Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[C:9](=O)([O:12]C)[O:10][CH3:11]>C[O-].[Na+].CO>[C:9](=[O:12])([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])[O:10][CH3:11]
Reactant: COC(=O)OC
Reactant: OCC(F)(F)C(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OCC(F)(F)C(F)F
Temperature: 120 °C
Yield: 48.5 %

Procedure:
In a flask (500-ml volume) equipped with 10 distillation columns, 2,2,3,3-tetrafluoropropanol (100 g, 0.76 mol), dimethyl carbonate (205 g, 2.3 mol) and a 28% sodium methoxide/methanol solution (1.4 g) were charged. The flask was heated to 120° C. to allow the starting materials to react for 10 hours while removing the methanol from the distillation columns by evaporation. After allowing the mixture to cool to room temperature, an aqueous solution of ammonium chloride was added to the mixture and the mixture was shaken to remove the sodium methoxide. The organic layer was washed with water, dried and distilled to give methyl 2,2,3,3-tetrafluoropropyl carbonate as a colorless liquid (70 g, yield 49%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 9 and FIG. 10 respectively and the mass spectrometry spectrum (M/e=190).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([C@H:16]([C:43]([NH:45][C@H:46]1[CH2:52][CH2:51][S:50][C@H:49]2[CH2:53][CH2:54][CH2:55][C@@H:56]([C:57]([O:59][CH3:60])=[O:58])[N:48]2[C:47]1=[O:61])=O)[CH2:17][CH2:18][C@@H:19]([C:24](=[O:42])[NH:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][C@@H:36]([C:37]([O:39][CH3:40])=[O:38])[N:28]2[C:27]1=[O:41])[CH2:20][C:21](O)=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[NH4+:69].[OH-:70]>C(Cl)Cl>[NH2:69][C:21](=[O:22])[CH2:20][C@H:19]([C:24](=[O:42])[NH:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][C@@H:36]([C:37]([O:39][CH3:40])=[O:38])[N:28]2[C:27]1=[O:41])[CH2:18][CH2:17][C@H:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:43]([NH:45][C@H:46]1[CH2:52][CH2:51][S:50][C@H:49]2[CH2:53][CH2:54][CH2:55][C@@H:56]([C:57]([O:59][CH3:60])=[O:58])[N:48]2[C:47]1=[O:61])=[O:70]
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)CC(=O)O)C(=O)N21
Reactant: [NH4+]
Reactant: [OH-]
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)CC(N)=O)C(=O)N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
Isobutyl chloroformate (3.0 mg, 0.022 mmol) was added to a 0° C. solution of (3R,6R)-6-benzyl-7-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-3-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamoyl)-7-oxoheptanoic acid (16 mg, 0.021 mmol) and NMM (2.5 mg, 0.025 mmol) in DCM (0.1 mL). After 30 min at 0° C., NH4OH (1.5 mg, 0.041 mmol) was added. The ice bath was removed and the reaction mixture was stirred at rt for 1 hr. The reaction mixture was concentrated. The residue was purified by RP prep-HPLC (Method A) to give methyl (4S,7S,10aS)-4-(((2R,5R)-7-amino-2-benzyl-5-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)carbamoyl)-7-oxoheptanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (8.5 mg, 0.010 mmol, 53% yield) as a colorless oil. Anal. Calcd. for C37H51N5O9S2 m/z 773.7. found: 7749.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.53 (1H, d, J=6.6 Hz), 7.28-7.11 (6H, m), 6.38 (1H, br. s.), 6.18 (1H, br. s.), 5.43-5.36 (2H, m), 5.20-5.14 (1H, m), 5.14-5.00 (3H, m), 4.03-3.80 (2H, m), 3.72 (3H, s), 3.69 (3H, s), 3.25-3.08 (2H, m), 2.97-2.89 (1H, m), 2.89-2.80 (2H, m), 2.79-2.66 (2H, m), 2.61-2.36 (4H, m), 2.32 (1H, dd, J=14.8, 4.9 Hz), 2.24-2.15 (1H, m), 2.08-1.94 (4H, m), 1.86-1.76 (1H, m), 1.74-1.57 (8H, m), 1.57-1.46 (2H, m).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[F:12][C:13]([F:30])([F:29])[C:14]1[C:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[F:30][C:13]([F:12])([F:29])[C:14]1[C:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=3)=[O:25])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-c2ncccc2C(F)(F)F)cc1
Product: C[Si](C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3C(F)(F)F)cc2)cc1
Yield: 68.3 %

