Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1.O.[OH-].[Na+]>C1COCC1>[NH2:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Nc1ncccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.4M lithium aluminum hydride in THF (181 mL g, 434 mmol) was added portionwise to a suspension of 2-amino-3-carboxypyridine (30.0 g, 217 mmol) in THF (350 mL) at 0° C. Once the addition was completed, the reaction mixture was stirred at room temperature for 15 minutes and then at reflux overnight. The mixture was then cooled to 0° C. and hydrolyzed by the successive addition of water (18 mL), a 1M solution of sodium hydroxide (18 mL) and water (50 mL). The resulting white suspension was stirred for one hour, filtered over Celite® and the cake was washed with THF (400 mL). After concentration to dryness of the filtrate, the title product was obtained as a light brown oil (25.1 g, 87%, py 93.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[CH2:19][NH:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:7][C:6]([CH2:26][C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.[OH-].[Na+].Cl>C(Cl)Cl>[C:30]([N:20]([CH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:17])([F:18])[F:16])[CH:13]=[CH:14][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([CH2:26][C:27]([OH:29])=[O:28])[CH:7]=1)[CH2:21][C:22]([OH:24])=[O:23])(=[O:32])[CH3:31]
Reactant: COC(=O)CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(CC(=O)O)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{6-Methoxy-2′[(methoxycarbonylmethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (0.094 g, 0.23 mmol), acetyl chloride (0.03 mL, 0.46 mmol), and triethylamine (0.08 mL, 0.57 mmol) were combined in CH2Cl2 (1 mL) and stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, aqueous 1N NaOH was added. After stirring at room temperature for 45 minutes, analytical LCMS indicated that both acids had been hydrolyzed to the free acid, and so the mixture was neutralized with aqueous 1N HCl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 440.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26](O)[N:27]([CH2:34][C:35]2[CH:36]=[C:37]([CH:47]=[CH:48][CH:49]=2)[CH2:38][NH:39]C(=O)OC(C)(C)C)[C:28]3=[O:33])=[O:22])=[CH:18][CH:17]=1>ClCCl>[NH2:39][CH2:38][C:37]1[CH:36]=[C:35]([CH:49]=[CH:48][CH:47]=1)[CH2:34][N:27]1[CH2:26][C:25]2[C:29](=[CH:30][CH:31]=[CH:32][C:24]=2[NH:23][C:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:22])[C:28]1=[O:33]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2O)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(CN2Cc3c(NC(=O)c4ccc(Cl)s4)cccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.21 ml (2.7 mmol) of TFA and 0.07 ml (0.45 mmol) of triethylsilane are added dropwise to a solution of 181 mg (purity 66%, 0.22 mmol) of tert-butyl 3-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-3-hydroxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzylcarbamate in 4.5 ml of dichloromethane. The solution is stirred at room temperature overnight and then concentrated and dried under high vaccum. The residue is taken up in dichloromethane/methanol and the mixture is washed with 1N sodium hydroxide solution, dried over magnesium sulfate and concentrated. Ether is added to the residue, the mixture is filtered off with suction and the product is dried under high vacuum. Yield: 84 mg (90.7% of theory); MS (DCI, NH3): m/z (%)=412 (M+H, 100); HPLC (Method 2): rt (%)=6.25 (80).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[Cl-:6].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.Cl.Cl.N(C(C1NCCN=1)(C)C)=NC(C1NCCN=1)(C)C>O>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH3:7][Cl:6].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9]
Reactant: [Cl-]
Agent: C=CC(=O)OCC
Agent: C=CC(N)=O
Agent: CC(C)(N=NC(C)(C)C1=NCCN1)C1=NCCN1
Solvent: O
Product: CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 10% solution of poly(AMD/DMAEA.MeCl/EA) was prepared as follows: 13.87 parts of 53.58% aqueous acrylamide (AMD), 25.31 parts of a 80% aqueous solution of ethacryloxyethyltrimethylammonium chloride (DMAEA.MeCl), 2.33 parts of ethyl acrylate (EA), 0.3 part EDTA, 258.16 parts of deionized water and 0.030 parts of VA-044 were added to a suitable glass vessel. The solution was sparged with nitrogen gas and stirred for about one hour at ambient temperature. The nitrogen sparge was changed to a nitrogen purge, and polymerization was initiated thermally by raising the temperature of the solution to 44° C. Stirring and heating were continued for about 21 hours to give a clear, viscous solution of poly(AMD/DMAEA.MeCl/EA) having a standard viscosity of about 2.0 centipoise.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]([C:18]([CH3:20])=[O:19])C(=O)C.[B-](F)(F)(F)F.[CH3:26][CH2:27][O+:28](CC)CC>ClCCl.CO>[C:27]([C:7]1[NH:8][C:9]2[C:5]([C:6]=1[CH2:12][CH2:13][NH:14][C:18](=[O:19])[CH3:20])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)(=[O:28])[CH3:26]
Reactant: CC[O+](CC)CC
Reactant: COc1ccc2[nH]cc(CCN(C(C)=O)C(C)=O)c2c1
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2[nH]c(C(C)=O)c(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To N-[2-(5-methoxyindol-3-yl)ethyl]diacetamide (4) (35 mg) dissolved in dichloromethane (3 ml), at 0° C., is added Meerwein's reagent (0.15 mmol, 0.15 ml). The mixture is maintained at room temperature for 12 h. The solution is filtered. A red precipitate is obtained. The precipitate is dissolved in methanol (1 ml). After reacting for 15 min, the methanol is evaporated off and the ethyl acetate is extracted out. N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide (2) is thus obtained, Yield=75%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]([CH3:18])([CH3:17])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C([O-])(=O)CC>>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]([CH3:18])([CH3:17])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)C(C)(C)c1cccc2cnccc12
Agent: CCC(=O)[O-]
Product: CC(C)(C(=O)O)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 249A using ethyl 2-(5-isoquinolinyl)-2-methylpropanoate instead of ethyl 2-5-isoquinolinyl)propanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1>C(OCC)C>[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:29])[C:26]([NH:1][C:2]3[CH:12]=[CH:11][C:5]4[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=4[CH:3]=3)=[O:27])[CH2:23][CH2:24]2)=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 7-amino-4H-benzo[1,4]oxazin-3-one [J. Med. Chem., 32, 1627. (1989)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 2. Melting Point: 209-212° C. (diethylether)
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)C.[ClH:27].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:27].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1cccc(F)c1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1cccc(F)c1
Yield: 81 %

