (20 ml) was added activated carbon-palladium (38 mg), the mixture was stirred under hydrogen atmosphere overnight, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-(2-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (349 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2([C:12]([O:14]CC)=[O:13])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]2)=[O:7])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To ethyl 1-[(4-chlorobenzoyl)amino]cyclopropanecarboxylate (157 g, 0.58 mol) in 1,4-dioxane (2.4 L), add a solution of lithium hydroxide (123.05 g, 2.93 mol) in water (1.2 L). Stir the reaction mixture at ambient temperature for 4 hours and then concentrate it under reduced pressure. Dilute the mixture with water (1 L) and immerse it in an ice water bath. Adjust the pH to approximately 2 with aqueous 5N HCl. Filter the precipitate, wash the cake with water (3×1 L), and dry (50° C., vacuum oven) to give (132 g, 94%) the title compound as a white powder: MS (m/z): 240 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]2[O:17][C@@H:10]3[CH2:11][CH2:12][CH2:13][C@@H:14]([C:15]#[N:16])[N:9]3[C@@H:8]2[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>>[NH2:16][CH:15]1[CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH:8]([CH3:18])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:17]1
Reactant: C[C@@H]1[C@H](c2ccccc2)O[C@@H]2CCC[C@@H](C#N)N12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC1C(c2ccccc2)OC(N)C2CCCCN12

Procedure:
This compound is prepared from (2S,3R,5S,8aR)-2-phenyl-3-methyl-5-cyanooxazolidino[3,2-a]piperidine by reduction with diisobutylaluminum hydride as in stage III of Example 1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[C:8]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: N#C[S-]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A solution of 3-(bromoacetyl)benzonitrile (7.72 g, 34.5 mmol) and potassium thiocyanate (3.35 g, 34.5 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 4.39 g (63.0% (2 steps)) of the desired product as a solid.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[C:7]([CH3:9])[O:6][N:5]=1)=[N+:2]=[N-:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:3]=[N:2][N:1]([C:4]3[CH:8]=[C:7]([CH3:9])[O:6][N:5]=3)[C:19]=2[NH2:20])=[CH:14][CH:13]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: Cc1cc(N=[N+]=[N-])no1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3cc(C)on3)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To an ice-cooled and stirred mixture of 3-azido-5-methyl-isoxazole (0.5 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.712 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.327 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (˜0.900 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 20% ethylacetate in hexane, to afford the title compound as a white solid (0.120 g, 11% yield). M.p. 136.3-141.2° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][C:5]=1[CH2:6][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1cc(O)ccc1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1cc(O)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of 4-hydroxy-2-methoxybenzaldehyde (1.0 g, 6.57 mmol) and morpholine (2.0 g, 23.0 mmol) in 50 ml dichloroethane was stirred at rt for 1 h. Sodium triacetoxyborohydride (2.0 g, 9.44 mmol) was added in portions over 20 minutes. The reaction mixture was stirred at rt over night. Aqueous NaHCO3 (sat.) was added, the phases were separated and the aqueous phase was extracted with DCM once. The solvent was removed by evaporation and the residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 1.19 g (81%) of 7A iii as a solid. 1H NMR (500 MHz, CDCl3): δ 2.41-2.71 (m, 4H), 3.52 (s, 2H), 3.72 (s, 3H), 3.69-3.79 (m, 4H), 6.27 (d, 1H), 6.32 (s, 1H), 7.10 (d, 1H).
Reaction SMILES: [Na+].Cl[Au-:3](Cl)(Cl)Cl.[SH:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11]>O>[SH:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11].[Au:3]
Reactant: Cl[Au-](Cl)(Cl)Cl
Agent: O=C(O)CNC(=O)CCS
Agent: [Na+]
Solvent: O
Product: [Au]

