Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[C:6]([CH3:10])(C)[CH:5]=[C:4]([C:11]([CH3:21])=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=2)[CH:3]=1.[CH2:22](C1OC1)Cl.C(O)(C)C.[OH-].[Na+]>O>[CH3:10][C:6]1[CH:5]=[C:4]([C:11]([CH3:21])=[CH:12][C:13]2[CH:14]=[C:15]([CH3:20])[C:16]([OH:19])=[C:17]([CH3:22])[CH:18]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:8]
Reactant: ClCC1CO1
Reactant: CC(=Cc1ccc(O)c(C)c1)C1=CC(C)(C)C(O)C(C)=C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=Cc1cc(C)c(O)c(C)c1)c1cc(C)c(O)c(C)c1
Temperature: 55 °C

Procedure:
3,3',5,5-Tetramethyl-4,4'-dihydroxy-alphamethylstilbene (211.78 grams, 1.50 hydroxyl equivalent) from A. above, epichlorohydrin (693.98 grams, 7.50 moles), deionized water (60.35 grams, 8.0 percent by weight of the epichlorohydrin used) and isopropanol (373.68 grams, 35 percent by weight of the epichlorohydrin used) are added to a two liter glass resin kettle reactor equipped with a chilled water condenser, mechanical stirrer, nitrogen purge (1 liter per minute), thermometer and thermostatically controlled infrared heating lamps and heated to 55° C. with stirring under a nitrogen atmosphere. Once the 55° C. reaction temperature is achieved, sodium hydroxide (54.0 grams, 1.35 mole) dissolved in deionized water (216 grams) is added dropwise to the reactor over a 45 minute period, so as to maintain reaction temperature between 55 and 58° C. Ten minutes after completion of the aqueous sodium hydroxide addition, the stirring is stopped and the aqueous layer which separates from the reaction mixture is pipetted off and discarded. Stirring is resumed and after a total of twenty minutes following completion of the initial aqueous sodium hydroxide addition, a second solution of sodium hydroxide (24.0 grams, 0.60 mole) dissolved in deionized water (96 grams) is added to the reactor over a twenty minute period and so as to maintain the 55° C. reaction temperature. Fifteen minutes after completion of the aqueous sodium hydroxide addition, the recovered reaction mixture is added to a separatory funnel and washed with 500 milliliters of deionized water. The separated organic layer is washed a second time (500 milliliters deionized water), recovered and then rotary evaporated under vacuum for 45 minutes at 110° C. then 30 minutes at 140° C. and 5 mm Hg. The product is recovered (293.84 grams) as a light amber colored, transparent liquid (at 24° C.) with an epoxide equivalent weight of 227.80.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[O:9]([CH2:16][CH:17]([OH:23])[CH2:18][NH:19][CH2:20][CH2:21][NH2:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[O:9]([CH2:16][CH:17]([OH:23])[CH2:18][NH:19][CH2:20][CH2:21][NH:22][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCNCC(O)COc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: OC(CNCCNc1ccc(Cl)nn1)COc1ccccc1

Procedure:
A mixture of 3.0 g. 3,6-dichloropyridazine, 4.2 g. 1-phenoxy-3-(2-aminoethylamino)-propan-2-ol, 3.5 ml. N-ethyldiisopropylamine and 30 ml. toluene is stirred for 24 hours at 100° C. The reaction mixture is then evaporated and the residue is digested simultaneously with 100 ml. water and 100 ml. methylene chloride, followed by suction filtration and recrystallization from isopropyl alcohol, with treatment with fullers' earth. There are obtained 1.4 g. (21% of theory) of the desired product in the form of colorless crystals; m.p. 147°-149° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13](OCC)=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:4][NH:3]1.O=[C:25]1[C:30](C(O)=O)=[CH:29]C(C2C=CN=CC=2)=N[NH:26]1.ON1C2C=CC=CC=2N=N1.NCC1C=CC=CN=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:29][CH:30]=[CH:25][N:26]=2)=[O:9])=[CH:6][C:5]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[N:4][NH:3]1
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: CCOC(=O)CCNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccn1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 13 for the preparation of ethyl 3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]propionate, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 30 cm3 of N,N-dimethylformamide, 0.233 g of 1-hydroxybenzotriazole, 0.18 cm3 of 2-(aminomethyl)pyridine, 0.31 cm3 of N,N-diisopropylethylamine and 0.65 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 0.125 g of 3-oxo-6-pyridin-4-yl-N-(pyridin-2-ylmethyl)-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a white solid melting at 242° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26]([N:1]3[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]3)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1
Reactant: O=C1CCNCC1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In N,N-dimethylformamide (10 ml) was suspended piperidin-4-one (monohydrochloric acid monohydrate, 1.54 g), followed by the addition of diisopropylethylamine (3.48 ml) and 6-chlorobenzo[b]thiophene-2-sulfonyl chloride (2.68 g). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was then added to the residue, followed by washing with 1N hydrochloric acid. After extraction, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate methylene chloride=3:1), followed by washing with hexane, whereby the title compound (colorless prism crystals, 1.92 g) was obtained.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CCO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:31]([C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1)#N>>[OH:2][CH2:1][CH2:31][C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 100 %