Procedure:
N-benzyloxycarbonyl-m-fluoroanilinoacetaldehyde diethyl acetal (15 g) and 3,4-dihydroxyphenethylamine hydrochloride (5.75 g) were added to a mixture of n-butyl alcohol (150 ml) and water (20 ml) and then the mixture was refluxed for 11 hours in a stream of nitrogen. The reaction mixture was concentrated to dryness and the residue was in turn washed with ether and with a mixture of ether: ethyl acetate (2:1) and then crystallized with acetone. The crystals were collected by filtration to give 1-(N-benzyloxycarbonyl-m-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (11.27 g), mp 184° to 186° C. (dec).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:20][N:21]([CH3:27])[S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23].O>O1CCCC1>[CH3:20][N:21]([CH3:27])[S:22]([CH2:25][CH2:26][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)(=[O:24])=[O:23]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: C=CS(=O)(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)CCOC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Benzyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 21.2 mmol) was dissolved in tetrahydrofuran (100 ml), and while cooling with ice, sodium hydride (content 55%) (1.0 g, 22.9 mmol) was added. The resulting mixture was stirred for 30 minutes while cooling with ice, to which 20 mL of a solution of N,N-dimethylethenesulfonamide in tetrahydrofuran (3.0 g, 22.2 mmol) was added dropwise over five minutes. The resulting mixture was stirred for 30 minutes while cooling with ice, and then for three hours at room temperature. The resulting reaction liquid was poured into water and then extracted with ethyl acetate. The resulting organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 50:50-0:100, V/V) to give the desired title compound (4.9 g, yield 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: COc1c(C=O)cccc1Oc1ccccc1Cl
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: COc1c(C=CC(=O)O)cccc1Oc1ccccc1Cl
Yield: 62.8 %

