Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[CH2:27]([O:29][CH2:30][C:31](O)=[O:32])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:27]([O:29][CH2:30][C:31]([N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:9]2[C:10]([CH3:11])=[C:5]([O:4][C:3]3[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:2]=3[F:1])[N:6]=[CH:7][N:8]=2)[CH2:14][CH2:15]1)=[O:32])[CH3:28]
Reactant: CCOCC(=O)O
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCOCC(=O)N1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2C)CC1
Temperature: 120 °C
Yield: 58.8 %

Procedure:
Mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (76 mg, 0.2 mmole), 2-ethoxyacetic acid (0.26 mmole, 1.3 eq), HATU (0.26 mmole, 1.3 eq), and TEA (0.4 mmole, 2 eq) in 2 mL THF was heated under microwave irradiation at 120° C. for 30 minutes. Mixture was purified by HPLC to give compound C163 as a white solid (55 mg, 59%). 1H NMR (CDCl3, 400 MHz) δ 1.25 (t, 3H), 1.86-1.90 (m, 2H), 2.01-2.09 (m, 2H), 2.22 (s, 3H), 3.10 (s, 3H), 3.51-3.69 (m, 2H), 3.59 (q, 2H), 3.76-3.87 (m, 2H), 4.21 (s, 2H), 5.41-5.44 (m, 1H), 7.43 (t, 1H), 7.78-7.82 (m, 2H), 8.21 (s, 1H). Exact mass calculated for C21H26FN3O6S 467.2, found 468.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[C:12]([NH:16][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1F
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a suspension of 4-chloro-2-fluorobenzoic acid (0.3494 g, 2.00 mmol) in methylene chloride (10 ml) were added t-butyl amine (0.32 ml, 3.05 mmol) and HOBt (0.3248 g, 2.40 mmol), and then WSC HCl (0.4596 g, 2.40 mmol) was added and stirred for 3 hours. The reaction mixture was added into water and extracted three times with ethyl acetate. The combined extracts were dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (0.4403 g; 96%).
Reaction SMILES: [BH4-].[Na+].[S:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C@H:22]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[C:32](=[O:34])[CH3:33])[CH2:23]1)[C@@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6].C(O)(=O)C.C(Cl)(Cl)Cl>C(O)C>[S:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C@H:22]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[CH:32]([OH:34])[CH3:33])[CH2:23]1)[C@@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium borohydride (60 mg) was added to a solution of 6-(pregn-5-en-20-one-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (250 mg) in absolute ethanol (7 ml). After stirring at room temperature for 4 hours, the solution was cooled and glacial acetic acid (10 ml) was slowly added. The solution was added to chloroform (100 ml) and successively washed with water (3 X), 1N sodium bicarbonate (2 X), and water (1 X) and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the product as a fine white solid. The 200 MHz NMR spectrum of the peracetylated derivative was in accord with the desired structure. TLC data and Rf values are given in the above Table.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11](#[N:14])[CH2:12][CH3:13].[OH-:15].[Na+]>O>[CH3:1][C:2]([NH:14][C:11](=[O:15])[CH2:12][CH3:13])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccccc1
Reactant: [OH-]
Reactant: CCC#N
Agent: [Na+]
Solvent: O
