Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([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)[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)=[O:16]>>[C:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)=[O:16])=[CH:40][CH:41]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 52 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1([F:53])[C:6]([F:8])([F:7])[C:5]([F:10])([F:9])[C:4]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20]C)=[CH:19][C:14]=3[O:13][C:12]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)=[C:3]1[C:32]1[C:36]2[CH:37]=[CH:38][C:39]([O:41]C)=[CH:40][C:35]=2[O:34][C:33]=1[C:43]1[CH:48]=[CH:47][C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:45][CH:44]=1.BrB(Br)Br>ClCCl>[F:10][C:5]1([F:9])[C:6]([F:8])([F:7])[C:2]([F:1])([F:53])[C:3]([C:32]2[C:36]3[CH:37]=[CH:38][C:39]([OH:41])=[CH:40][C:35]=3[O:34][C:33]=2[C:43]2[CH:44]=[CH:45][C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:47][CH:48]=2)=[C:4]1[C:11]1[C:15]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=2[O:13][C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][CH:27]=1
Reactant: COc1ccc2c(C3=C(c4c(-c5ccc(C(C)(C)C)cc5)oc5cc(OC)ccc45)C(F)(F)C(F)(F)C3(F)F)c(-c3ccc(C(C)(C)C)cc3)oc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2oc3cc(O)ccc3c2C2=C(c3c(-c4ccc(C(C)(C)C)cc4)oc4cc(O)ccc34)C(F)(F)C(F)(F)C2(F)F)cc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
In a one neck round bottom flask containing a solution of 3,3′-(perfluorocyclopent-1-ene-1,2-diyl)bis(2-(4-(tert-butyl)phenyl)-6-methoxybenzofuran) (1 g, 1.365 mmol) in anhydrous dichloromethane (Ratio: 1, Volume: 50 ml) at room temperature was added dropwise tribromoborane (1.8 ml, 18.68 mmol). The reaction mixture was stirred at reflux for 2 hours. The TLC after 2 hours showed that all the starting material was consumed. The reaction was quenched with methanol (vigorous reaction). The crude was washed with an aqueous solution of 10% HCl, extracted with DCM, then dried over anhydrous magnesium sulfate. The solid obtained was deposited on silica gel and purified by chromatography column using CombiFlash Rf eluting with pure DCM to obtain the product 3,3′-(perfluorocyclopent-1-ene-1,2-diyl)bis(2-(4-(tert-butyl)phenyl)benzofuran-6-ol) (0.96 g, 1.362 mmol, 100% yield) as fluffy yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.1 (AB, J=8.4 Hz, 8H), 7.06 (m, 2H), 6.73 (d, J=2.1 Hz, 2H), 6.54 (dd, J=8.6, 2.2 Hz, 2H), 4.77 (s, 2H), 1.18 (s, 18H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:35](=[O:59])[NH:36][C@H:37]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=1)[C:38]([O:40]CC1C=CC=CC=1)=[O:39])[CH2:10][CH2:11][C:12](=[O:34])[N:13]([CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.O.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:35](=[O:59])[NH:36][C@H:37]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=1)[C:38]([OH:40])=[O:39])[CH2:10][CH2:11][C:12](=[O:34])[N:13]([CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of (12S,15R)-benzyl 12-(tert-butoxycarbonylamino)-8-(2-(tert-butoxycarbonylamino)ethyl)-2,2-dimethyl-4,9,13-trioxo-15-(4-(trifluoromethyl)benzyl)-3-oxa-5,8,14-triazahexadecan-16-oate (3 g, 3.58 mmol) in a mixture of EtOH/H2O (18 mL/2 mL) was added palladium (wet) on carbon (catalytic amount). The reaction mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The catalyst was filtered through a pad of Celite. The filtrate was evaporated under reduced pressure to give (12S,15R)-12-(tert-butoxycarbonylamino)-8-(2-(tert-butoxycarbonylamino)ethyl)-2,2-dimethyl-4,9,13-trioxo-15-(4-(trifluoromethyl)benzyl)-3-oxa-5,8,14-triazahexadecan-16-oic acid (CLXVI) as white crystals (2.66 g, 3.56 mmol, 99% yield). 