Procedure:
2-Methoxy-3-(2-chlorophenoxy)benzaldehyde (7.0 g) and malonic acid (5.60 g) were dissolved in pyridine (60 ml). To the solution was added piperidine (0.6 ml) and the mixture was heated gradually to 80° C., while carbon dioxide was produced. Thereafter, the mixture was refluxed under heating for 30 minutes. After cooling, the reaction mixture was poured into water (300 ml), acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated. The crystalline residue (7.10 g) was recrystallized from diisopropyl ether to give 3-[2-methoxy-3-(2-chlorophenoxy)phenyl]acrylic acid (5.1 g). mp 145°-147° C.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC([O-])(C)C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>O.[Pd]>[N:11]1([C:2]2[C:10]3[NH:9][CH:8]=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCNC1
Reactant: Brc1cccc2nc[nH]c12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Product: c1cc(N2CCCNCC2)c2[nH]cnc2c1
Temperature: 25 °C

Procedure:
A suspension of 4-bromobenzimidazole (42 mmol), homopiperazine (256 mmol) and NaOt-Bu (59 mmol) in dry oxylene, under N2, is treated with a catalytic amount of Pd(OCOCH3)2.P(t-Bu)3 (P/Pd=4), heated at 120° C. for 3 hr, cooled to room temperature and diluted with water. The aqueous mixture is extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by flash chromotography to give 4-(homopiperazin-1-yl)benzimidazole.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH3:24])=[C:8]([CH:21]=1)[C:9]([O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])=[O:10]>C(OCC)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH3:24])=[C:8]([CH:21]=1)[C:9]([O:11][CH:12]([Br:1])[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[O:10]
Reactant: BrBr
Reactant: CCOc1ccc(Cl)cc1C(=O)OCC(=O)c1ccccc1
Solvent: CCOCC
Product: CCOc1ccc(Cl)cc1C(=O)OC(Br)C(=O)c1ccccc1

Procedure:
Bromine (0.6 g, 3.7 mmol) is added dropwise to a solution of 5-chloro-2-(2-ethoxybenzoyloxy)-acetophenone (1.19 g, 3.7 mmol) in dry diethyl ether (30 ml) at room temperature. The mixture is stirred for an additional hour. The reaction mixture is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound in pure form.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:31]([F:41])[CH:30]=2)[CH3:28])[N:26]=1.[CH3:42][N:43]=[C:44]=[S:45]>O1CCCC1>[CH3:42][NH:43][C:44]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[C:31]([F:41])[CH:30]=2)[CH3:28])[N:26]=1)=[S:45]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Reactant: CN=C=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CNC(=S)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
The lithium diisopropylamide in tetrahydrofuran prepared with diisopropylamine (0.187 g, 1.85 mmol) and n-butyllithium (1.9 mmol) was added 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g, 1.68 mmol) in tetrahydrofuran at -70° C. After the mixture was stirred for 20 min, methylisothiocyanate (0.131 g, 1.8 mmol) in tetrahydrofuran was added to the mixture. After the mixture was stirred at room temperature for 3.5 h, the mixture was evaporated under reduced pressure to a residue, which was extracted with chloroform. The extracts were washed with water, dried over, and evaporated under reduced pressure to a residue, which was chromatographed and recrystallized to afford N-methyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea (0.233 g, 35% yield) as crystalline material: mp 180.5°-181.0° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:15][NH2:16]>O1CCOCC1.ClCCl>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:16][N:15]=1
Reactant: O=C(c1nccs1)c1cccnc1Cl
Reactant: NN
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cnc2[nH]nc(-c3nccs3)c2c1
Temperature: 150 °C

Procedure:
To a suspension of 2-chloro-3-[(2-thiazolyl)carbonyl]pyridine (257.5 Mg, 1.2 Mmol, 1 equiv) in dioxane (3 mL) in a sealed tube was added hydrazine (2 mL). The mixture was heated at 150° C. overnight, cooled to room temperature and concentrated in vacuo to provide a crude residue. The resultant residue was diluted with dichloromethane (300 mL), washed with water (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide 3-thiazol-2-yl-1H-pyrazolo[3,4-b]pyridine (212.3 Mg) as a yellow powder which used without further purification: LCMS (ES) M+H 203.5, Rf 2.68 min (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C., 1 mL/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: B.[Na].O.[OH:4][C:5]([C:14]([F:17])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])[C:6](OC)=[O:7].Cl>C(OCC)C>[F:11][C:10]([F:12])([F:13])[C:5]([C:14]([F:15])([F:17])[F:16])([OH:4])[CH2:6][OH:7]
Reactant: COC(=O)C(O)(C(F)(F)F)C(F)(F)F
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: OCC(O)(C(F)(F)F)C(F)(F)F
Yield: 95.8 %

