Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][CH:20]1[CH2:22][CH2:21]1.O>CS(C)=O>[CH:20]1([CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: ClCC1CC1
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1cccc2ccc(OCC3CC3)cc12
Reaction time: 2 h
Yield: 59.9 %

Procedure:
17.1 g (0.085 mol) of N-(7-hydroxynaphth-1-yl)acetamide in solution in 50 ml of dimethyl sulphoxide are added under a nitrogen atmosphere to a suspension of 3.4 g (0.085 mol) of sodium hydride in oil, washed beforehand with dry pentane), in 100 ml of dimethyl sulphoxide, while the mixture is cooled with an ice-water bath. Stirring is continued at room temperature for 2 h. 9.05 g (0.1 mol) of (chloromethyl)cyclopropane are added, and the mixture is stirred at room temperature for 4 h and left to stand overnight. The mixture is poured into 1 l of water, stirred for 1 h and left to stand overnight under cold conditions. The solid is separated by filtration, washed with water and dried. 13 g of a product melting point: 154°-155° C., are obtained which is used as it is in the following step.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[CH2:13][CH2:14][S:15][C:16](=[O:34])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)[NH2:18])(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][C@@H:17]([C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:36])=[O:5])=[O:35])=[O:34])[NH2:18])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCSC(=O)[C@@H](N)Cc1cccc(C(=O)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@@H](Cc1cccc(C(=O)c2ccccc2)c1)C(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
The product of Example 12 was deprotected by reaction with trifluoroacetic acid in anisole. The reaction mixture was incubated at room temperature for one hour, following which trifluoroacetic acid and anisole were removed in vacuo at 32° C. The reaction mixture was then partitioned between saturated NaHCO3 and ethyl acetate in the cold. The bicarbonate phase was washed twice with ethyl acetate and once with ether. Then, in the presence of ethyl acetate, the bicarbonate phase was acidified with HCl, and, after extraction, the ethyl acetate phase was collected and washed with saturated NaCl, dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The product was further purified by chromatography on Sephadex G-25, trademark Pharmacia Company, Uppsala, Sweden, using a 1.2 cm×96 cm column eluted with butanol:acetic acid:water, 4:1:5 (volume ratio). 2.20 me fractions were collected. Most of the product was found in fractions 21 through 23 as determined by positive reaction with o-tolidine/chlorine reagent and with phenazine methosulfate at pH 5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2B(O)O)[CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:35]5[CH:34]=[CH:33][CH:32]=[C:31]6[C:36]=5[N:27]=[CH:28][CH:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: OB(O)c1cccc2cccnc12
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cccc6cccnc56)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and quinoline-8-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=0.64 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].N(CC)(CC)CC.FC(C(O)=O)(F)F.C(O)(C(F)(F)F)=O>C(O)(C)C.CCN(CC)CC>[F:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[NH:14][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccncn1
Reactant: Nc1cc(C(=O)O)ccc1F
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(F)c(Nc2ncccc2-c2ccncn2)c1
Reaction time: 0.5 h

