Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:16]([O:18][C:19](=[O:35])[CH:20]([C:25]1[S:29][N:28]=[C:27]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[N:26]=1)[CH2:21][C:22]([OH:24])=O)[CH3:17].C(Cl)Cl.[O:39]1[C:43]2[CH:44]=[CH:45][C:46]([CH2:48][CH2:49][NH2:50])=[CH:47][C:42]=2[O:41][CH2:40]1>CCOC(C)=O>[CH2:16]([O:18][C:19](=[O:35])[CH:20]([C:25]1[S:29][N:28]=[C:27]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[N:26]=1)[CH2:21][C:22]([NH:50][CH2:49][CH2:48][C:46]1[CH:45]=[CH:44][C:43]2[O:39][CH2:40][O:41][C:42]=2[CH:47]=1)=[O:24])[CH3:17]
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C(CC(=O)O)c1nc(-n2ccnc2)ns1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(=O)NCCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.5 %

Procedure:
BOP-Cl (784 mg, 3.08 mmol) was added all at once to a solution 2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-succinic acid 1-ethyl ester (389 mg, 1.54 mmol) and DCM (10 mL) and stirred at room temperature for 30 min prior to addition of 2-benzo[1,3]dioxol-5-yl-ethylamine (620 mg, 3.08 mmol) and TEA (859 μL, 6.16 mmol). The reaction mixture stirred at r.t. for an additional 20 h. The solvent was evaporated to afford a white slurry oil, diluted with EtOAc (50 mL), washed with sat. NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to a white solid. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 17 mg (3%) of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-succinamic acid ethyl ester as a white solid. [M+H]+ 443.90; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.74 (s, 1H), 7.15 (s, 1H), 6.66-6.52 (m, 3H), 6.04 (br s, 1H), 5.86 (s, 2H), 4.31 (q, 2H), 3.78 (t, 1H), 3.63 (t, 2H), 3.16 (t, 2H), 2.83 (d, 2H), 1.32 (t, 3H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10](O)=[O:11].B(F)(F)F.CCOCC>ClCCl.O>[CH3:9][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])=[O:11]
Reactant: CC(=O)O
Reactant: Oc1ccccc1O
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cccc(O)c1O
Temperature: 25 °C
Yield: 10.4 %

Procedure:
To a solution of 1,2-dihydroxybenzene (28)(2.0 g, 18.2 mmol) in AcOH (1.3 g, 21.7 mmol) was added boron trifluoride diethyl ether (98% in Et2O, 2 mL). The mixture was reacted under microwave irradiation (300 W) for 1.5 min and then cooled to 25° C. The reaction mixture was dissolved in dichoromethane (10 mL) and H2O (about 20 mL). The organic lay was washed with 10% NaHCO3 and then with water, dried over MgSO4 and concentrated. The crude was purified by column chromatography (SiO2, CH2Cl2) to give 30. Yellow solid; yield: 10.4%; mp 76-77° C.; 1H-NMR (CDCl3,200 MHz): δ 2.58 (s, 3H), 5.79 (s, 1H), 6.79 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 12.45 (s, 1H); 13C-NMR (CDCl3, 50 MHz): δ 26.73, 118.79, 119.52, 120.39, 121.44, 145.40, 149.50, 205.08; Anal. calcd for C8H8O3: C, 63.15; H, 5.30. Found: C, 63.10; H, 5.33.
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:35])[CH:20]([C:22](=[O:34])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[CH3:21])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH2:9][NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:35])[CH:20]([CH3:21])[C:22]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=1)=[O:34])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)C(C)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)C(C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (173 mg, 0.46 mmol, prepared as described in WO PCT 0250019) was dissolved in 5 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with 2-methyl-malonic acid (54 mg, 0.46 mmol), meta-trifluoromethylaniline (0.06 mL, 0.46 mmol), N,N-diisopropylethylamine (0.8 mL, 4.6 mmol) and HATU (434 mg, 1.1 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 17% yield). MS found: (M+Na)+=528.4. (25b) A solution of {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 0.08 mmol) in MeOH (2 mL) was charged with 5% Pd/C, Degussa style (8 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (2 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.009 mL, 0.06 mmol) and sodium cyanoborohydride (5 mg, 0.08 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=494.4.
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)[CH2:19][CH2:18]2.[Li+].C[Si]([N-:36][Si](C)(C)C)(C)C>C1COCC1.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]>[CH3:30][N:27]1[CH2:28][CH2:29][CH:24]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([NH2:36])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[CH2:25][CH2:26]1
Reactant: CN1CCC(N2CCc3cc(Br)ccc32)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1CCC(N2CCc3cc(N)ccc32)CC1
Temperature: 100 °C
Yield: 35.7 %