1H NMR (DMSO-d6) δ ppm 1.32 (s, 27H), 1.52-1.78 (m, 2H), 2.07-2.26 (m, 2H), 2.9-3.03 (m, 4H), 3.14-3.23 (m, 4H), 3.31 (brs, 2H), 3.83-3.92 (m, 1H), 4.4-4.46 (m, 1H), 6.74-6.85 (m, 2H), 6.88-6.94 (m, 1H), 7.38 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H), 7.94-8.01 (m, 1H); 19F NMR (DMSO-d6) δ ppm −60.24 (s, 3F); ESIMS found for C34H52F3N5O10 m/z 748.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH2:30][CH:31]1[CH2:33][CH:32]1[S:34](Cl)(=[O:36])=[O:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([CH:32]2[CH2:33][CH:31]2[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:36])=[O:35])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1CC1COCc1ccccc1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2COCc2ccccc2)c2n(c1=O)CCO2
Yield: 40.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.08 g, 0.0002 mol) in dry pyridine (2 ml) was reacted with 2-benzyloxymethyl-cyclopropanesulfonyl chloride (57 mg, 0.0002 mol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 51 mg of the product (21% yield).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]([C:12]1[S:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:17][C:14]1[S:13][C:12]([C:10](=[O:11])[CH:3]([NH:2][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CC(N)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of ethyl 3-amino-4-(5-chlorothiophen-2-yl)-4-oxobutyrate hydrochloride (596 mg), 4-fluorobenzoyl chloride (380 mg) and sodium hydrogen carbonate (1.0 g) in ethyl acetate (10 ml) and water (10 ml) was stirred at room temperature for 2 hours. To the reaction mixture were added ethyl acetate (30 ml) and water (30 ml), and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with hexane to obtain a crude product of ethyl 4-(5-chlorothiophen-2-yl)-3-[(4-fluorobenzoyl)amino]-4-oxobutyrate (732 mg) as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][C:14]1[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=1[S:25](Cl)(=[O:27])=[O:26]>>[CH3:13][C:14]1[CH:19]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:16][C:15]=1[S:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:27])=[O:26]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-methyl-4-trifluoromethoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (41.7 mg) with purity >90%. MS (pos) m/z 425.3.
Reaction SMILES: [CH:1]1([CH:7]([CH3:12])[C:8]([O:10]C)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>CO.O>[CH:1]1([CH:7]([CH3:12])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A reaction mixture of methyl 2-cyclohexylpropanoate (0.30 g, 1.8 mmol) and lithium hydroxide monohydrate (0.12 g, 2.8 mmol) in methanol (3.0 mL) and water (1.0 mL) was stirred at 60° C. for 2 h. The mixture was concentrated to remove methanol, washed with ether to remove some impurity, then adjusted to pH=2 with 1 N HCl (aqueous). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the crude product which was directly used for next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:17]COC)[CH:5]=1)(=[O:3])[CH3:2].C1CNC(=O)C1.[Br:27][Br-]Br.O>O1CCCC1>[Br:27][CH2:2][C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([OH:17])[CH:5]=1)=[O:3]
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1OCOC
Agent: O=C1CCCN1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C(=O)CBr)cc1O
Temperature: 25 °C
Reaction time: 21 h
Yield: 46 %