Procedure:
4-(2-Chloro-pyridin-3-yl)-pyrimidine (240 mg, 1.2 mmol), 3-amino-4-fluorobenzoic acid (217 mg, 1.40 mmol), and 340 mg Et3N-TFA salt were mixed together in a sealed tube under argon. (The liquid Et3N-TFA reagent was generated by adding 2.5 mL TFA dropwise to a 0° C. solution of 3 mL Et3N in isopropanol, then concentrating by rotary evaporator followed by 30 minutes under high vacuum.). The mixture was melted at 95° C., and heating was continued overnight. The residue was triturated with a small amount of methanol and filtered to obtain the title compound as a solid. MS m/z=311 [M+H]+. Calc'd for C16H11FN4O2: 310.29.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH3:21])[C:15]([C:22]([O:24]C)=[O:23])=[C:14]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1OCCOCCOCCOCCOCCOC1>CCO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH3:21])[C:15]([C:22]([OH:24])=[O:23])=[C:14]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(C)nc2ccc(NC3Cc4ccccc4C3)cc2c1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CCO
Product: Cc1nc2ccc(NC3Cc4ccccc4C3)cc2c(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of the product of Step 3 (0.98 g, 2.4 mmol), 2MKOH aq (3.6 ml, 7.2 ml) and 18-crown-6 ether (0.63 g, 0.24 mmol) in EtOH (50 ml) was refluxed for 30 h under N2. After cooling to room temperature the organic solvent was removed under reduced pressure and the residue was diluted to 5 ml with H2O, filtered and the filtrate was acidified to pH˜5 with 10% aqueous citric acid. The precipitate formed was filtered off, washed with H2O, small volume of EtOH, Et2O and dried in vacuo to give pure product as a deep yellow solid (0.89 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J=9.0 Hz, 1H), 7.3-7.5(m, 5H), 7.06-7.18(m, 5H), 6.31(m, 1H), 6.28(d, J=2.4 Hz, 1H), 3.92(m, 1H), 3.08(dd, J=7, 16 Hz, 2H), 2.72(dd, J=7 Hz, 16H), 2.48(s, 3H). LCMS, Rt=1.48 min, >99%, m/z (%): 395 (M+·, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:17]=[CH:18][C:13]([CH:11]=[O:12])=[CH:14][CH:15]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Add 1-bromo-2-nitrobenzene (13.30 g, 65.83 mmol), 4-formylphenylboronic acid (10.89 g, 72.41 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.61 g, 1.97 mmol) and 2M aqueous sodium carbonate (164.57 mL, 329.15 mmol) in DMF, and heat to 80° C. with stirring. After 18 hours, cool and pour into water. Extract the mixture with ethyl acetate. Combine the organic extracts, and wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify by flash chromatography eluting with methylene chloride to provide the title compound. 1H NMR (400 MHz; CDCl3) δ-10.02(s, 1H), 7.92-7.99(m, 3H), 7.65(t, 1H), 7.58(t, 1H), 7.44-7.49(m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:19](=[O:20])[CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Ic1cnc2c(c1)NCCN2
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)N1CCNc2ncc(I)cc21
Yield: 31 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with phenyl acetyl chloride as in General Procedure 2 to give the title compound as a pale yellow foam (31% yield). M.p. (foam), LCMS: m/z=379.86 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.32-3.45 (m, 2H), 3.75-3.85 (m, 2H), 3.87 (s, 2H), 5.25 (bs, 1H), 7.21-7.38 (m, 5H), 8.01 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH2:16]1[C:19]2([CH2:22][NH:21][CH2:20]2)[CH2:18][O:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:21]2[CH2:22][C:19]3([CH2:16][O:17][CH2:18]3)[CH2:20]2)=[O:15])=[CH:4][N:3]=1
Reactant: C1NCC12COC2
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CC4(COC4)C3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-oxa-6-azaspiro[3.3]heptane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)#[N:32]>C(O)C>[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)#[N:32]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: N#Cc1cccc(C=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 3-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (23.6 mg, yield: quantitative).
Reaction SMILES: FC1C=CC=C(F)C=1C([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=O.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([OH:28])=O>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:28]
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: COc1ccc(Cl)cc1C(=O)O
Product: COc1ccc(Cl)cc1C(=O)Nc1c[nH]nc1C(=O)O

Procedure:
The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D), but using 5-chloro-2-methoxy-benzoic acid as the starting acid to give 4-(5-chloro-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (12 g) as a colourless solid. (LC/MS: Rt 2.48, [M−H+]− 294)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.I[C:13]1[CH:14]=[CH:15][C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][CH2:19][CH2:18][C:17]=3[CH:21]=2)[CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Ic1ccc2c(c1)CCO2
Product: Clc1cc(-c2ccc3c(c2)CCO3)nc2ccccc12

Procedure:
The title compound, m. p. 130-132° C., MS: m/e=281 (M+), was prepared from 4-chloro-quinoline and 5-iodo-2,3-dihydrobenzofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(OCC)(=O)C>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 34.8 %