Procedure:
Pd2(dba)3 (0.077 g, 0.084 mmol) in dry THF (3 mL) was treated with PtBu3 (1.04 mL, 0.338 mmol, 10% wt in hexanes) at room temperature. The mixture was treated with compound 3 (0.5 g, 1.693 mmol) in dry THF (7 mL) followed by LiHMDS (3.4 mL, 3.387 mmol, 1 M solution in THF) and the resulting mixture was stirred at 100° C. (sealed tube) for 2 h. The reaction was brought to room temperature, quenched with 1 N HCl solution (10 mL) and stirred for 10 min. The solution was made basic with 1 N NaOH solution (50 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography on silica gel (2 M NH3 in MeOH:CH2Cl2, 2:98 to 5:95) to obtain compound 4 (0.14 g, 36%) as a foam that was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[C:8](=[O:14])[C:7]=2[CH:15]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>CC#N.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.O>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[C:8](=[O:14])[C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)N(C)CCC2
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])CCCN(C)C2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
A mixture of 8-Methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (227 mgs, 1.1 mmol) in MeCN/TFAA (1:1, 2 mL) was cooled to 0° C. and treated with potassium nitrate (123 mg, 1.2 mmol), then warmed to room temperature and stirred for 2 h. Poured mixture in water, extracted (EtOAc), washed with brine and the organic layer dried (MgSO4), filtered and concentrated. ISCO purification (0 to 100% EtOAc/hexane, 40 g SiO2 column) provided 8-Methoxy-2-methyl-7-nitro-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (40 mgs). 1H-NMR (CDCl3) δ δ 7.63 (s, 1H), 7.41 (s, 1H), 3.98 (s, 3H), 3.24 (t, J=6.3 Hz, 2H), 3.19 (s, 3H), 2.78 (t, J=7.1 Hz, 2H), 2.10-2.04 (m, 2H); LC/MS (ESI+): 250.98 (M+H). The regioisomer 8-Methoxy-2-methyl-9-nitro-2,3,4,5-tetrahydro-benzo[c]azepin-1-one was also isolated as a mixture with 8-Methoxy-2-methyl-7-nitro-2,3,4,5-tetrahydro-benzo[c]azepin-1-one. 1H-NMR (CDCl3) δ 7.22 (d, J=8.6 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 3.32 (t, J=6.1 Hz, 2H), 3.15 (s, 3H), 2.72 (t, J=6.8 Hz, 2H), 2.06-1.99 (m, 2H); LC/MS (ESI+): 250.98 (M+H).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH:22]=1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1cccnc1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccnc2)c1
Yield: 23.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (88 mg, yield: 23.1%).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Br:13])[NH:4][C:3]1=O.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Br:13])[N:4]2[CH:16]=[N:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]12
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Product: CCOC(=O)c1ncn2c3cccc(Br)c3c(=O)n(C)c12

Procedure:
M.p. 272° C. by reaction between 3-methyl-5-bromo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([P:9]([CH2:16][CH:17]([C:19]#[N:20])[CH3:18])(=[O:15])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8].O>C(OCC)C>[CH2:7]([P:9]([CH2:16][CH:17]([CH3:18])[CH2:19][NH2:20])(=[O:15])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8]
Reactant: CCCCOP(=O)(CC)CC(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCOP(=O)(CC)CC(C)CN
Yield: 85 %