Procedure:
Compound A-04 can be synthesized according to method 2. Just R1 and R3 of Scheme 2 are, respectively, CF3 and p-SiMe3. namely: compound 6 is 4-trimethylsilyl aniline (compound 6a 35 mg); compound 10 is 4-(3-trifluoromethylpyridine-2-yl)benzoic acid (compound 10b); compound 12 is compound A-04 (60 mg, yield 68.3%).
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40]CC)=[O:39])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+]>O1CCCC1.C(O)C>[C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:13][CH:12]([NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:38]([OH:40])=[O:39])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C3CCCCC3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (0.26 g) was dissolved in a mixed solvent of tetrahydrofuran (5 ml) and ethanol (5 ml), aqueous lithium hydroxide monohydrate (0.18 g) solution (5 ml) was added, and the mixture was stirred at room temperature for 3 hour. The reaction mixture was concentrated under reduced pressure, the residue was weakly acidified with 1N hydrochloric acid, and extracted with chloroform. The organic layer was successively washed with water and saturated brine, the solvent was evaporated under reduced pressure, and diisoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 0.20 g of the titled compound as yellow-white powder (Yield: 82%)
Reaction SMILES: C1(N2C(=O)C3=CNC4[CH:14]=[C:15]([N:19]5[CH2:24]CN[CH2:21][CH2:20]5)C=CC=4C3=N2)C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:32]3[C:33]([C:38](=[O:49])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[N:40]=3)=[CH:34][NH:35][C:36]=2[CH:37]=1.CN1CCNCC1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([N:39]2[C:38](=[O:49])[C:33]3=[CH:34][NH:35][C:36]4[CH:37]=[C:28]([N:27]5[CH2:21][CH2:20][N:19]([CH3:24])[CH2:15][CH2:14]5)[CH:29]=[CH:30][C:31]=4[C:32]3=[N:40]2)=[CH:42][CH:43]=1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)ccc3c-2nn1-c1ccccc1
Reactant: COc1ccc(-n2nc3c4ccc(N)cc4[nH]cc-3c2=O)cc1
Agent: CN1CCNCC1
Product: COc1ccc(-n2nc3c4ccc(N5CCN(C)CC5)cc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 14a using 13c and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.32 (3H, s), 2.67 (4H, brm), 3.40 (4H, brm), 3.85 (3H, s), 6.88 (2H, m), 7.02 (1H, d, J=2.47 Hz), 7.31 (1H, dd, J=9.06, 2.20 Hz), 7.66 (2H, m), 8.16 (1H, d, J=9.06 Hz), 8.52 (1H, s). m/z 390.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[C:15]([CH2:16][C:17]([O:19]CC)=O)=[N:14][N:13]=[N:12]1.[CH:22](OCC)(OCC)OCC.[Cl-].[Cl-].[Cl-].[Al+3]>ClC(Cl)C(Cl)Cl>[NH:14]1[C:15]([C:16]2[C:17](=[O:19])[N:6]3[C:2]([O:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=43)=[N:1][CH:22]=2)=[N:11][N:12]=[N:13]1
Reactant: Nc1nc2ccccc2o1
Reactant: CCOC(=O)Cc1nnn[nH]1
Reactant: CCOC(OCC)OCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: O=c1c(-c2nnn[nH]2)cnc2oc3ccccc3n12

Procedure:
A mixture of 1.34 g (10.0 mmole) of 2-aminobenzoxazole, 1.56 g (10.0 mmole) of ethyl tetrazol-5-ylacetate, 1.65 g (11.1 mmole) of triethyl orthoformate and 0.3 g (2.2 mmole) of aluminum trichloride in 25 ml of 1,1,2,2-tetrachloroethane was heated under a nitrogen atmosphere at 125° to 130° C. for about 19 hours. The mixture was cooled and the resulting solid was separated by filtration and washed with methanol to provide 0.72 g (28%) of crude-3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]benzoxazol-4-one. Infrared spectral analysis of the crude product showed that it was the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]1([CH2:24][CH3:25])[CH2:23][O:22][CH2:21]1>CN(C)C=O>[CH2:24]([C:20]1([CH2:19][O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH2:21][O:22][CH2:23]1)[CH3:25]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCC1(COCCCCBr)COC1
Solvent: CN(C)C=O
Product: CCC1(COCCCCOc2ccc(C(=O)O)cc2)COC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
In a 300 ml three neck flask, 5.2 g (31 mmol) of ethyl p-hydroxybenzoate, 4.7 g (34 mmol) of potassium carbonate anhydride, and 7.8 g (31 mmol) of the 3-[(4-bromobutoxy)methyl]-3-ethyloxetane were dissolved in 50 ml of dimethylformamide. After the solution remained turbid was heated to a temperature of 80° C. and stirred for 4 hours, the solvent was completely distilled out in a vacuum. To the resulting yellow oily substance were added 15 ml of a 7% sodium hydroxide aqueous solution and 15 ml of methanol. The mixture was refluxed for two and half hours. 1 N (normality) of hydrochloric acid was added to the mixture such that the pH is adjusted to about 3. The resulting white precipitate was filtered and dried in a vacuum thereby obtaining 8.6 g (28 mmol) of 4-[7-(3-ethyl-3-oxetanyl)-1,6-dioxaheptyl]benzoic acid (yield: 89%, identified with 1H-NMR). The resulting compound was no more purified and used in the following reaction.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:8]([Cl:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl-:15].[CH2:8]([N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: ClCc1ccccc1
Agent: *O[Si](*)(C)C
Product: CC[N+](CC)(CC)Cc1ccccc1
Product: [Cl-]

