Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7](=O)[CH3:8].[CH3:28][O:29][C:30]([CH2:32][C:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:34])=[O:31].C[O-].[Na+].[Na]>CO>[OH:34][C:33]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:7]([CH3:8])[CH:6]=[C:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:27])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:32]=1[C:30]([O:29][CH3:28])=[O:31]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)CC(=O)CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1c(C)cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 44 h
Yield: 103.5 %

Procedure:
To a solution of 7-hydroxy-7,11,15,19-tetramethyleicosane-2,4-dione (72.5 g) and dimethyl acetonedicarboxylate (29.6 g) in methanol (190 ml) at 0° was added a solution of sodium methoxide in methanol from 2.44 g of sodium and 90 ml of methanol). The solution as stirred at room temperature for 44 hr and was concentrated on a rotary evaporator to remove approx. 100 ml of methanol. The residual solution was poured onto ice (500 g) and 20% (v/v) aqueous hydrochloric acid (45 ml). The mixture was extracted with ether (3 × 300 ml) and the combined extracts were washed with brine and dried over anhydrous sodium sulfate and were concentrated on a rotary evaporator to give 91.65 g of crude dimethyl 2-hydroxy-4-methyl-6(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as an orange oil. A 90.2 g portion of the oil was dissolved in ether (400 ml) and was washed with 20% by weight aqueous potassium carbonate (to remove the unreacted dimethyl acetonedicarboxylate), brine and was dried over anhydrous sodium sulfate. The solution was concentrated on a rotary evaporator to give 83.13 g of partially purified diester dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate. The total material was chromatographed on 2.45 kg of silica gel eluting with 20-30% by volume ether in hexane to give 30.83 g of dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:12]1[C:17](Cl)=CC=C(Cl)[CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:13][CH2:12][CH3:17])[CH:5]=1
Reactant: Clc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(O)cc1
Product: CCCc1cc(C(=O)OC)ccc1O

Procedure:
The synthesis begins with the allylation of readily available methyl-4-hydroxybenzoate (Scheme 1). The allylated phenol is then thermally rearranged in dichlorobenzene and subsequently hydrogenated to provide the desired Methyl-4-hydroxy-3-n-propylbenzoate in good overall yield. ##STR27##
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[C:17]([CH3:20])[CH:16]=[CH:15][C:14]=3[N:21]([CH3:30])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:8][CH2:7]1)C.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([N:21]([CH3:30])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[C:13]2[C:18]=1[CH:19]=[C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:31])=[O:3])[CH2:7][N:8]=1)[NH:12]2
Reactant: CCOC(=O)CC1CN=C(c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 107.3 %

Procedure:
Ethyl(2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.99 g) was dissolved in a mixed solvent of tetrahydrofuran (12 mL)-methanol (12 mL), and the mixture was ice-cooled. Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.35 g) in water (5 mL)) was added to this solution, and the mixture was stirred from under ice cooling to room temperature for 15 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (1.00 g, yield: 95%) as pale-yellow crystals. MS:450(MH+). melting point 269-270° C.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:19][C:20]([C:22]2[N:23]=[N:24][N:25](CC3C=CC=CC=3)[N:26]=2)=[O:21])[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[CH:3][CH:2]=1>CO.CCOC(C)=O.[Pd]>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:19][C:20]([C:22]2[N:23]=[N:24][NH:25][N:26]=2)=[O:21])[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[CH:3][CH:2]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn(Cc2ccccc2)n1)C(=O)NS(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nn[nH]n1)C(=O)NS(C)(=O)=O
Reaction time: 2 h

