Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].C([O:17][C:18](=[O:20])[CH3:19])(=O)C>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:12][C:2]([CH2:19][C:18]([OH:17])=[O:20])=[O:1]
Reactant: CC(=O)OC(C)=O
Agent: O=C(O)C=Cc1ccc(O)c(O)c1
Solvent: c1ccncc1
Product: CC(=O)CC(=O)O

Procedure:
A method for producing compounds of the formula: ##STR8## wherein A is selected from the group consisting of alkali metal cations and alkaline earth metal cations which comprises reacting 3,4-dihydroxycinnamic acid with acetic anhydride in pyridine for 18-30 hours, in organic solvents, giving 3,4-dihydroxycinnamic acid, diacetate, then converting to 3,4-dihydroxycinnamic acid chloride by treating with thionyl chloride in dimethylformamide at -20° to -18° C. for 30-90 minutes; reacting 4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes, extracting in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate, then catalytically reducing, giving 4-Oα-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester); reacting a solution of the 3,4-dihydroxycinnamic acid chloride in dimethylformamide at -20° to -15° C. with a solution of the 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate in pyridine at -15° to -5° C. for 20-40 minutes, then at -5° to 20° C. for 1-2 hours followed by extracting with organic solvents, giving N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide, nonaacetate (nonaester), then converting to N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide by reacting in a mixture of methanol, triethylamine and water, under an inert atmosphere for 20-30 hours followed by heating at reflux for 2-6 hours and extracting in organic solvents, reacting this derivative with triethylamine sulfur trioxide in N,N-dimethylacetamide under an inert atmosphere at 50°-70° C. for 15-20 hours, and then treating with an alkali metal or alkaline earth metal acetate in water.
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:38][CH:37]=2)[C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN(C)C.[CH:60]([O:62][CH2:63][CH2:64]Cl)=[CH2:61]>CS(C)=O>[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH:60]([O:62][CH2:63][CH2:64][O:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:36]2[CH:37]=[CH:38][C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][CH:41]=2)[C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[CH2:61]
Reactant: C=COCCCl
Reactant: CC(C)(C)c1ccc([S+](c2ccc(O)cc2)c2ccc(C(C)(C)C)cc2)cc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CS(C)=O
Product: C=COCCOc1ccc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
4-Hydroxyphenyldi(4-t-butylphenyl)sulfonium perfluorobutanesulfonate salt (28.4 g), potassium carbonate (8.56 g), and N,N,N′,N′-tetramethylethylenediamine (0.50 g) were dissolved in dimethyl sulfoxide (143 g). Chloroethyl vinyl ether (6.30 g) was added to the solution, followed by heating to 80° C. The reaction mixture was stirred for 15 hours and cooled to 30° C. or lower. After removal of solid through filtration, water (220 g) and dichloromethane (113 g) were added to the filtrate, whereby the target substance was extracted to the dichloromethane layer. The organic layer was repeatedly washed with distilled water until the pH of the separated aqueous layer was shifted to 7. The solvent was removed by means of a rotary evaporator, and the formed oily substance was dissolved in acetonitrile (100 g). The acetonitrile layer was washed five times with hexane (85 g). The solvent was removed by means of a rotary evaporator, to thereby yield 24.5 g of a brown oily substance. Through 1H-NMR and ion chromatography, the substance was identified to be 4-vinyloxyethoxyphenyldi(4-t-butylphenyl)sulfonium perfluorobutanesulfonate salt.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C@@H:14]([OH:30])[CH2:15][NH:16][C:17]([C@H:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([I:29])[CH:25]=4)[O:20]3)=O)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.B.CSC>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C@@H:14]([OH:30])[CH2:15][NH:16][CH2:17][C@H:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([I:29])[CH:25]=4)[O:20]3)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc([C@@H](O)CNC(=O)[C@H]2CCc3cc(I)ccc3O2)cn1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc([C@@H](O)CNC[C@H]2CCc3cc(I)ccc3O2)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of (2R)-N-{(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide (Example 355, 7.67 mmol, 1 eq.) in THF (150 mL) at room temperature was added slowly borane-methyl sulfide complex (2M in THF, 38.4 mmol, 5.0 eq.). After completion of the addition, the reaction mixture was heated to reflux for 2 hours and was then cooled to room temperature. The excess borane was quenched by the dropwise addition of EtOH (9 mL) followed by the slow addition of 2 M HCl (40 mL). The resulting mixture was heated to reflux for 1 hour and was then allow to cool to room temperature. The mixture was basified with 1N NaOH and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, using a gradient of 1:4 hexanes:EtOAc to 1:10 MeOH:EtOAc). The product was obtained as a pale yellow oil in 63% yield. MH+=503.9, RT=3.23 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:33]1[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[NH2:22][C:20]1[S:21][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([N:33]3[CH2:34][CH2:35][S:36](=[O:39])(=[O:40])[CH2:37][CH2:38]3)(=[O:31])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3nnc(N)s3)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: Nc1nnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCS(=O)(=O)CC3)cc2F)s1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amine and 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. for C18H17FN4O4S2, 468.04; m/z found, 469.0 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.19 (m, 1H), 8.15 (dd, J=8.0, 1.1, 1H), 7.76 (m, 1H), 7.67 (m, 1H), 7.45 (dd, J=7.6, 1.2, 1H), 7.39 (dd, J=11.9, 1.4, 1H), 7.36 (dd, J=8.1, 1.6, 1H), 3.42-3.33 (m, 4H), 3.09-3.02 (m, 4H).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][NH2:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>O1CCCC1>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[C:28](=[O:29])[NH:12][N:11]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: C1CCOC1
Product: CCCc1nc(C)n2c(=O)[nH]nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 73.7 %