Procedure:
In the manner described in Example 4, 101 g of triethylamine (1 mole) was dissolved in 200 g of polydimethylsiloxane. 137 g (1 mole) of benzyl chloride was stirred into this solution. After a reaction time of 5 hours at 80° C., a large amount of solid had formed, which was filtered out and washed with methyl ethyl ketone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[ClH:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[NH:36][CH2:35][CH2:34][CH2:33]2.C([BH3-])#N.[Na+]>C(O)(C)C>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][CH:14]([N:36]3[C:37]4[C:32](=[CH:31][C:30]([O:29][CH3:28])=[C:39]([O:40][CH3:41])[CH:38]=4)[CH2:33][CH2:34][CH2:35]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc2c(cc1OC)NCCC2
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1ccc(C2(C#N)CCC(N3CCCc4cc(OC)c(OC)cc43)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexanone (3.5 mmol), triethylamine (3.5 mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroquinoline hydrochloride (3.5 mmol) and sodium cyanoborohydride (5 mmol) in 50 ml iso-propanol was stirred at 25° C. for several days, poured onto ice water and extracted with ethyl acetate. The salt was prepared from anhydrous HCl in ethyl acetate. ##STR15##
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH3:12])[CH:6]=1>C(O)(C)(C)C>[OH:11][C:10]1[CH:9]=[CH:8][C:7]([CH:12]=[O:3])=[CH:6][CH:5]=1.[OH:11][C:10]1[CH:5]=[CH:6][C:2]([C:1]([OH:4])=[O:3])=[CH:8][CH:9]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(O)cc1
Product: O=Cc1ccc(O)cc1

Procedure:
The catalyst (1 g) prepared in Example 3 was reacted according to the operating procedure of Example 2, except that the acetic acid was replaced by tert. butanol and the reaction temperature was 80° C. The p-cresol conversion was 50%. 2.2 mmole of p-hydroxybenzaldehyde and 0.2 mmole of p-hydroxybenzoic acid were obtained.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH2:8]=[O:9]>>[CH3:6][C:5]([CH:4]([CH2:8][OH:9])[C:2](=[O:1])[CH3:3])=[CH2:7]
Reactant: CC(=O)C=C(C)C
Reactant: C=O
Product: C=C(C)C(CO)C(C)=O

Procedure:
contacting mesityl oxide with formaldehyde in the presence of 0.1 to 10 mol percent of a bicyclic amidine per mol of mesityl oxide whereby to obtain 2-methyl-3-hydroxymethyl-pent-1-en-4-one; and
Reaction SMILES: [H-].[Na+].N1C=CN=[CH:4]1.[CH2:8]([NH:15][C:16](=[O:40])[C@@H:17]([CH2:38][OH:39])[NH:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CI>O1CCCC1.O>[CH2:8]([NH:15][C:16](=[O:40])[C@@H:17]([CH2:38][O:39][CH3:4])[NH:18][C:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
To a mixture of sodium hydride (6.59 g), imidazole (1.564 g) and tetrahydrofuran (150 ml), a solution of Example 5 product (i.e. N-benzyl-N2-trityl-D-serinamide, 50 g) in tetrahydrofuran (500 ml) was slowly added at −15° C. and the mixture was stirred for 45 minutes at −15° C. Methyl iodide (24.38 g) was slowly added to the mixture for 15 minutes at −15° C. to −5° C. and the formed reaction mixture was stirred at −5° C. for 3 hours. The reaction mixture was cooled to 0° C., water was added to it and then the tetrahydrofuran was recovered completely under vacuum at 40° C. Hexane (250 ml) was added to it and stirred for 15 minutes. The layers were separated and the aqueous layer was neutralized with acetic acid till pH=6.0. Dichloromethane (2×150 ml) was added to the aqueous layer and layers were separated. Oily product was recovered under vacuum at 35° C. to 40° C. from the organic layer. Hexane (100 ml) was added to the oily product and the solution formed was stirred for 15 minutes, filtered and dried to get the titled product of Formula Va.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.C[Si]([N:37]=[C:38]=[O:39])(C)C>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:38]([NH2:37])=[O:39])=[CH:25][CH:24]=1
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a stirred suspension of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (2.8 g, 6.8 mmol) and Et3N (9.1 mL, 68.5 mmol) in CH2Cl2 (50 mL) was added trimethylsilylisocyanate (3.8 mL, 27.4 mmol), and the resulting solution was stirred at rt for 1.5 h. The solution was then partitioned between CH2Cl2 (500 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (5% to 10% CH3OH in CH2Cl2) afforded the title compound as a white solid (2.2 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CCOCC.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: Nc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Yield: 66.3 %