Procedure:
Next, A solution of 2-benzyl-2H-tetrazole-5-carboxylic acid ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide in MeOH/EtOAc is hydrogenated under H2 baloon by catalyst 10% Pd/C wet for 2 hours. The reaction is filtered off the catalyst and is concentrated. Reverse phase HPLC [35 to 80% ACN—H2O (0.1% TFA) over 10 min by Sunfire C18 column] provides 2H-Tetrazole-5-carboxylic acid ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (d, J=7.1 Hz, 2H), 1.66 (ddd, J=13.8, 10.9, 3.5 Hz, 1H), 1.91 (ddd, J=13.7, 10.7, 3.4 Hz, 1H), 2.54-2.63 (m, 1H), 2.79-2.86 (m, 1H), 2.86-2.93 (m, 1H), 3.24 (s, 3H), 4.15-4.28 (m, 1H), 7.27 (d, J=8.3 Hz, 2H), 7.30-7.36 (m, 1H), 7.43 (t, J=7.6 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H), 7.59-7.65 (m, 2H), 9.19 (br. s., 1H), 11.54 (br. s., 1H). HPLC retention time=1.24 min (method C): MS (m+1)=457.1.
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.Br.[CH3:9][N:10]1[CH2:16][CH2:15][C:14]2=[CH:17][C:18](=[O:22])[C:19](=[O:21])[CH:20]=[C:13]2[CH2:12][CH2:11]1>CO>[OH:22][C:18]1[C:19]([OH:21])=[CH:20][C:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:16][CH2:15][C:14]=2[C:17]=1[S:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccco1
Reactant: CN1CCC2=CC(=O)C(=O)C=C2CC1
Agent: Br
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(SCc3ccco3)c2CC1

Procedure:
Following the procedures outlined in Example 17, 0.9 g. (0.0075 mole) of furfuryl mercaptan and 2 g. (0.0073 mole) of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrobromide were reacted in 200 ml. of methanol to yield 7,8-dihydroxy-6-furfurylthio-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, free base m.p. 162°-165° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[NH2:28][C@H:29]([C:34]([NH:36][C@H:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[C@H:30]([CH2:32][CH3:33])[CH3:31].Cl>>[NH2:1][C@H:2]([C:15]([NH:28][C@H:29]([C:34]([NH:36][C@H:37]([C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42])[CH:38]([CH3:39])[CH3:40])=[O:35])[C@H:30]([CH2:32][CH3:33])[CH3:31])=[O:16])[CH2:3][CH2:4][C:5](=[O:6])[OH:14]
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C