Procedure:
At room temperature, 2.3 g (0.06 mol) of lithium aluminum hydride in 100 ml absolute diethyl ether in a three-neck flask equipped with stirrer, dropping funnel and high-performance condenser are, while continuously stirring, admixed with a solution of 21.7 g (0.1 mol) of butyl ethyl(2-cyano-2-methylethyl)phosphinate (produced similarly to Example 10) in 100 ml of diethyl ether added dropwise at such a rate that there is a moderate boil of the diethyl ether. This is followed by refluxing for 1 hour and admixing of the reaction solution with 1.8 g (0.1 mol) of water, and the insoluble salts are filtered off, the solvent is removed in vacuo and the product is purified by chromatography to obtain 18.8 g (85% of theory) of butyl ethyl(2-methyl-3-aminopropyl)phosphinate as colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=2[C:24](O)=[S:25])[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1.[NH2:38][C:39]1[C:40]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=2)=[O:46])=[N:41][CH:42]=[CH:43][CH:44]=1>CN(C=O)C.C(Cl)Cl>[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:16][CH2:17][C@H:18]([O:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=2[C:24]([NH:38][C:39]2[C:40]([C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=3)=[O:46])=[N:41][CH:42]=[CH:43][CH:44]=2)=[S:25])[CH2:19][CH2:20]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: Cc1ccc(C(O)=S)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.18 h

Procedure:
A solution of oxalyl chloride (1.6 mL, 18 mmol) and CH2Cl2 (12 mL) was added over 7 min to a solution of 2-(cis-4-tert-butoxycarbonylaminocyclohexyloxy)-4-methylthiobenzoic acid (7.00 g, 18.3 mmol), DMF (71 μL, 0.92 mmol), pyridine (1.5 mL, 18.9 mmol) and CH2Cl2 (62 mL) cooled in an ice bath. The bath was removed after the addition was complete. After 1 h the resulting yellow solution was added dropwise over 35 min to a slurry of 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (4.48 g, 18.0 mmol), pyridine (2.2 mL, 28 mmol), and CH2Cl2 (52 mL) cooled in an ice bath. At the end of the addition the bath was removed, and the mixture became homogeneous over 10-12 min, but became opaque again within 2 h. After 4 h the mixture was poured into satd citric acid (100 mL) and water (50 mL). The organic layer was extracted with a 1:1.5 solution of satd citric acid/water (125 mL), and the combined aqueous layers were back-extracted with CH2Cl2 (50 mL). The combined organic layers were rinsed with 25% NaCl (50 mL), heated to reflux on a steam bath to dissolve residual solids, dried (Na2SO4) and concentrated to a bright yellow solid (12.30 g) which was purified by flash chromatography (5% EtOAc/CH2Cl2, followed by 10% EtOAc/CH2Cl2) to provide 8.98 g (80%) of white foam.
Reaction SMILES: [C:1]12([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=5)[CH:19]=4)[CH2:14][C:13]3=[O:29])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[CH2:31][C:32]1[N:33]=[CH:34][N:35]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[C:1]12([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=5)[CH:19]=4)[C:14]([CH2:31][C:32]4[N:33]=[CH:34][N:35]([C:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[CH:36]=4)([CH2:31][C:32]4[N:33]=[CH:34][N:35]([C:37]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:36]=4)[C:13]3=[O:29])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: N#Cc1ccc(-c2ccc3c(c2)N(CC24CC5CC(CC(C5)C2)C4)C(=O)C3)cc1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc3c(c2)N(CC24CC5CC(CC(C5)C2)C4)C(=O)C3(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 8 h
Yield: 26.5 %