Procedure:
33.4 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, are dissolved in 600 ml of tetrahydrofuran. 15.2 g of carbonyldiimidazole are added and the mixture is heated to reflux for 1 h 30 min. The solvent is evaporated off under vacuum and the residue is taken up with water and then extracted with chloroform. The organic phase is dried over magnesium sulphate and evaporated under vacuum; the residue obtained crystallises in an ether/ethyl acetate mixture to give 26.4 g of 7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo-[4,3-c]pyrimidin-3(2H)-one in the form of crystals of melting point 196° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.[H][H]>C(O)CO>[CH3:1][C:2]1([CH3:10])[CH2:9][CH2:7][CH2:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: [H][H]
Solvent: OCCO
Product: CC1(C)CCCC(=O)C1
Yield: 4 %

Procedure:
Sasson et al. achieved reduction of dimedone via transfer hydrogenation in ethylene glycol as hydrogen donor in the presence of the homogenous catalyst RuCl2 (PPh3)3. Among a number of different reduction products 3,3-dimethylcyclohexan-1-one was obtained only in 4% yield which is an unacceptable low selectivity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[OH:10]N1C2C=CC=CC=2N=N1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: On1nnc2ccccc21
Product: COc1ccc(C=O)cc1
Yield: 48 %

Procedure:
195 mg (1.60 mmol) of 4-methylanisole were reacted analogously to Example 1 in the presence of 24.3 mg (0.180 mmol) of 1-hydroxy-1H-benzotriazole. After a reaction time of 22 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 48% of 4-methoxybenzaldehyde (approx. 90%, based on conversion).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=O)[CH2:7][CH2:6]2)[O:4]CC1.[BH4-].[Na+].B(F)(F)F.CCOCC.C(O)(=O)C>O1CCCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[CH2:18][CH2:19][N:14]([CH2:12][CH2:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH2:15][CH2:16]1
Reactant: O=C(CC1CCC2(CC1)OCCO2)N1CCN(c2ccccn2)CC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1CCC(CCN2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of 1-(1,4-dioxaspiro[4,5]dec-8-yl-acetyl)-4-(2-pyridinyl)piperazine (17.0 g) (Example I) in 500 ml of dry tetrahydrofuran is treated with sodium borohydride (6.81 g) under nitrogen and the resulting suspension is treated dropwise with a solution of boron trifluoride etherate (29.5 ml) in 100 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature overnight. A solution of glacial acetic acid (10.3 ml) in 100 ml of tetrahydrofuran is added dropwise, and the mixture stirred at room temperature for two hours. The solvent is evaporated in vacuo and the residue refluxed with 250 ml of a 10% solution of hydrochloric acid and 250 ml of acetone for two hours. The mixture is concentrated in vacuo to about one-half of the original volume. The remaining aqueous solution is washed twice with ethyl acetate and made basic with ammonium hydroxide. The crude product is extracted into ethyl acetate (2×300 ml). The organic extract is dried over magnesium sulfate and concentrated in vacuo. The reaction mixture is purified by MPLC (silica; 2% methanol, 98% chloroform) to give 9.73 g of the title compound as a colorless solid; mp 104°-106° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:49]1([CH2:55][C:56](Cl)=[O:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:56](=[O:57])[CH2:55][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)Cc1ccccc1
Reaction time: 8 h