Procedure:
37 g of Z-Glu(OBzl)OH are reacted with 32 g of H-Ile-Val-OBut.HCl and the product is worked up, as described in Example 21 (C). After catalytic hydrogenation the compound is a single substance according to chromatography.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])=[O:3].[C:11]([O:15][C:16](=[O:47])[NH:17][C:18]([C:20]1[S:21][C:22]([S:45][CH3:46])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([NH2:40])=[CH:38][C:37]([N+:41]([O-])=O)=[CH:36][C:35]=3[CH3:44])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:15][C:16](=[O:47])[NH:17][C:18]([C:20]1[S:21][C:22]([S:45][CH3:46])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([NH:40][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][C:37]([NH2:41])=[CH:36][C:35]=3[CH3:44])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2N)c1
Reactant: CS(=O)(=O)CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)CCCS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
The procedure in Example 261: step b was followed using 4-methanesulfonyl-butyryl chloride (Example 209: step a (53 mg, 0.29)), {[4-(6′-amino-2′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 130 mg, 0.23 mmol), and Et3N (192 μL, 1.38 mmol) in DCM (5 mL). After stirring for 1 h, starting material remained and an additional 20 mg of acid chloride was added. The solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. The solution was concentrated and the residue was purified by SiO2 flash column chromatography to yield 126 mg of the amide product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4Cl (1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture was vigorously stirred at 80° C. for 30 min. The solution was filtered through a 0.22 μm filter and was then partitioned between EtOAc (70 mL) and water (20 mL). The layers were separated, the organic solution was dried over sodium sulfate, and the solution was concentrated to give the crude title compound which was used without further purification. 1HMR (CDCl3): δ 7.99 (s, 1H), 7.96 (m, 2H), 7.77 (s, 1H), 7.57 (t, 1H, J=7.9 Hz), 7.43 (dt, 1H, J=1.3, 7.7 Hz), 7.10 (br s, 1H), 7.04 (br s, 1H), 6.43 (br s, 1H), 3.85 (br s, 2H), 2.92 (m, 2H), 2.88 (s, 3H), 2.56 (s, 3H), 2.20 (t, 2H, J=6.7 Hz), 1.98 (m, 2H), 1.90 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:12][Mg]Br.O>O1CCCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]([OH:6])[CH3:12])[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: O=Cc1c(F)ccc(Br)c1F
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1c(F)ccc(Br)c1F
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-2,6-difluorobenzaldehyde (5 g) in tetrahydrofuran (50 ml) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 24.9 ml) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.91 g).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[N:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]3[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C.O>[Br:1][C:2]1[CH:23]=[N:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]3[N:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:8]=3[N:9]([CH3:26])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCN1c2nc(C(F)(F)F)ccc2NC(=O)c2cc(Br)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(C(F)(F)F)nc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To a solution of the 8-bromo-5,11-dihydro-11-ethyl-2-(trifluoromethyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (200 mg, 0.52 mmol) in DMF (2.6 mL) was added NaH (20 mg, 0.78 mmol), and the mixture was heated to 50° C. for 30 min. The reaction mixture was cooled to room temperature and treated with MeI (97 μL, 1.56 mmol). After 16 h, the reaction mixture was diluted with water. The resulting mixture was extracted with EtOAc (3×). The combined organic layer was successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 8.5:1.5) to give the title compound (110 mg 53% yield) as a white foam.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[CH:33]=O>>[CH2:1]([N:3]([CH2:33][C:32]1[CH:35]=[CH:36][C:37]([O:38][CH:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[C:30]([F:29])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:15]2[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN1CCC(Oc2ccc(C=O)cc2F)CC1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 28.3 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 3-fluoro-4-(1-methylpiperidin-4-yloxy)benzaldehyde (55 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]>O>[CH2:9]([N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)C1
Solvent: O
Product: O=C(O)C1CN(Cc2ccccc2)C1

Procedure:
The N-benzylazetidine-3-carboxylic acid methyl ester product is then hydrolyzed by treatment with hot, preferably boiling, water. The completion of hydrolysis is usually marked by the transformation of the initial oily, two-phase system into a homogeneous system, and normally requires about one hour. The water may be removed from the final mixture by evaporation, and the desired product, N-benzylazetidine-3-carboxylic acid, is readily isolated as a solid. Alternatively, if it is desired to proceed with the ultimate preparation of the deprotected azetidine-3-carboxylic acid, the major part of the water may be removed (e.g., by evaporation), and the crude, wet N-benzyl acid subjected to a conventional deprotection treatment, e.g., palladium catalyzed hydrogenolysis.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([C:28]#[C:29][CH2:30][O:31][CH2:32][CH2:33][NH:34]C(=O)C(F)(F)F)[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]>[NH4+].[OH-]>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([C:28]#[C:29][CH2:30][O:31][CH2:32][CH2:33][NH2:34])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1nc(=O)n([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)cc1C#CCOCCNC(=O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: NCCOCC#Cc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)nc1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The purified protected triphosphate 12 was taken up in concentrated aqueous NH4OH (4 mL) and stirred for 2.5 h at room temperature. The reaction mixture was concentrated to give the propargylethoxyamido nucleotide 13. The concentrated compound was then formulated as a bulk with 0.1M TEAB pH 7.0 to a concentration of 2.6 mM. The concentration and purity of the formulated bulk were confirmed by UV/Vis spectroscopy and analytical ion pair HPLC as described above, respectively. See FIG. 5.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]([NH:47][C:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45](=[O:46])[NH:47][C:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 63 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][CH:11]1[CH2:17][C:16]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:15]=2[CH2:14][CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][CH2:24][CH2:25]Br.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:3]([NH:10][CH:11]1[CH2:12][CH2:13][CH2:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH:24]([CH3:25])[CH3:23])=[CH:18][C:16]=2[CH2:17]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reactant: CCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reaction time: 0.5 h