Procedure:
To a mixture of 25.0 g of sodium boron hydride, 500 g of water, and 500 g of diethyl ether, with stirring, 100 g of methyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate was added dropwise. The mixture was stirred for 10 hours, after which hydrochloric acid was added to quench the reaction. An organic layer was separated from the reaction mixture, concentrated, and distilled, obtaining 83.9 g of 3,3,3-trifluoro-2-trifluoromethyl-1,2-propane diol (yield 96%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:66]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[S:75](Cl)(=[O:77])=[O:76])([O-:68])=[O:67]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:75]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=3[N+:66]([O-:68])=[O:67])(=[O:76])=[O:77])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 46) in dry methylene chloride (2 ml) is added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The yellow solution is stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compound.
Reaction SMILES: [OH:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:12]2=[C:13]([OH:16])[CH:14]=[CH:15][C:10]3=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9]3)=[N:5]1>C(O)C>[CH2:15]([O:16][C:13]1[C:12]2[N:4]([CH2:3][CH:2]([OH:1])[CH3:17])[N:5]=[C:6]3[CH2:7][CH2:8][CH2:9][C:10]([C:11]=23)=[CH:15][CH:14]=1)[C:10]1[CH:11]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(O)Cn1nc2c3c(ccc(O)c31)CCC2
Solvent: CCO
Product: CC(O)Cn1nc2c3c(ccc(OCc4ccccc4)c31)CCC2
Yield: 109.8 %

Procedure:
A solution of the product from Step D (0.59 g, 2.6 mmol) in ethanol (20 mL) was treated as described in Step F of Example 1 to provide a solid (0.46 g, 54%): m.p 95-97° C.; MS (ES) m/z 323 (M+); 1H NMR (CDCl3) δ 7.34 (5H, m), 7.14 (1H, s), 5.08 (2H, s), 4.31 (2H, m), 4.13 (2H, m), 3.02 (5H, m), 2.19 (3H, m), 1.27(3H, t, J=6.0 Hz).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20].C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu]=O.CO.C1(C)C=CC=CC=1.CC1C=CC=CC=1C>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: Cc1cccc(C)c1Br
Reactant: O=C1CCc2c(O)cccc21
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1Oc1cccc2c1CCC2=O
Temperature: 130 °C
Reaction time: 18 h
Yield: 2.2 %

Procedure:
A mixture of 2-bromo-1,3-dimethylbenzene (15.0 g, 81.1 mmol), 4-hydroxyindan-1-one (10.0 g, 67.5 mmol), copper(II) oxide (9.13 g, 114 mmol), potassium carbonate (18.7 g, 135 mmol), pyridine (200 mL) and o-xylene (100 mL) was stirred under a nitrogen atmosphere at 130° C. for 18 hr. After cooling the reaction mixture, a mixed solvent of toluene and methanol was added. The insoluble material was filtered off, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chloroform was added to the residue, the insoluble material was filtered off and the filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=90/10-hexane/ethyl acetate=0/100) to give the title compound (0.373 g, yield 2%) as a yellow oil.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]1[CH:17]2[CH2:18][C:19]3([NH2:22])[CH2:21][CH:15]([CH2:16]2)[CH2:14][CH:13]1[CH2:20]3>C1(C)C=CC=CC=1>[C:19]12([NH:22][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:1]([OH:6])=[O:11])[CH2:20][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:12]3)[CH2:18]1)[CH2:21]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
A mixture of 25 g (0.17 mole) of phthalic anhydride and 100 ml of toluene was prepared. To this mixture was added a solution of approximately 25.5 g (0.17 mole) of adamantamine in 100 ml of toluene. The resulting mixture was stirred at room temperature for 15 hours. The solid was collected by vacuum filtration and dried in a vacuum oven at room temperature to yield approximately 49 g of N-adamantylphthalamic acid.