Procedure:
The title compound II-al was prepared in 100% yield from 3,3:17,17-bis(ethylendioxy)-6α-(2-hydroxyethyl)androstane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, dmso-d6, ppm from TMS): δ 4.32 (t, 1H), 3.39 (m, 2H), 2.46-0.54 (m, 23H), 0.98 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: NC1C=CC(C(N[C@@H](CCSC)C(OC)=O)=O)=C(CC2C=CC=CC=2)C=1.[OH2:27].[OH2:28].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Br:40][C:41]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:42]=1[CH3:50].S(=O)(=O)(O)O>C(O)(=O)C>[Br:40][C:41]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:42]=1[C:50]([OH:28])=[O:27]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Temperature: 105 °C
Yield: 27.8 %

Procedure:
Compound 21 used in the preparation of compound 24 was prepared as follows. Sodium dichromate dihydrate (151 gm) was added to glacial acetic acid (575 ml) followed by 2-bromo-4-nitro-toluene (49.7 gm). To this solution was added dropwise sulphuric acid (175 ml) at such a rate to maintain the temperature between. 75-85° C. This mixture was heated to 100-110° C. for 3 h cooled to 50° C. and poured onto ice (1 litre). The aqueous phase was extracted with ethyl acetate, the organic layer back extracted with Aqueous sodium hydroxide solution and the resulting basic aqueous layer acidified with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and air dried to give 15.72 gm (28%) of 2-bromo-4-nitro-benzoic acid (compound 26) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26]CC4C=CC=CC=4)[CH:21]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(#N)C.[ClH:37]>C(O)C>[N:1]1([C:7]2[N:8]=[C:9]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1.[ClH:37]
Reactant: c1ccc(COc2cccc(-c3cc(Nc4cccnc4)nc(N4CCOCC4)n3)c2)cc1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: Oc1cccc(-c2cc(Nc3cccnc3)nc(N3CCOCC3)n2)c1
Reaction time: 20 h