Product: CCC(=O)NC(C)(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of (2-methyl-propenyl)-benzene (2.6 g, 19.67 mmol) in propionitrile (20 g, 363 mmol) H2SO4 (39.33 mmol) was added at 10° C. The mixture was stirred at room temperature for 16 h. Then the mixture was poured into water and adjusted to an alkaline pH with NaOH. The aqueous layer was extracted three times with ethyl acetate, the organic layers combined, washed with water and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (1.6 g, 40%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N:8]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:21]#[N:22].C[Si](Cl)(C)C.[CH2:35]([Mg]Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC>[F:17][C:18]1[CH:19]=[C:20]([C:21]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N:8]=2)([NH2:22])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccnc(Br)c1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)ccn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried round bottomed flask was added nBuLi (2.5 M in hexanes, 0.95 ml, 2.38 mmol, 1.17 eq) at −60° C. under N2. An Et2O solution (5 mL) of 2-bromo-4-trifluoromethylpyridine (448 mg, 2.0 mmol) was added dropwise at −60 to −55° C. The resulting solution was stirred at the above temperate for 30 min. The mixture was cooled to −78° C., an Et2O solution (2 mL) of 3-fluoro-5-trifluoromethyl-benzonitrile (390 g, 2.06 mmol) was added dropwise. The resulting solution was stirred −78 to −70° C. for 1.5 h. Pretreated TMSCl (0.26 ml) was added dropwise at −78° C. The mixture was stirred at −78° C. for 15 min, and then warmed up to r.t. for 45 min. It was cooled back to −78° C., and benzyl magnesium chloride (1.0 ml, 2.0 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, and then at r.t. for 0.5 h. It was quenched by adding sat'd NH4Cl and 1N HCl, and stirred for 10 min. It was extracted with EtOAc, washed with 1N NaOH, sat'd NaHCO3, H2O, brine, dried (MgSO4), filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(4-(trifluoromethyl)pyridin-2-yl)ethanamine as light brownish gum (0.57 g, yield: 66.6%). LC-MS ESI (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=3.32 min, 429.13 (M+H).
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:14][N:15](CCO)[CH3:16]>>[N:1]1([CH2:6][C:7]([O:9][CH2:10][CH2:11][N:15]([CH3:16])[CH3:14])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCO
Reactant: CCOC(=O)CN1CCCC1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOC(=O)CN1CCCC1
Temperature: 150 °C

Procedure:
To a mixture of 80 g (0.51 mol) of ethyl 1-pyrrolidineacetate and 0.5 g of sodium hydride (in the form of a 60% by weight suspension in mineral oil) was added 48 g (0.54 mol) of 2-(N,N-dimethylamino)ethanol. The mixture was purged with nitrogen gas, heated gradually and then maintained at about 150° C. while collecting the ethanol by-product in a Dean-Stark trap. The liquid reaction product was distilled at 85° C. at a pressure of 100 μmHg to provide 2-(N,N-dimethylamino)-ethyl 1-pyrrolidineacetate. The structure of the product was confirmed by nuclear magnetic resonance and infrared spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:24][CH3:25])[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:25])[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: CNCC(C)C
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.01 g, 10.5 mmol) and N-isobutyl-methylamine (4.56 g, 52.3 mmol) in DMSO (30 mL) at 55° C. according to the general procedure C. Obtained as a yellow oil (1.84 g, 52%).
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH2:41][CH3:42])[C:9]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH2:41][CH3:42])[C:9]=2[C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[CH2:6][CH2:7]1
Reactant: CCCOc1cc(CN2CCC(N3CCc4nc(CCC)c(C(=O)OC)cc4C3=O)CC2)cc(C2CC2)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCOc1cc(CN2CCC(N3CCc4nc(CCC)c(C(=O)O)cc4C3=O)CC2)cc(C2CC2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-4′-fluoro-6-propoxybiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (475 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (360 mg).
