Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[N:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][O:15][C:16]3=[O:21])=[CH:6][CH:5]=1.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.[Na].[CH2:33]([OH:35])[CH3:34]>C(OCC)(=O)CC>[CH3:23][N:2]([CH3:1])[C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH:30]([C:26]3[N:25]([CH3:24])[CH:29]=[CH:28][N:27]=3)[C:14](=[O:15])[C:13]3[C:17]([C:16]([O:35][CH2:33][CH3:34])=[O:21])=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11]2)=[CH:6][CH:5]=1)=[O:22]
Reactant: Cn1ccnc1C=O
Reactant: CN(C)C(=O)c1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: CCO
Agent: [Na]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(=O)N(C)C)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
(E)-N,N-Dimethyl-4-((1-oxo-1,3-dihydroisobenzofuran-4-ylimino)methyl)benzamide (924 mg, 3.0 mmol), 1-methyl-1H-imidazole-2-carbaldehyde (363 mg, 3.3 mmol), sodium (276 mg, 12 mmol) in ethanol (30 mL) and ethyl propionate (45 mL) were added and the mixture was stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 1:2) to afford the title compound as a yellow solid (500 mg, yield 37%). LC-MS (ESI) m/z: 447 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]#N.[H-].[Na+].[CH3:22]I.O.C[N:26]([CH3:29])C=O>>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[C:17]([CH3:18])([CH3:22])[C:29]#[N:26]
Reactant: CN(C)C=O
Reactant: CI
Reactant: COc1c(CC#N)cccc1Oc1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1c(Oc2ccccc2C)cccc1C(C)(C)C#N
Reaction time: 0.5 h

Procedure:
A solution of 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetonitrile (5.2 g) in dimethylformamide (10 ml) was added dropwise to a mixture of 50% sodium hydride (1.1 g) and dimethylformamide (20 ml) below 7° C. in 10 minutes and stirred at the same temperature for 30 minutes. Methyl iodide (6.2 g) was added dropwise to the mixture below 7° C. in 15 minutes and stirred at the same temperature for an hour. Chilled water (200 ml) was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with water, aqueous sodium hydrogen sulfite and water successively, dried over magnesium sulfate and then evaporated to give oily 2-[2-methoxy-3-(o-tolyloxy)phenyl]-2,2-dimethylacetonitrile (5.7 g).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH]Cl>CO>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][OH:43])[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:54])[F:53])[CH:8]=1
Reactant: Cc1ccc(F)cc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [CH]Cl
Solvent: CO
Product: Cc1ccc(F)cc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H) -yl]-4-(5-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D56, 110 mg) was dissolved in dry MeOH (2 mL), cooled in an ice-salt bath before adding cHCl solution (˜0.2 mL), and stirring at R.T. for 2 hours. Poured directly onto a 5 g SCX column. Washed with MeOH (2×10 mL), before eluting the compound with NH3 in MeOH 94×10 mL). Solvent evaporated. Residue purified on a 5 g sek-pak column eluting with Pent to EtOAc to 10% MeOH/EtOAc. Solvent evaporated to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].ClC(Cl)(Cl)C([C:8]1[CH:9]=[C:10]([C:13]#[N:14])[NH:11][CH:12]=1)=O.[CH3:17][OH:18]>>[C:13]([C:10]1[NH:11][CH:12]=[C:8]([C:1]([O:18][CH3:17])=[O:2])[CH:9]=1)#[N:14]
Reactant: N#Cc1cc(C(=O)C(Cl)(Cl)Cl)c[nH]1
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Product: COC(=O)c1c[nH]c(C#N)c1
Reaction time: 16 h
Yield: 98 %

Procedure:
Sodium methoxide (17.8 g, 329 mmol) was added to a solution of 4-(trichloroacetyl)-1H-pyrrole-2-carbonitrile (39.0 g, 164 mmol) in methanol (350 mL). The reaction was stirred for 16 h and then the methanol was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (800 mL) and the solution was adjusted to pH 6 using 1 M hydrochloric acid. The layers were separated and then the organic layer was washed with water and brine, dried (magnesium sulfate) and evaporated under reduced pressure to afford the expected product (24.2 g, 98%). 1H NMR (DMSO-d6) δ 7.76 (s, 1H), 7.28 (s, 1H), 3.72 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCCCCC>[CH2:18]([N:25]1[CH2:30][CH2:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)([OH:31])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2ccc(OC(F)(F)F)cc2)CCN(Cc2ccccc2)CC1