Procedure:
{2-Morpholin-4-yl-6-[3-(phenylmethoxy)phenyl]pyrimidin-4-yl}-3-pyridylamine (1 eq) is suspended in ethanol in a round bottom flask, purged with N2. 10% Pd/C (20% wt) was added. The flask was evacuated and filled up with H2 (contained in a balloon) for five times, then the reaction mixture was stirred under H2 for 20 h. The catalyst was filtered off through a pad of celite washing thoroughly with EtOH, MeOH, CH2Cl2, and acetonitrile (almost one liter of the mixture of solvents was used to ensure the complete solubilization of the product). The solvent was evaporated under reduced pressure and the residue purified by reverse phase chromatography (Buffer A: 0.1% TFA in H2O, Buffer B: 0.1% TFA in CH3CN; Column: Waters, C18, 47×300 mm; gradient: 1.1%, 10%-60% B in 45 min). The free base thus obtained was lyophilized from a 1:1 mixture of acetonitrile and 1N HCl, obtaining the desired 3-[2-morpholin-4-yl-6-(3-pyridylamino)pyrimidin-4-yl]phenol as the bis HCl salt. The spectral data are the following:
Reaction SMILES: [C:1]([Si:5]([O:8][C@H:9]([CH2:13][CH3:14])/[CH:10]=[CH:11]/I)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Si:15]([O:22][C@H:23]([C:31]#[C:32]/[CH:33]=[CH:34]/[CH:35]=[CH:36]/[C@H:37]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:38][C:39]#[CH:40])[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]([C:31]#[C:32]/[CH:33]=[CH:34]/[CH:35]=[CH:36]/[C@H:37]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:44])[CH2:38][C:39]#[C:40]/[CH:11]=[CH:10]/[C@H:9]([O:8][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:6])[CH3:7])[CH2:13][CH3:14])[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:17])[CH3:16]
Reactant: CC[C@H](/C=C/I)O[Si](C)(C)C(C)(C)C
Reactant: C#CC[C@H](/C=C/C=C/C#C[C@H](CCCC(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Product: CC[C@H](/C=C/C#CC[C@H](/C=C/C=C/C#C[C@H](CCCC(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
Sonogashira coupling between (R,E)-tert-butyl(1-iodopent-1-en-3-yloxy)dimethylsilane and (5S,8E,10E,12R)-methyl 5,12-bis(tert-butyldimethylsilyloxy)pentadeca-8,10-dien-6,14-diynoate (the product of Example 2 or Example 3), using a procedure analogous to that of Example 2, Step 1 gave the product in 80% yield. 1H NMR (500 MHz, C6D6): δ 6.59 (dd, J=15.2 Hz and 10.9 Hz, 1H), 6.24 (dd, J=15.2 and 11.0 Hz, 1H), 6.14 (dd, J=15.5 Hz and 5.3 Hz, 1H), 5.86 (d, J=15.4 Hz, 1H), 5.67 (dd, J=14.8 Hz and 5.6 Hz, 1H), 5.59 (d, J=15.5 Hz, 1H), 4.54 (t, J=5.7 Hz, 1H), 4.24 (q, J=5.9 Hz, 1H), 3.94 (q, J=5.6 Hz, 1H), 3.35 (s, 3H), 2.46 (m, 2H), 2.17 (t, J=7.1 Hz, 2H), 1.84 (m, 4H), 1.44 (m, 2H), 1.04 (s, 9H), 1.02 (s, 9H), 1.00 (s, 9H), 0.86 (t, J=7.5 Hz, 3H), 0.28 (s, 3H), 0.19 (s, 3H), 0.14 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H). 13C NMR (125 MHz, C6D6): δ 173.131, 145.665, 141.248, 138.411, 129.420, 111.518, 109.904, 93.989, 87.526, 84.119, 81.048, 73.998, 72.025, 63.570, 50.913, 38.321, 33.587, 31.253, 29.235, 26.014, 21.163, 18.413, 9.221, −4.207, −4.421, −4.603, −4.621, −4.772, −5.094.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:23])[CH:11]=[N+:12]([O-])[C:13]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]2=[O:24])=[CH:4][CH:3]=1.C[O-:28].[Na+:29]>C(OC(=O)C)(=O)C>[CH2:20]([O:19][C:17]([C:13]1[NH:12][C:11](=[O:28])[C:10]([O-:23])=[C:9]2[C:14]=1[CH2:15][CH2:16][N:7]([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]2=[O:24])=[O:18])[CH3:21].[Na+:29]
Reactant: CCOC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1[nH]c(=O)c([O-])c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate 2-oxide (2.3 gm, 6.38 mmol) in neat acetic anhydride (24 mL) was stirred under nitrogen at 100° C. for 1 hour. The reaction was concentrated to an oil under reduced pressure and dry methanol (20 mL) was added followed by a methanolic sodium methoxide solution (30% by wt) (4.54 mL, 25.2 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to an oil under reduced pressure and crystallized from a small amount of methanol (˜5 mL). The crystals were collected by filtration, washed an additional 10 mL of methanol and dried in vacuo to give the desired product.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:22][C@H:11]1[CH2:10][C@@H:9]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Triethylamine (0.49 mL, 3.49 mmol) was added to a 0° C. solution of (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (250 mg, 1.16 mmol) and methanesulfonyl chloride (0.14 mL, 1.74 mmol) in dichloromethane (4.5 mL). The resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (10 mL) was added. The organic layer was separated and washed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (315 mg, 92%) as a colorless oil that slowly solidified to a white solid upon standing. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (d, J=7.04 Hz, 3H), 1.38 (s, 9H), 1.63-1.76 (m, 1H), 1.85-1.90 (m, 3H), 2.96-3.06 (m, 1H), 3.18 (s, 3H), 3.72-3.78 (m, 1H), 4.16-4.24 (m, 1H), 4.93-4.98 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[I:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:32](Br)[CH:33]=[CH2:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[I:29])[CH2:34][CH:33]=[CH2:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1I
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A solution of 27 (160 mg, 0.31 mmol) in anhydrous DMF (5 mL) under Ar was treated with NaH (19 mg, 0.47 mmol, 1.5 equiv, 60% oil dispersion) and the reaction mixture was stirred for 30 min at 0° C. Allyl bromide (194 mg, 139 μL, 1.55 mmol, 5 equiv) was added dropwise over 5 min and the solution was allowed to warm to 25° C. and stirred for 2 h. Saturated aqueous NaHCO3 (10 mL) was added and the aqueous phase was extracted with EtOAc (4×10 mL), dried (Na2SO4) and concentrated. Chromatography (SiO2, 2×15 cm, 10% EtOAc-hexane) afforded 28 (155 mg, 168 mg theoretical, 92%) as a clear oil which crystallized under vacuum: 1H NMR (CDCl3, 400 MHz) δ8.60 (s, 1H), 8.38 (d, 1H, J=8.6 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.47-7.34 (m, 5H), 6.90 and 6.79 (two s, 1H), 5.94-5.84 (m, 1H), 5.27 and 5.22 (two d, 2H, J=12.3 Hz), 5.00 (m, 2H), 4.50 (dd, 1H, J=5.3, 14.4 Hz), 3.81 (dd, J=7.0, 14.4 Hz), 1.57 and 1.29 (two s, 9H); 13C NMR (CDCl3, 100 MHz) δ154.8, 144.9, 138.7, 135.7, 134.8, 133.2, 128.8, 128.3, 127.3, 126.9, 126.8, 124.2, 118.8, 118.4, 117.2, 112.2, 110.7, 80.8, 70.7, 53.3, 52.0, 28.4; IR (film) vmax 2977, 2228, 1703, 1593, 1503, 1410, 1368, 1324, 1250, 1223, 1150, 1108, 931, 830, 735, 696 cm-1 ; FABHRMS (NBA-CsI) m/z 672.9948 (M+ +Cs, C26H25IN2O3, requires 672.9964).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1)[CH3:11].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:16]=1)[CH3:11]
Reactant: Cc1ccc(CN)cc1
Reactant: CCOC(=O)Cc1cccc(C=O)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
A solution of 4-methylbenzylamine (0.097 mL, 0.76 mmol) and (3-formyl-phenyl)-acetic acid ethyl ester (138 mg, 0.72 mmol) in MeOH (2 mL) was stirred for 3 h at room temperature. The reaction was cooled to 0° C. and NaBH4 (43 mg, 1.15 mmol) was added. After stirring at room temperature for 10 minutes, a 1:1 mixture of saturated aqueous NaHCO3:H2 was added. The product was extracted into CH2Cl2 (3×) and the organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (231 mg). 1H NMR (400 MHz, CDCl3) δ 7.13–7.30 (m, 8H), 4.14 (q, 2H), 3.83 (d, 4H), 3.78 (s, 2H), 2.34 (s, 3H), 1.25 (t, 3H); MS 298 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 78 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound IV-16) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: CCN(CC)CC.C(O)=O.FC(F)(F)S(O[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C@H:23]([OH:34])[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:18]=1)(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:34][C@@H:23]([C:19]1[CH:18]=[CH:17][CH:22]=[CH:21][CH:20]=1)[CH2:24][CH2:25][NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1ccccc1