Procedure:
To a suspension of 1-(4-fluorophenyl)-4-[ (4-nitrophenyl)methyl ]piperazine (1.5 g, 0.005 M) in 15 ml of anhydrous ether is added dropwise a solution of 15 ml of titanium trichloride in water (20% solution in water), under nitrogen at room temperature. After complete addition, the mixture is quenched with 10% ammonium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is washed with water, dried (anhydrous sodium sulfate), and concentrated to a yellow solid. This, after recrystallization from ethyl acetate/Skellysolve® B, gives 900 mg (64%) of white crystalline 1-[ (4-aminophenyl)methyl ]-4-(4-fluorophenyl)piperazine of melting point 130° - 132° C.
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[S:20][CH2:19]1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+]>[C:6]([C@@H:8]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[S:20][CH2:19]1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 2 h
Yield: 58 %

Procedure:
In 4 ml of 0.1N aqueous sodium hydroxide solution is dissolved 0.15 g of 3(R)-[1(S)-ethoxycarbonyl-3-(4-piperidyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide as obtained in Example 72, and the solution is allowed to stand at room temperature for 2 hours. The solution is made weakly acidified with 1 ml of acetic acid, and purified by Amberlite XAD-2 column chromatography (methanol:water=1:1). The eluate is concentrated under reduced pressure, and the residue is lyophilized to give 0.06 g of 3(R)-[1(S)-carboxy-3-(4-piperidyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH2:20][OH:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C)C=O>[NH2:18][C@@H:19]([CH:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)[CH2:20][OH:21]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H](CO)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC([C@H](N)CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 4-((1S)-1-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2-hydroxyethyl)piperdine-1-carboxylate (0.95 g, 2.03 mmol) was added 20% piperidine in dimethylformamide (20 mL) all at once. The reaction was stirred overnight at 25° C. The dimethylformamide was evaporated off and the crude residue was subjected to flash chromatography using methylene chloride-methanol-ammonium hydroxide, 95-5-0.1% as eluent. This yielded the amine product as an oil that crystallized upon standing (0.392 g, 80%). MS (+ESI) 245.2 ([M+M]+); 189.2; 150.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O>CO.[Cl-].[Na+].O>[CH2:5]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)c(F)c1
Temperature: 70 °C
Yield: 184.1 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid (25.0 g) in methanol (150 mL) was added sulfuric acid (20.0 mL), and the mixture was heated under reflux for 1 day. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in DMF (200 mL) were added potassium carbonate (33.2 g) and benzyl bromide (21.0 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in a mixed solvent of THF (100 mL) and methanol (100 mL) was added 2 M aqueous sodium hydroxide solution (160 mL), and the mixture was stirred with heating at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (36.3 g).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][CH3:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([OH:30])=O)[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)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:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([N:14]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]5)[CH3:15])=[O:30])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CNc1ccc2[nH]c(C(C)(C)C)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)C1(c2ccc3c(c2)OCO3)CC1)c1ccc2[nH]c(C(C)(C)C)cc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N-methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 391.3 (M+1)+. Retention time of 3.41 minutes.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[C:8](OC(=O)C)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5])(=[O:10])[CH3:9]
Reactant: OCC(CO)CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(CO)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To a solution of 2-(hydroxymethyl)-1,3-propanediol (1 g, 9.4 mmol) in pyridine (7.5 mL) at 0° C. was added acetic anhydride (0.89 mL, 9.4 mmol) slowly. The resulting solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and chromatographed by eluting with methanol-dichloromethane (1:9) to give 510 mg of pure 2-acetoxymethyl-1,3-propanediol.