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 8.5, starting with 20 g of 1-bromo-4-(trifluoromethoxy)benzene in 300 ml of THF, 89.3 ml of a 1.6M solution of n-butyllithium in hexane and 24.1 ml of 1-benzyl-4-piperidinone in 50 ml of THF. 18.5 g of the expected product are obtained.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.S(=O)(=O)(O)O.[CH3:21]O>>[N:1]1([C:6]2[N:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH3:21])=[O:14])=[CH:10][N:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)Cc1cnc(-n2cnnn2)nc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cnc(-n2cnnn2)nc1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a solution of 2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)acetic acid (100 mg, 0.485 mmol) in methanol (30 mL) was added sulfuric acid (1 mL, 18.8 mmol). Stirred at room temperature and sonicated to dissolve all acid starting material. Reaction was complete within about 2-3 min. The reaction was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, extracted with DCM (2 times), washed organics with brine, dried over magnesium sulfate. Solvent was removed under reduced pressure and residue dried on high vacuum overnight. LC/MS: [(M+1)]+=221.0;
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]=1.[CH2:17]([N:19](CC)[CH2:20]C)C>>[CH3:17][N:19]([CH3:20])[CH2:3][CH:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1.[ClH:2].[CH3:4][NH:5][CH3:6]
Reactant: ClCC1=NCCc2c1[nH]c1ccccc21
Reactant: CCN(CC)CC
Agent: Cl
Product: CN(C)CC1NCCc2c1[nH]c1ccccc21
Product: CNC
Yield: 72 %

Procedure:
By a similar operation as in Starting Material Synthetic Example 21 and adding triethylamine (1.28 ml), dimethyl(2,3,4,9-tetrahydro-1H-β-carboline-1-ylmethyl)amine (305 mg, yield 72%) was obtained from dimethylamine hydrochloride (751 mg) and 1-chloromethyl-4,9-dihydro-3H-β-carboline hydrochloride (synthesized according to the method described in J. Med. Chem., 34, 8, 1991, 2624-2633, 470 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[CH:3]=1.[H-].[Na+].[H][H].[C:27]1([CH:33]([CH3:37])[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:27]1([CH:33]([CH3:37])[C:34]([O:1][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:4](=[O:22])[CH:3]=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1cc(O)c2cccnc2n1-c1cccc(C(F)(F)F)c1
Reactant: CC(C(=O)Cl)c1ccccc1
Reactant: [H][H]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)Oc1cc(=O)n(-c2cccc(C(F)(F)F)c2)c2ncccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (919 mg, 3.0 mmol) in DMF (24 mL) was added sodium hydride (purity of about 60%, 120 mg, 3.0 mmol, 1.0 eq.). The mixture was stirred until no more hydrogen was generated, to obtain a solution. Then, 2-phenylpropionyl chloride (1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 1 hour. To the mixture was added a saturated sodium hydrogencarbonate aqueous solution, and the resulting precipitate was separated by filtration, washed with water, and dried to give 4-(2-phenylpropionyloxy)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.00 g, yield 76%).
Reaction SMILES: [C@@H:1]12[O:11][CH2:10][C@@H:8]([O:9]1)[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]2[OH:3].[OH2:12]>>[O:12]=[CH:10][C@H:8]([C@@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:11])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: O
Reactant: O[C@H]1[C@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Product: O=C[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Temperature: 100 °C
Reaction time: 8.5 h