Procedure:
500 mg of the compound obtained in Step A of Example 12 are dissolved in 10 ml of ethyl acetate; 0.353 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.226 ml of phenylacetyl chloride is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[Cl:25]>ClCCl>[Cl:25][C:19]1[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:14]([C:10]1[CH:9]=[C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:13]=[CH:12][N:11]=1)=[O:16]
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccc(O)cc1Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1Cl)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-3-chlorophenol (Chontech), the title compound was obtained as a white solid after trituration in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24](OCC)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CCO>[Cl:18][C:6]1[CH:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([OH:29])=[CH:31][CH:32]=3)=[O:25])[O:21][N:20]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1nc(-c2cc(Cl)c(OCc3ccc(OC)cc3)c(Cl)c2)no1
Reactant: NCc1ccc(O)cc1
Solvent: CCO
Product: COc1ccc(COc2c(Cl)cc(-c3noc(C(=O)NCc4ccc(O)cc4)n3)cc2Cl)cc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
Ethyl 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (4 g, 9.46 mmol) and 4-hydroxybenzylamine (2.33 g, 18.91 mmol) were heated in EtOH (150 mL) at 80° C. forming a yellow solution. After 1 h a colourless precipitate formed and the mixture was cooled to room temperature. The solid was filtered off, washed with EtOH and dried in a vacuum oven giving the title compound (4.16 g, 8.32 mmol, 88%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 3.81 (2 H, s), 4.41 (2 H, d, J=6.08 Hz), 5.12 (2 H, s), 6.76 (2 H, d, J=8.08 Hz), 7.00 (2 H, d, J=8.20 Hz), 7.20 (2 H, d, J=8.06 Hz), 7.49 (2 H, d, J=8.18 Hz), 8.13 (2 H, s), 9.38 (1 H, s), 9.95 (1 H, t, J=6.15 Hz). LCMS (10 cm_esci_AmmBicarb_MeCN) tR 4.18 min; m/z 498 [M]−.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:26])[CH2:13][CH2:14][NH:15][S:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:26])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCNS(=O)(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)Cc1ccccc1

Procedure:
Prepared from 1-fluoro-4nitro-benzene, N-(2-dimethylamino-ethyl)-C-phenylmethanesulphonamide and sodium hydride as base
Reaction SMILES: [C:1]([CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[C:1]([CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)#[N:2]
Reactant: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(C#N)Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
1-Carbamoyl-2-[4-(2-{4-tert-butyloxycarbonylaminophenyl}ethoxy)phenyl]-1-ethoxyethane(0.63 g, 1.47 mmole) was dissolved in dioxane (20 ml) and pyridine (0.35 g, 4.41 mmole) was added. The mixture was placed in a ultrasonic bath for 5 minutes, then trifluoroacetic acid anhydride (0.37 g, 1.76 mmole) was added. After stirring at room temperature for 16 hours it was checked using HPLC that all the starting material was consumed. Sodium carbonate solution was added and extracted three times with dichloromethane. The organic phase was dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (70-80%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.47 g (75% yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][C:23](N1C=CN=C1)=[O:24].[OH:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33].[H-].[Na+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([O:30][C:31]([C:32]([OH:34])=[O:33])([CH3:36])[CH3:35])=[O:24]
Reactant: CC1(C2CCCC2)Cc2cc(OCCCC(=O)n3ccnc3)c(Cl)c(Cl)c2C1=O
Reactant: CC(C)(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(OC(=O)CCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 1-{(+) 4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butanoyl}imidazole (0.002 mole) prepared in Step A at 0° C. is added with stirring 2-hydroxyisobutyric acid (0.21 g., 0.002 mole) and a catalytic amount of sodium hydride (10 mg). After stirring overnight at the ambient temperature, the colorless reaction mixture is concentrated in vacuo at 50° C. The resultant yellow liquid is chromatographed using a silica-gel (60 gm) column and eluted with a mixture of methylene chloride, tetrahydrofuran and acetic acid (100/2/1 v.v.v) to give analytically pure 1-carboxy-1-methylethyl (+) 4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-])=O.[Sn].O.[OH-].[Na+]>C(O)C.Cl>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1
Reactant: O=[N+]([O-])c1cc2c(c(-c3cccnc3)c1)OCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc2c(c(-c3cccnc3)c1)OCC2
Temperature: 50 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
2,3-Dihydro-5-nitro-7-(pyrid-3-yl)benzofuran (D63) (0.19 g, 0.00079 mole) in ethanol (20 ml) was treated with a solution of tin II chloride (0.75 g, 0.0040 mole) in conc. hydrochloric acid (1 ml) and heated at 50° C for 2 hours. A further 0.38 g tin II chloride in conc. hydrochloric acid (0.5 ml) was added and the mixture was heated at 50° C. for ½ hour and stirred at ambient temperature for 18 hours. Deionised water (5 ml) was added and the mixture was basified with 10% sodium hydroxide solution, extracted into ethyl acetate, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.13 g, 82%) as a dark oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][CH2:10]O.C(=O)(O)[O-].[Na+].ClCC=O>[Na+].[Cl-]>[N:1]1[CH:9]=[CH:10][N:3]2[C:4]([NH2:8])=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CCO
Reactant: Nc1cccc(N)n1
Agent: O=C([O-])O
Agent: O=CCCl
Agent: [Cl-]
Product: Nc1cccc2nccn12
Temperature: 70 °C
Yield: 22 %