Procedure:
A solution of 3-nitrobenzoyl chloride (4.76 g) in dichloromethane (20 ml) was added to a suspension of aluminum chloride (3.42 g) in dichloromethane (50 ml) at 25° C., and the mixture was stirred at the same temperature for an hour. A solution of indole (3.0 g) in dichloromethane (20 ml) was added to the mixture at 25° C. After stirring for an hour at 25° C., the reaction mixture was poured into a mixture of ethyl acetate and ice water. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of solvent, the crystalline residue was recrystallized from ethyl acetate to give 3-(3-nitrobenzoyl)indole (2.37 g) as pale red crystals. The mother liquid was purified by column chromatography on silica gel (20 g) with chloroform as eluent to give another crystals of 3-(3-nitrobenzoyl)indole (0.277 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH:8]=[CH:9][NH:10]2)=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COc1cc2[nH]ccc(=O)c2cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc2nccc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A two neck RBF equipped with CaCl2 guard tube was charged with 7-Methoxy-1H-[1,6]naphthyridin-4-one (28 g, 159 mmol) and POCl3(280 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into ice water and the pH was carefully adjusted to 8 with solid sodium carbonate (highly exothermic reaction). The product was extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=O)[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].Cl.[O:17]([NH2:19])[CH3:18].C([O-])(=O)C.[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH:19][O:17][CH3:18])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CON
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NOC
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A 2 L 3-necked round bottom flask, equipped with magnetic stirring and nitrogen inlet, was charged with 153 g (0.71 mol) of (4R,5R)-4,5-dimethyl-3-oxo-octanoic acid ethyl ester and 600 mL of anhydrous EtOH. The solution was cooled to 0° C.-5° C. with an ice bath and 65.6 g (0.79 mol) of methoxylamine hydrochloride was added, followed by 58.6 g (0.71 mol) of sodium acetate. This flask contents were slowly warmed to room temperature (about 2 hours) and the reaction mixture was stirred at room temperature for another 24 hours. The solvent (EtOH) was removed under reduced pressure and the mixture was charged with CH2Cl2 (2×300 mL), which was subsequently removed. The mixture was cooled to RT, diluted with CH2Cl2 (300 mL), stirred at room temperature for 0.5 hours, and filtered under 5 psig of nitrogen. The filter cake was washed with CH2Cl2 (150 mL). The filtrate was concentrated under vacuum (50° C.) to give 172 g (99% yield) of the titled compound as a light yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) 0.87 (t, J=3.5 Hz, 5H), 0.89 (d, J=7.2 Hz, 3H), 1.08 (d, J=7.0 Hz, 3H), 1.24 (t, J=7.2 Hz, 4H), 1.3-1.55 (m, 2H), 2.25 (m, 1H), 3.15 (q, J=19.5 Hz, 2H) 3.81 (s, 3H), 4.14 (q, J=7.0 Hz, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:43]1([CH2:46][NH2:47])[CH2:45][CH2:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:47][CH2:46][CH:43]3[CH2:45][CH2:44]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NCC4CC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and cyclopropylmethanamine
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:19])([F:18])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=[CH:17][C:8]=1[O:7][C:6]([F:5])([F:19])[F:18]
Reactant: COC(=O)c1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Fuming nitric acid (5 mL) was cooled on an ice bath. Methyl 2-(trifluoromethoxy)benzoate (5 g, 22.7 mmol) was slowly added within 30 min keeping the temperature below 15° C. The reaction was then stirred at 60° C. for 1 hour and 2 hours at room temperature. The mixture was poured on ice water whereupon an oil separated. The aqueous supernatant was decanted and additional water (50 mL) was added to the oil. After neutralisation with sodium hydrogen carbonate, the mixture was extracted with ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (15 mL) once more. The combined organic phases were washed with saturated sodium chloride (2×15 mL), dried (magnesium sulphate), and concentrated in vacuo to give 5.69 g of 5-nitro-2-trifluoromethoxybenzoic acid methyl ester. 1H NMR (DMSO-d6): δ 3.93 (3H, s), 7.82 (1H, d), 8.58 (1H, d), 8.67 (1H, s); HPLC-MS (method B): m/z: 266; Rt=6.0 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](O)[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(O)n2ncnc2n1
Product: CCOC(=O)c1cc(Cl)n2ncnc2n1
Temperature: 60 °C