Procedure:
0.16 g (1.00 mmol) of the compound (3) was dissolved in 50 ml of water, followed by adding 4.00 g of amberlight IR-120B (proton type cation exchange resin) to the resultant solution. The system thus prepared was kept stirred for 8.5 hours at 100° C. Then, the amberlight IR-120B was removed from the reaction system by means of filtration, followed by washing the cation exchange resin with water. Further, the solvent was removed from the filtrate and the washing water by means of distillation under reduced pressure. Formation of the desired compound of the present invention, i.e., D-altrose (compound 4), was confirmed by thin layer chromatography. It was also confirmed that the raw material compound (3) was mixed with the product compound (4). The mixing ratio of these compounds (3) and (4) was about 1:1.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:13][CH:10]2[CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH2:9]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1COC(c2ccccc2)OC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2COC(c3ccccc3)OC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 2 liter round bottom flask was added 2-phenyl-1,3-dioxan-5-ol (50 g, 277 mmol), triethyl amine (42.1 g, 416 mmol), DMAP (3.39 g, 27.7 mmol) and dichloromethane (1 L). The reaction was cooled to 0° C. To this solution was added tosyl chloride (58.2 g, 305 mmol) and the reaction was stirred overnight at RT. The reaction was poured onto water (800 mL) and extracted into DCM. The organic layers were combined and concentrated to dryness. The crude mixture was recrystallized from EtOAc:Hex to afford 88 g (96% yield) of a white solid. 1H NMR (CDCl3, 400 MHz), δ: 2.44 (3H, s), 4.09 (2H, dd, J=13.6, 2 Hz), 4.27 (2H, dd, J=13.6, 1.6 Hz), 4.51 (2H, pseudo t, J=1.6 Hz), 7.33-7.36 (5H, m), 7.44-7.45 (2H, m), 7.85 (2H, d, J=8.39 Hz). Mass Spec (lo-res): Calc'd for C17H18O5S: 334.09; found: 335.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccc(F)c2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13i, and 3-fluorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 569 (M+1).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2]O.C([N:7](CC)CC)C.C1C(CC2C=CC([N:25]=[C:26]=[O:27])=CC=2)=CC=C([N:28]=[C:29]=[O:30])C=1.C(O)C>CN1CCCC1=O>[NH2:25][C:26]([O:4][CH2:1][CH3:2])=[O:27].[NH2:7][C:29]([NH2:28])=[O:30]
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Reactant: OCCO
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: CN1CCCC1=O
Product: CCOC(N)=O
Product: NC(N)=O

Procedure:
In an argon atmosphere, ethylene glycol (0.28 ml, 4.95 mmol) and triethylamine (0.5 ml) were dissolved in dry N-methylpyrrolidinone (5.0 ml) in a three-necked flask to give a solution. At room temperature, a solution of 4,4′-diphenylmethane diisocyanate (1.37 g, 5.50 mmol) in dry N-methylpyrrolidinone (5.0 ml) was slowly added dropwise to the solution. After the completion of the dropwise addition, the resultant solution was stirred for 1 hour at room temperature and was combined with a solution of the compound (4) (0.20 g, 0.55 mmol) prepared in Example 1 in dry N-methylpyrrolidinone (3.0 ml). The resultant mixture solution was stirred for 2 hours at room temperature. After the reaction, the reaction solution was poured into excess ethanol to precipitate the obtained polymer. The precipitated polymer was filtered off and dried under reduced pressure to give 1.34 g of a poly(urethane-urea) having a phosphorylcholine group represented by the above formula PUU-1 as light brown powder. The structure was identified by the 1H-NMR spectrum given below:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[H][H]>C(O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]
Reactant: OCCCCCC=CCCCCCCCCCCBr
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCCCCCCCCCCCCCCCCBr
Yield: 76.8 %

Procedure:
17-Bromoheptadec-6-en-l-ol (33.8 g) was subjected to hydrogenation in a Paar hydrogenation apparatus (50 psi initial hydrogen pressure), using ethanol as solvent and 10% palladium on charcoal as catalyst, to yield 17-bromoheptadecan-1-ol (26.1 g, 76% yield).
Reaction SMILES: [Na].[CH2:2]([N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH:3]([CH3:5])[CH3:4].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:2]([N:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CN=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=NCC(C)C)cc1
Reaction time: 10 h
Yield: 62 %