Procedure:
To a solution of 2,6-diaminopyridine (5.00 g, 45.8 mmol) in 1:1H2O:EtOH (10 mL) were added sodium bicarbonate (5.00 g, 59.5 mmol) and chloroacetaldehyde (4.31 g, 27.5 mmol). The reaction mixture was heated to 70° C. overnight, then cooled to rt, diluted with saturated aqueous NaCl (100 mL), and extracted with n-butanol (3×200 mL). The organic layers were combined, dried (MgSO4), and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give imidazo[1,2-a]pyridin-5-ylamine (1.32 g, 22%). MS (ESI+): calcd for C7H7N3 m/z 133.06, found 134.1 (M+H)+. 1H NMR (d6-DMSO): 8.23-8.21 (m, 1H), 7.91 (d, J=1.3, 1H), 7.50 (dd, J=8.8, 7.4, 1H), 7.22 (d, J=8.8, 1H), 6.97 (br s, 2H), 6.37 (dd, J=7.4, 0.9, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:10][N:11]=2)=[N:4][O:5][N:6]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:12][C:13]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([C:17]([F:16])([F:25])[F:26])[CH:19]=3)=[O:15])[CH2:9][CH2:10][N:11]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C1=NCCN1CC(=O)O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nonc1C1=NCCN1CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
2-(2-(4-amino-1,2,5-oxadiazol-3-yl)-4,5-dihydroimidazol-1-yl)acetic acid (170 mg, 0.8 mmol) was dissolved in DMF and to this solution 3-trifluoromethyl aniline (1.2 g, 7.4 mmol) was added followed by benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent) (0.44 g, 1.0 mmol) and DIEA (0.4 mL, 2.3 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with saturated sodium bicarbonate and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to an oil which was purified by column chromatography (20–60% ethyl acetate/hexanes) to afford the title compound as a white solid, 35 mg, (0.1 mmol, 12%. 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 4.47 (s, 2H), 4.06 (t, J=10.0 Hz, 2H), 3.65 (t, J=10.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:51][C@H:52]([CH:57]([CH3:59])[CH3:58])[C:53]([O:55][CH3:56])=[O:54]>CN(C=O)C>[CH3:56][O:55][C:53](=[O:54])[CH:52]([NH:51][C:9](=[O:11])[CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:21][CH:20]=1)[CH:57]([CH3:59])[CH3:58]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)NC(COc1ccc(Br)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of the compound obtained in step e above (22e) (816 mg, 2.27 mmol), NMM (0.55 mL, 4.922 mmol) and HOBt (521 mg, 3.864 mmol) in DMF (10 mL) was stirred at 0° C. for 10 minutes, then the reaction was cooled to −15° C., and EDCI (478 mg, 2.497 mmol) was added. The reaction was stirred for 30 minutes at −15° C. and then allowed to warm to room temperature, (R)-methyl 2-amino-3-methylbutanoate hydrochloride (417 mg, 2.497 mmol) was added. After being stirred overnight, the reaction mixture was concentrated under vacuum; the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the residue was purified by silica gel column chromatography to give the title compound as colourless oil (900 mg, 84%).