Procedure:
Et3N (2.0 mL, 14.35 mmol) and HCOOH (0.4 mL, 10.60 mmol) were added to a solution of (R)-3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenyl trifluoromethanesulfonate (1.05 g, 2.63 mmol) and Ar was bubbled through the mixture for one minute. 1,3-Bis(diphenylphosphino)propane (1,3-dppp) (0.080 g, 0.194 mmol) and Pd(OAc)2 (0.050 g, 0.223 mmol) were added to the reaction mixture and the later was degassed by applying vacuum/Ar cycle three times. The reaction mixture was heated at +60° C. for 5 h and concentrated under reduced pressure. Aqueous NH4Cl (25%) was added to the residue and the mixture was extracted with MTBE twice. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (10%-50% EtOAc-hexanes gradient) gave (R)-tert-butyl (3-hydroxy-3-phenylpropyl)carbamate as a colorless oil. Yield (0.64 g, 97%); 1H NMR (400 MHz, DMSO-d6) δ 7.22-7.30 (m, 4H), 7.14-7.21 (m, 1H), 6.72 (br. t, 1H), 5.14 (d, J=4.4 Hz, 1H), 4.51 (dd, J=6.5, 10.9 Hz, 1H), 2.87-2.98 (m, 2H), 1.60-1.70 (m, 2H), 1.33 (s, 9H).
Reaction SMILES: S1C23C=CC=CC2=NC=CC3=C(C(O)=[O:15])C1.[S:17]1[C:21]23[CH:29]=[CH:28][CH:27]=[CH:26][C:22]2=[N:23][CH:24]=[CH:25][C:20]3=[C:19]([C:30]([N:32]2[CH:37]([CH3:38])CC[CH2:34][CH:33]2C)=[O:31])[CH2:18]1>>[S:17]1[C:21]23[CH:29]=[CH:28][CH:27]=[CH:26][C:22]2=[N:23][CH:24]=[CH:25][C:20]3=[C:19]([C:30]([N:32]2[CH2:37][CH2:38][O:15][CH2:34][CH2:33]2)=[O:31])[CH2:18]1
Reactant: O=C(O)C1=C2C=CN=C3C=CC=CC32SC1
Reactant: CC1CCCC(C)N1C(=O)C1=C2C=CN=C3C=CC=CC32SC1
Product: O=C(C1=C2C=CN=C3C=CC=CC32SC1)N1CCOCC1

Procedure:
By following the same procedure as above using benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid as the starting material, 1-(benzo[b]thieno[2,3-c]pyridine-3-carbonyl)-2,6-dimethyl-piperidine and 4-(benzo[b]thieno[2,3-c]pyridine-3-carbonyl)-morpholine were obtained. (See Table 13-1, Table 13-2, Table 13-3).