Procedure:
A suspension of 5-ethoxycarbonyl-7-hydroxy-s-triazolo[1,5-a]pyrimidine (6.8 g) in 40 ml of phosphorus oxychloride was heated at 60° C. with stirring, the resultant clear, orange solution was further refluxed for one hour, excess phosphorus oxychloride was distilled off, the brown residue was dissolved in 100 ml of chloroform, and the solution was slowly added to 100 ml of water with stirring. The chloroform solution was separated, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography, affording 4.6 g of the objective compound as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[F:14])#[N:2].[OH-:15].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[CH3:13][C:9]1([CH3:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([F:14])=[C:3]([C:1]([NH2:2])=[O:15])[C:11]=2[O:10]1
Reactant: [OH-]
Reactant: CC1(C)Cc2ccc(F)c(C#N)c2O1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)Cc2ccc(F)c(C(N)=O)c2O1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
In a flask were placed 140.0 g (0.732 mole) of 7-cyano-2,3-dihydro-2,2-dimethyl-6-fluorobenzofuran, 147.91 g (2.64 moles) of powdered potassium hydroxide, and 950 mL of t-butanol. This mixture was heated at reflux for 50 minutes after which it was cooled to ambient temperature. It was then poured into a mixture of 1500 mL of crushed ice and 1500 mL of a saturated aqueous solution of sodium chloride. The resulting mixture was extracted twice with 750 mL of ethyl acetate. The extracts were combined and washed once with a saturated aqueous solution of sodium chloride. After being dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated from the filtrate under reduced pressure, yielding 136.09 g of 2,3-dihydro-2,2-dimethyl-6-fluorobenzofuran-7-ylcarboxamide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].C([CH2:14][C:15]([OH:17])=[O:16])#N>>[OH:11][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH2:14][C:15]([OH:17])=[O:16])=[CH:2]1
Reactant: N#CCC(=O)O
Reactant: O=C1c2ccccc2CC1O
Product: O=C(O)CC1=CC(O)c2ccccc21

Procedure:
In an alternative preparation scheme, the intermediate hydroxy-indanone can be reacted with cyanoacetic acid to give the corresponding hydroxyindene-3-acetic acid, which is then esterified before introduction of the R5 -methylene grouping in order to facilitate the purification of desired intermediates. Since introduction of the R5 -methylene grouping is accompanied by ester hydrolysis, the intermediate free acid is re-esterified to facilitate purification followed by reaction with an appropriate halo-alkyl-A group to yield the desired final product ##STR15## can be prepared by reacting a halo-indene-3-acetic acid with a A(CH2)n -containing benzaldehyde prepared from the corresponding individual components ##STR16##
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[NH2:5].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[NH2:36][C@H:37]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][CH:40]=1.Cl.CN1CCOCC1>ClCCl.CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:36][C@H:37]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[CH:43][CH:44]=1)=[O:9])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Boc-Asn-OH (3.5 g 15 mmol) is dissolved in dichloromethane (100 ml amylene stabilised free of alcohol) and HOBt (2.24 g dry 16.5 mmol) is added. The mixture is cooled in an ice/water bath and DIC (2.45 ml 16 mmol) is added. The mixture will be allowed to react for 20 min. The HOBt on the bottom will react and a precipitate of DIU (on top) will form. H-Tyr(tBu)-OtBu×HCl (5.1 g 15.4 mmol) is dissolved in DMF (30 ml dry). The dichloromethane mixture containing the activated ester is filtered from the DIU directly into the DMF solution. The combined mixture is cooled in ice/water and NMM (1.75 ml 15.8 mmol) is added. The mixture is allowed to react over night. The solvents will be removed in vacuo. Ethyl acetate 200 ml is added and a precipitate is removed and the solution is washed with citric acid (2×50 ml 10%), sodium hydrogen carbonate (2×50 ml saturated) and brine (2×50 ml). The solution is dried with magnesium sulfate and the solvent removed in vacuo ending at 0.2 mBar for 30 min. The raw product will be suspended in pentane (40 ml) and filtered from a precipitate of DIU. The pentane will be removed in vacuo yielding the title compound.