Procedure:
Under nitrogen, to a suspension of sodium hydride (60% in oil, 47 mg) in N,N-dimethylformamide (3 ml) was dropwise added 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (300 mg) in N,N-dimethylformamide (2 ml) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To this one was added n-propyl bromide (0.10 ml), and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=50:1 to 30:1) to give N-benzyl-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (278 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.[Ag]=O>[C:19]1([CH2:18][CH2:17][N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C2CCCNC2)cc1OC
Reactant: BrCCc1ccccc1
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2CCCN(CCc3ccccc3)C2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
500 mg of silver oxide were added to a mixture of 1 g of 3-(3',4'-dimethoxyphenyl)-piperidine in 5 ml of chloroform and then 0.7 ml of phenethyl bromide was added thereto dropwise. The mixture was stirred for 6 hours at room temperature and then 250 mg of silver oxide and 0.35 ml of phenethyl bromide were added thereto. The mixture was stirred at room temperature for 16 hours and was filtered to remove insolubles. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 6-3-1 cyclohexane-chloroform-triethylamine mixture yielded 1.045 g of amorphous N-(β-phenylethyl)-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]CC)=[O:13])[NH:9]2)=[CH:5][C:4]=1[C:17]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]3[CH3:34])=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=2)[O:19][N:18]=1.[OH-].[Li+].O>C1COCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][C:4]=1[C:17]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]3[CH3:34])=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=2)[O:19][N:18]=1
Reactant: CCOC(=O)c1cc2cc(-c3noc(-c4ccc(N5CCCCC5C)c(C(F)(F)F)c4)n3)c(OC)cc2[nH]1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2[nH]c(C(=O)O)cc2cc1-c1noc(-c2ccc(N3CCCCC3C)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
To a solution of example 20 (71 mg; 0.13 mmol) in THF (4.5 mL) was added lithium hydroxide (16 mg; 0.67 mmol) (1.50 ml), followed by water (2 mL) and the resulting mixture was stirred at RT for 24 hours. The solution was diluted with NaOH (0.1 M) washed with Et2O and acidified to pH 1 with 1M HCl (1 M). The formed precipitate was filtered, washed with water and dried under high vacuum to give the title compound as an off-white solid (56 mg, 83%). 1H NMR (DMSO-d6) δ 12.97 (bs, 1H), 11.86 (bs, 1H), 8.45-8.41 (m, 1H), 8.37-8.36 (m, 1H), 8.31 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 1H), 3.90 (s, 1H), 3.15 (m, 1H), 2.97-2.93 (m, 1H), 2.64-2.57 (m, 1H), 1.80-1.76 (m, 2H), 1.63-1.29 (m, 4H), 0.78 (d, J=6 Hz, 3H). HPLC (Method A) Rt 5.43 min (Purity: 99.1%). LC/MS (method A): 501.3 (M+H)+.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14]O.S(=O)(=O)(O)O>ClCCCl>[C:1]1([C:11]([O:13][CH3:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1cccc2ccccc12
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: COC(=O)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
The synthesis method of Example 7-(1) was applied. 1--Naphthoic acid (4.97 g), methanol (10 ml), 1,2-dichloroethane (12 ml) and concentrated sulfuric acid (0.6 ml) were used as reagents and the mixture was stirred at 60° C. for 17 hours. After the reaction, the mixture was extracted with ether to give 4.35 g of a pale-yellow transparent liquid (yield 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OCC)(OCC)(OCC)[CH3:22]>C(O)(=O)C>[CH3:21][C:22]1[N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCc1ccccc1
Solvent: CC(=O)O
Product: Cc1nc2cnc3ccccc3c2n1CCc1ccccc1

Procedure:
Using the method of Example 49, 3-amino-4-[2-(phenyl)ethylamino]quinoline (from Example 130, Part B) was reacted with triethyl orthoacetate and acetic acid to provide 2-methyl-1-[2-(phenyl)ethyl]-1H-imidazo[4,5-c]-quinoline.