Reaction SMILES: [CH2:1]([C:8]1([CH:17]=[CH:16][C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH2:13]1)[CH2:9][CH:10]([OH:12])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=[O:28])[CH:26]=[CH2:27].CC1C=CC(S(O)(=O)=O)=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C1(C)C=CC=CC=1>[C:25]([O:12][CH:10]([NH2:11])[CH2:9][C:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH2:17]1)(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)O
Reactant: NC(O)CC1(Cc2ccccc2)C=CC(Cc2ccccc2)=CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: Cc1ccccc1
Product: C=CC(=O)OC(N)CC1(Cc2ccccc2)C=CC(Cc2ccccc2)=CC1
Temperature: 80 °C

Procedure:
In a three-aperture flask, 10.5 g (33 mmol) of p-dibenzyl-aminophenethyl alcohol, 9.51 g (132 mmol) of acrylic acid, 0.56 g (3.3 mmol) of p-toluene sulfonate, and 30 mL of dehydrated toluene were poured, and the mixture was heated at 80° C. under an argon atmosphere with stirring. To the reaction solution, 3.8 g (18.2 mmol) of dicyclohexylcarbodimide and 2.5 g (16.5 mmol) of 4-pyrrolidinopyridine were added, and the reaction solution was further heated with stirring for 5 hours. The reaction solution was cooled to the room temperature and then diluted with toluene, followed by washing with water three times. The toluene solution was dried with anhydrous magnesium sulfate, and then the solvent was distilled away to purify the toluene solution by silica gel chromatography using a mixture solvent of hexane/ethyl acetate (4/1) as an eluent to thereby synthesize 4.05 g (yield: 33% by mass) of p-dibenzyl-aminophenethyl acrylate of the exemplified compound No. 23 represented by the following structural formula.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[C:9]([F:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:19]1[N:28]=[C:27]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)[C:26]([F:34])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C([O-])=O.[NH4+]>CO.[Pd]>[F:17][C:9]1[C:10]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5].[F:34][C:26]1[C:27]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)=[N:28][CH:19]=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(F)c(-n2nccn2)nc1Cl
Reactant: COC(=O)c1cc(F)c(-n2ccnn2)nc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cnc(-n2ccnn2)c(F)c1
Product: COC(=O)c1cnc(-n2nccn2)c(F)c1

Procedure:
The mixture of methyl 2-chloro-5-fluoro-6-(2H-1,2,3-triazol-2-yl)nicotinate and methyl 2-chloro-5-fluoro-6-(1H-1,2,3-triazol-1-yl)nicotinate obtained in the 1st step was dissolved in MeOH (5 ml) and ammonium formate (300 mg) and 10% Pd/C (200 mg) were added thereto, followed by reflux for 4.5 hours. The reaction solution was adjusted to room temperature and filtered through Celite, the filtrate was collected, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A white solid of methyl 5-fluoro-6-(2H-1,2,3-triazol-2-yl)nicotinate (250 mg) and a white solid of methyl 5-fluoro-6-(1H-1,2,3-triazol-1-yl)nicotinate (160 mg) were thus obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]=2)[C:5]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:4]=2[O:3]1.C(OCC)(=[O:29])C>>[C:24]([C:21]1[CH:22]=[CH:23][C:4]2[O:3][C:2]([CH3:26])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10][N+:9]=3[O-:29])[C:5]=2[CH:20]=1)#[N:25]
Reactant: CC1(C)CC(c2ccc(-c3ccccc3)cn2)c2cc(C#N)ccc2O1
Reactant: CCOC(C)=O
Product: CC1(C)CC(c2ccc(-c3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4-(5-phenyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-phenylpyridine N-oxide of melting point 174°-176° C. (from ethyl acetate).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:25]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][CH2:27][OH:28])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl>[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:25]([C:29]#[C:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26][CH:27]=[O:28])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc(C(C#Cc2ccccc2)CCO)cc1OC1CCCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(C(C#Cc2ccccc2)CC=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 61.8 %

Procedure:
To a solution of oxalyl chloride (0.265 mL, 3.0 mmol) in CH2Cl2 (11 mL) at -78° C. under an argon atmosphere was added DMSO (0.43 mL, 6.0 mmol). After 0.03 h, (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-5-phenylpent4ynol (0.96 g, 2.74 mmol) was added in CH2Cl2 (15 mL). After 0.25 h, triethylamine (2.0 mL, 13.7 mmol) was added. The mixture was allowed to warm to room temperature. Aqueous NH4Cl was added, the mixture was extracted three times with CH2Cl2, the organic extract was washed with 1N HCl, was dried (Na2SO4) and was evaporated. Purification by flash chromatography (silica gel, 25% EtOAc/Hex) provided the title compound as a yellow oil (0.59 g, 62%).MS(EI) m/e 349 [M+H]+.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH2:14]([O:21][C:22]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (20.0 g, 116.2 mmole) in dry DMF (150 mL) at RT was added N-(benzyloxycarbonyloxy)succinimide (31.84 g, 127.76 mmole) and triethylamine (13.0 g. 127.76 mmole). After 12 h, the reaction contents were poured into H2O (150 mL) and extracted with EtOAc (2×200 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure gave a yellow oil. Purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (34.48 g. 97%) as a white solid: MS (ES) m/e 307 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][NH2:11])[CH:3]1[CH3:13].C(N(CC)CC)C.[S:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22]1>C(Cl)Cl.CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH2:9][CH2:10][NH:11][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])([CH3:12])[CH:3]1[CH3:13]
Reactant: O=C(Cl)c1ccsc1
Reactant: CC1CCN(C)C(C)C1(C)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC1CCN(C)C(C)C1(C)CCNC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
A solution of 1,2,3,4-tetramethyl-3-piperidineethanamine (2.9 g, I6 mmol), triethylamine (10 mL) and methylene chloride (25 mL) was cooled to 0° C. and 3-thiophenecarboxylic acid chloride (2.3 g, 16 mmol) in methylene chloride (15 mL) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with ether (200 mL) and washed with saturated sodium bicarbonate (2×50 mL), water (50 mL), then brine (50 mL). The organic layer was separated, dried over Na2SO4 and treated with charcoal. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ether (100%), then 2% diisopropylamine/ether, followed by 5% isopropylamine/ether to afford 2.9 g (62%) of N-[2-(1,2,3,4-tetramethyl-3-piperidinyl)-ethyl]-3-thiophenecarboxamide as an oil. The product was dissolved in ethanol (7 mL), cooled to 0° C., treated with 3.2N ethanolic HCl and diluted with ether to afford 3.1 g of the hydrochloride salt as a yellow solid. The salt was recrystallized from ethanol/ether and had a melting point of 228°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][C:28]([CH:31]([OH:35])[CH2:32][NH:33][CH3:34])=[CH:27]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:33]([CH2:32][CH:31]([C:28]4[CH:29]=[CH:30][O:26][CH:27]=4)[OH:35])[CH3:34])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ccoc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2ccoc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(3-furyl)-2-(methylamino)ethanol (Preparation 64) (54 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5.0 mL) was stirred at room temperature for 24 hours. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (102 mg) as a white solid.
Reaction SMILES: [N:1]1([C:30](OC(C)(C)C)=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:45](C(O)=O)[CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CCN(CC)CC>[NH:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:45]([C:30]([N:1]1[CH2:29][CH2:28][CH2:27][C@@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:31])[CH2:46][O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared as an oily product from 12 g of Boc-D-Pro-Arg(NO2)-OBzl, 60 ml of 4N HCl-AcOEt, 3.3 ml of Et3N, 7 g of Boc-Ser(Bzl)-OH, 4.2 g of HOBt and 5.1 g of DCC in the same manner as in Example 7-(2).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)([CH3:5])[CH2:3][OH:4].I[CH3:18].[H-].[Na+].O>CS(C)=O.CCOCC>[CH3:18][O:4][CH2:3][C:2]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)([CH3:1])[CH3:5]
Reactant: Cc1ccc2cccc(C(C)(C)CO)c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COCC(C)(C)c1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution of 2-methyl-2-(2-methylquinolin-8-yl)propan-1-ol (0.43 g, 2.00 mmol) and iodomethane (0.37 mL, 5.99 mmol) in DMSO (10 mL) was added NaH (0.16 g, 3.99 mmol) at ambient temperature and stirred at ambient temperature for 30 minutes. Water (10 mL) and ether (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 8-(1-methoxy-2-methylpropan-2-yl)-2-methylquinoline (0.43 g, 93.0%) as an oil.