Procedure:
A solution of sodium tetrachloroaurate (35g) in distilled water (200 ml) was slowly added to a solution of ethyl 2-hydroxethyl sulphide (20.5g) in distilled water (200 ml). Solid addition of mercaptopropionyl-glycine (5.21g) followed by vigorous stirring yielded gold mercaptopropionylglycine as a white solid (yield, based on gold, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C(C)(C)C)=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(O)cc1
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
(1R,2R)-2-(4-tert-Butoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (5.9 g, 22.5 mmol) is cooled to 0° C. and trifluoroacetic acid (14 mL, 182.5 mmol) is added. The mixture is stirred for 5 minutes and then concentrated under vacuum. The residue is reevaporated 3 times from dichloromethane then purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to give the title compound (yield 3.10 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@@H:17]3[CH2:20][CH2:19][N:18]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=[N:13][CH:14]=2)=[CH:3][CH:2]=1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@@H:17]3[CH2:20][CH2:19][N:18]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=[N:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C=Cc2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 81.7 %

Procedure:
To a solution of 5-(2-(4-pyridinyl)vinyl)-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 59a (188 mg, 0.51 mmol) in methanol (10 mL) was added Pd/C (20 mg), and the mixture was stirred at room temperature for 40 hours. The catalyst was filtered off, and the solvent was removed under vacuum. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 10:2 to 10:5 to afford the title compound (154 mg). MS (CI/NH3) m/z 370 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.32 (m, 2H), 3.89 (m, 2H), 4.10 (m, 1H), 4.28 (m, 1H), 4.50 (m, 1H), 7.02 (m, 1H), 7.02 (m, 1H), 7.08 (m, 2H), 8.06 (m, 1H), 8.20 (m, 1H), 8.51 (m, 2H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15](N(OC)C)=[O:16])[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O.Cl>O1CCCC1>[Cl:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15](=[O:16])[CH2:1][CH3:2])[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)c1cc2c(Cl)cccc2s1
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (1M solution in tetrahydrofuran; 17.2 ml) was added under nitrogen to a stirred solution of 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (4 g; prepared in a manner similar to that described in Example 18) in tetrahydrofuran (120 ml) then the mixture was allowed to stand at ambient temperature for 30 minutes, heated under reflux for 30 minutes and allowed to stand at ambient temperature for 30 minutes. Further ethylmagnesium bromide (1M solution in tetrahydrofuran; 7.0 ml) was added and the mixture was allowed to stand at ambient temperature for 2 hours. Water (200 ml) and 5M hydrochloric acid (15 ml) were added, and the product was extracted into dichloromethane (2×90 ml). The combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 1-(4-chlorobenzo[b]thiophen-2-yl)propan-1-one (1.88 g) as a pale yellow solid, m.p. 96-98° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:26][C@H:15]3[C:16]=2[N:17]([C:19]2[CH:24]=[C:23](Br)[CH:22]=[CH:21][N:20]=2)[N:18]=1)=[O:10])[C:4]([CH3:7])([CH3:6])[CH3:5].C[C:28]([N:30](C)C)=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:26][C@H:15]3[C:16]=2[N:17]([C:19]2[CH:24]=[C:23]([C:28]#[N:30])[CH:22]=[CH:21][N:20]=2)[N:18]=1)=[O:10])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 120 °C

Procedure:
(1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (2.38 g, 5.68 mmol) was dissolved in DMA (10 mL). Nitrogen was bubbled through the solution for 20 min. Zinc(II) cyanide (1.333 g, 11.35 mmol) and palladium tetrakistriphenylphosphine (0.328 g, 0.284 mmol) were added. The reaction was heated under microwave at 120° C. for 1 h. The reaction was diluted with 100 mL ethyl acetate, filtered, then concentrated. The residue was purified by silica gel column chromatography and then crystallized from EtOAc/hexanes to give the title compound as a white solid (1.78 g). LCMS m/z=366.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.06 (s, 9H), 1.25 (td, J=8.0, 4.9 Hz, 1H), 2.26-2.32 (m, 1H), 2.35 (t, J=5.5 Hz, 1H), 2.78-2.83 (m, 1H), 2.93 (d, J=17.2 Hz, 1H), 3.03 (dd, J=16.7, 6.3 Hz, 1H), 3.66-3.72 (m, 1H), 3.94-4.01 (m, 2H), 7.01 (d, J=8.6 Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.15 (dt, J=1.1 Hz, 1H), 8.62 (dd, J=5.1, 0.8 Hz, 1H).