Procedure:
To a solution of ethyl 2-(4-acetyl-2-methoxymethoxyphenoxy)acetate (1.51 g) in tetrahydrofuran (30 ml) was added pyrrolidone hydrotribromide (2.92 g), and the mixture was stirred for 21 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/diethyl ether/dichloromethane=3/2/2) and subsequent crystallization from hexane and diethyl ether (1/1) gave ethyl 2-[4-(2-bromoacetyl)-2-hydroxyphenoxy]acetate (780 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:24]([C:26]1[CH:36]=[CH:35][C:29]([C:30]([N:32]=[C:33]=[O:34])=[O:31])=[CH:28][CH:27]=1)#[N:25]>C(#N)C>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33](=[O:34])[NH:2][C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)=[O:31])=[CH:35][CH:36]=1)#[N:25]
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Reactant: COC(=O)COc1ccc(N)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Yield: 52.6 %

Procedure:
Methyl 4-aminophenoxyacetate, hydrochloride salt (1.09 g), was dissolved, with warming, in acetonitrile (50 ml) containing diisopropylethylamine (0.86 ml). To this solution at ambient temperature was added gradually with stirring a solution of 4-cyanobenzoyl isocyanate (1 g, preparation described in Weikert, R. J. et al (1991), J. Med. Chem. 34, 1630) in acetonitrile (5 ml). The precipitated solid was crystallised from boiling acetonitrile to give methyl 4-[3-(4-cyanobenzoyl)ureido]phenoxyacetate (930 mg) as an off-white solid: m.p. 214°-217° C.; NMR Spectrum (DMSO-d6) 3.70 (3H, s), 4.77 (2H, s), 6.94 (2H, d), 7.48 (2H, d), 8.02 (2H, d), 8.12 (2H, d), 10.49 (1H, s), 11.19 (1H, s); Mass Spectrum m/Z 354 (M+H)+.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:20][CH3:21])=[N:12][C:13]([CH3:19])=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)C=CC=CC=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH2:35][CH2:34]2)=[O:22])[C:11]([O:20][CH3:21])=[N:12][C:13]=1[CH3:19])([CH3:17])[CH3:18]
Reactant: COc1nc(C)c(C(C)C)cc1NC(=O)Oc1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc(C)c(C(C)C)cc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 59 %

Procedure:
Phenyl-N-(5-isopropyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([N:14]1[C:18]2=[N:19][CH:20]=[CH:21][C:22](O)=[C:17]2[CH:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[CH2:7]([N:14]1[C:18]2=[N:19][CH:20]=[CH:21][C:22]([Cl:2])=[C:17]2[CH:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Oc1ccnc2c1cnn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2c1cnn2Cc1ccccc1
Temperature: 0 °C
Yield: 57679.9 %

Procedure:
Phosphorus oxychloride (60 ml) and phosphorus pentachloride (20 mg) were added to 1-benzyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine (13.8 g) and the mixture was refluxed under heating for 2 hours. After completion of the reaction, phosphorus oxychloride was distilled away under reduced pressure and the residue obtained was poured into ice water. The mixture was neutralized with 2N aqueous solution of sodium hydroxide and the resultant crystals were collected by filtration. After drying, the crystals were recrystallized from ethyl acetate-hexane to give 13.5 g of 1-benzyl-4-chloro-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].Cl.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26]>C(O)C>[ClH:14].[CH2:2]([CH:1]1[N:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])[C:25]([NH2:26])=[N:27][C:28]([NH2:30])=[N:29]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC=O
Reactant: N=C(N)NC(=N)Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(F)cc1F

Procedure:
100 ml of ethanol, 6.6 ml (29.9 mmol) of 1-dodecanal and 0.9 ml of concentrated hydrochloric acid were added to 5.0 g (20.0 mmol) of N1-(2,4-difluorophenyl)-biguanide hydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and recrystallized from 70% aqueous acetonitrile to obtain 3.9 g of colorless crystals having a melting point of 206 to 208° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](OCC)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)N1CCC(CO)CC1
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of ethyl 1-isopropylpiperidine-4-carboxylate (10.0 g, 50.2 mmol) in THF (250 mL) at 0° C. was treated with lithium aluminum hydride (2.1 g, 55 mmol). After 1 h, the mixture was treated with a saturated aqueous solution of sodium potassium tartrate, partitioned with EtOAc, and the aqueous layer washed with EtOAc (2×). The combined extracts were dried (Na2SO4), concentrated, and the residue purified by column chromatography (SiO2: 10% methanol:methylene chloride) affording 4.30 g (54%) of the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(O)c2cc(I)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)c2cc(I)ccc2n1
Temperature: 0 °C