Procedure:
(a) To 100 ml of absolute ethanol is added 0.80 g of sodium, and 5.5 g of 4-(N-isobutylformimidoyl)phenol is added to the solution. Subsequently, 6.78 g of ethyl 2-bromo-2-methylpropionate is further added. The mixture is refluxed under heating and with stirring for 10 hours. After distilling off the ethanol from the reaction mixture, water is added to the residue, which is then extracted three times with benzene. The extract is washed with water twice and dried, and the solvent is removed therefrom to give 5.61 g of ethyl 2-[4-(N-isobutylformimidoyl)phenoxy]-2-methylpropionate in the form of a pale orange oil.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:10][CH:9]=1)[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:5]([CH3:6])[CH2:4][OH:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
48 g of ethyl-α-[4-(2,4-dichlorophenoxy)phenoxy]propionate was dissolved in 80 ml of anhydrous diethyl ether and the solution was added dropwise to a dispersion of 5 g of lithium aluminum hydride in 200 ml of anhydrous diethyl ether while cooling. After completion of the addition, the mixture was allowed to stand for 12 hours at room temperature and then heated under refluxing for 1.5 hours to complete the reaction. The reaction mixture was poured into an appropriate amount of ice water, and the ethereal layer was separated. The ethereal layer was again extracted with diethyl ether and the extract was dried over anhydrous sodium sulfate. The ether was removed by distillation from the dried extract, and the residue was distilled under reduced pressure to obtain 40 g of the desired product having a boiling point of 201° to 205° C./2 mmHg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[N:25]1([C:23](=[O:24])[CH:22]=[CH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)N3CCOCC3)cn2)CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C=Cc1ccc(OC2CCNCC2)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
A solution of 3-[2-(1-t-Butyloxycarbonyl piperidin-4-yloxy)pyridin-5-yl]-1-(morpholin-4-yl)prop-2-ene-1-one (0.7 grams, 0.0016 moles) in dichloromethane (20 mL) was treated with trifluoroacetic acid (1.3 mL, 0.016 moles) at room temperature. The reaction mass was stirred for 6 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mass was poured on to chilled water (30 mL) and basified with 40% lye solution (pH˜9). The layers were separated and the aqueous layer was further extracted with dichloromethane (2×20 mL). The combined organic phase was washed with water (30 mL), brine solution (30 mL) and dried over sodium sulphate. The organic phase was concentrated on rotavacuum to afford the title compound (0.48 grams).
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:5])C.[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:5])[CH3:13]
Reactant: CCOC(=O)c1nnc(S)o1
Reactant: CCN
Product: CCNC(=O)c1nnc(S)o1

Procedure:
This product (m.p. 210° C. with decomp.) was prepared by reacting 2-ethoxycarbonyl-1,3,4-oxadiazole-5-thiol with ethylamine in a manner similar to that described in the procedure of Example XVI, Part C as hereinafter set forth.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1>CCOC(C)=O>[NH2:33][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]([CH2:29][CH:30]2[CH2:31][CH2:32]2)[S:25]([CH3:28])(=[O:26])=[O:27])[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1

Procedure:
(2R)-2-Amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl) (methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one was prepared according to the procedure for Preparation XVI using N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}-piperazinyl)-2-oxoethyl](tert-butoxy)carboxamide (Step 2) (560 mg, 0.95 mmol). The resulting crude material was diluted with EtOAc and washed with satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to afford 449 mg. MS (ESI, pos. ion) m/z: 491 (M+H), (ESI, neg. ion) m/z: 489 (M−H). Calc'd for C24H31ClN4O3S: 491.05.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:11]([OH:13])=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].Cl.[NH2:16][C@@H:17]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=[CH:34][C:29]([CH2:28][C@H:17]([NH:16][C:11]([C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:13])[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC1(C(=O)O)CCCC1
Reactant: N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A solution of 1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxylic acid (672 mg, 3.36 mmol), (S)-benzyl 2-amino-3-(biphenyl-4-yl)propanoate hydrochloride (957 mg, 2.60 mmol), WSC.HCl (833 mg, 4.34 mmol), 1-hydroxy-7-azabenzotriazole (591 mg, 4.34 mmol) and DIPEA (0.759 ml, 4.34 mmol) in DMF (15 ml) was allowed to stir at room temperature for 2 hours. The reaction was quenched with H2O (10 ml) and 35% NH4OH aqueous (2 ml). The mixture was stirred for 30 minutes. The product was extracted with EtOAc, washed twice with 1 M HCl aqueous, once with H2O, and then once with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 60:40) to give (S)-benzyl 3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoate (1.143 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccc(Br)cc1)c1ccccc1Cl)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-(2-chloro-phenyl)-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI−): m/z=429.9 [M−H]−.