Procedure:
4-Hydroxy-6-iodo-2-methylquinoline (10 g; see step (i) above) in phosphorous oxychloride (70 mL) was heated at 80° C. for 1 hour. The reaction mixture was then cautiously added to ice/water and solid sodium carbonate until the solution reached pH 8.0. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The resulting solid was triturated with diethyl ether to give the sub-title compound (6.4 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:32]12(O)[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2>C1COCC1.CN(C)C1C=CN=CC=1.CC(O)=O.CCOC(C)=O>[C:32]12([O:15][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Benzyloxycarbonyl-D-alanine (11.15 g, 50 mmol) was dissolved in 250 mL THF and treated with DCC (10.3 g, 50 mmol), 1-adamantanol (7.7 g, 51 mmol) and 1.45 g of 4-dimethylaminopyridine. The reaction mixture was stirred at room temperature. At the end of 24 hours, a few drops of HOAc was added and the reaction mixture was stirred for an additional 15 minutes. DCU was filtered off, the filtrate was evaporated to dryness under reduced pressure. The oily residue so obtained was dissolved in EtOAc and the solution was refrigerated overnight. More DCU was filtered off. The filtrate was then washed with 0.1N HCl (3×), H2O (3×), 0.1N NaOH (3×), H2O (3×) and dried over anhydrous Na2SO4. The solution was evaporated to dryness to give a clear oil. The oil was subjected to sublimation at 100°/0.1 mm for 5 hours. The oily residue was crystallized from hexane: mp 72°-74°, yield 11.6 g (75%), 250 MHz nmr (CDCl3, ppm) 1.37 (d, 3H, J=7.35 Hz, β--CH3 of Ala), 1.65 (s, 6H, adamantyl aliphatic protons of C's 4, 6 and 10), 2.09 (s, 6H, 1-adamantyl aliphatic protons of C's 2, 8 and 9), 2.16 (s, 3H, 1-adamantyl aliphatic protons of C's 3, 5 and 7), 4.23 (m, 1H, α--H of Ala), 5.09 (s, 2H, Ar--CH2 --O--), 5.32 (br.d, amide proton), 7.33 (s, 5H, ArH5).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C@H:8]([NH2:7])[CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A solution of 1.41 g (3.3 mmol) [2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethyl]-carbamic acid tert-butyl ester in 5 mL dichloromethane was treated with 1.5 mL 2,2,2-triflouroacetic acid and the resulting solution stirred 16 hours at 25° C. The mixture was concentrated at reduced pressure to a viscous amber oil to which was added 50 mL saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure affording a soft solid, that was recrystallized from 2,2,4-trimethylpentane containing about 5% ethyl acetate to afford 804 mg (77%) of (S)-2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylamine as light tan crystals; mp 180-182° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].CCOCC>[F:11][C:12]1[CH:13]=[C:14]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=2)[CH:15]=[CH:16][C:17]=1[CH:18]=[O:19]
Reactant: NC(=O)c1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOCC
Product: NC(=O)c1cccc(-c2ccc(C=O)c(F)c2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A 10 mL conical vial equipped with magnetic spin vane was charged with 3-bromobenzamide (0.200 g; 1.00 mmol; Ex IV-6), 3-fluoro-4-formyl-phenyl boronic acid (0.185 g; 1.1 mmol), tetra-n-butyl ammonium bromide (0.323 g; 1.0 mmol), Pd(OAc)2 (0.0011 g; 0.005 mmol), K2CO3 (0.345 g; 2.5 mmol) and sealed with a septum. The vial was evacuated/backfilled with nitrogen (×3), water was added via syringe and the mixture was stirred at 80° C. for 2.5 h. Upon cooling, the mixture was poured into water, layered with Et2O and sonicated ca. 2 min. Solid was collected by filtration and washed with Et2O, affording the title compound as a cream-colored solid (used without further purification). LC/MS (method A) 2.02 min; m/z 244 (M+H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[N:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCCC2)C1
Yield: 26.4 %

Procedure:
A solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (350 mg, 1.07 mmol), pyrrolidine (0.274 ml, 3.27 mmol), X-phos (30.5 mg, 0.064 mmol), tris(dibenzylideneacetone)dipalladium(0) (19.3 mg, 0.0212 mmol) and sodium tert-butoxide (154 mg, 1.60 mmol) in dioxane (7 ml) was stirred under an argon atmosphere for 2 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (90.0 mg, 26.4%) as an oil.