Procedure:
4-(1-Adamantan-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzonitrile (191 mg, 0.50 mmol) and 4-chloromethyl-1-trityl-1H-imidazole compound (449 mg, 1.25 mmol) were dissolved in 5 ml of anhydrous THF under an atmosphere of dry N2. To this solution was added 95% KHMDS (220 mg, 1.05 mmol) and the reaction mixture was subsequently stirred overnight. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a purple foam which was chromatographed on flash silica gel eluting with a gradient of CHCl3 to CHCl3/MeOH/NH4OH (98/2/0.01) to give 136 mg of the titled compound as a pink oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5].[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:25])[C:4]([NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:26])[CH:32]=2)=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(OS(=O)(=O)C(F)(F)F)cc1O
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)NC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 85 °C
Yield: 73 %

Procedure:
To a degassed solution of 2-[(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester (0.17 g, 0.44 mmol) in 1,4-dioxane (3 mL) at room temperature under N2 is added 3-chlorophenyl boronic acid (0.082 g, 0.53 mmol), K3PO4 (0.112 g, 0.53 mmol) and Pd(dppf)Cl2 (0.036 g, 0.04 mmol). The resulting suspension is heated to 85° C. in a sealed tube for 20 hours. After cooling, the reaction solution is filtered through Celite™ and the collected solids are washed with additional MeOH. The filtrate and washings are concentrated under reduced pressure and the residue dissolved in CH2Cl2 and washed with 10% citric acid. The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified over silica (EtOAc:heptane 1:4) to afford 0.112 g (73% yield) of the desired compound as a colorless oil. 1H NMR (250 MHz, CDCl3) δ ppm 11.83 (1 H, br s), 8.29 (1 H, br s), 8.10 (1 H, d, J=2.0 Hz), 7.40 (1 H, m), 7.08-7.34 (4 H, m), 3.65 (3 H, s), 1.55 (6 H, s). HPLC-MS: m/z 349 [M+H]+.
Reaction SMILES: [I:1]Cl.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1>CO.C(O)(=O)C>[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[I:1]
Reactant: ClI
Reactant: NC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 30.2 %

Procedure:
A sample of 47 g (0.29 mole) of ICl was added to a solution of 40 g (0.29 mole) of 4-hydroxybenzamide in 400 ml of MeOH and 800 ml of acetic acid in the absence of light. The mixture was stirred for 70 hr under N2 at 25° C. A precipitate was collected by filtration. The filtrate was diluted with water and a second crop of crystals collected by filtration. A third crop was obtained by evaporation of solvent from the second filtrate. The combined solids were recrystallized from 95% ethanol. The solid which precipitated and was collected (28 g). It was largely diiodinated material. The filtrate was evaporated in vacuo and the residue recrystallized from MeOH. The precipitated solid was collected by filtration (2.0 g). It was again diiodinated material. The filtrate was concentrated to dryness in vacuo to give 23 g (30% yield) of brownish crystalline 4-hydroxy-3-iodobenzamide, mp 90°-95° C.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[C:27]=4[F:35])=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[C:27]=3[F:35])=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91 %

Procedure:
A solution of (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared in Example 118, 0.163 g, 0.30 mmol) in tetrahydrofuran (15 mL) was treated with 2N aqueous hydrochloric acid (7.5 mL). The reaction mixture was stirred for 3.5 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by ISCO column chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100%, (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.135 g, 90%) as an off-white solid: HR-ES-MS m/z calculated for C23H28F2N4O6, [M+H]+ 495.205 observed 495.205; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.43 (br. s., 1H), 1.49-1.67 (m, 1H), 1.67-1.87 (m, 1H), 3.18-3.32 (m, 2H), 3.69-3.86 (m, 2H), 3.87 (s, 3H), 4.09 (dd, J=13.6, 2.7 Hz, 1H), 4.27 (d, J=18.7 Hz, 1H), 4.63 (d, J=18.7 Hz, 1H), 4.71 (t, J=4.8 Hz, 1H), 4.81-4.91 (m, 1H), 4.94 (d, J=4.8 Hz, 1H), 5.06 (s, 1H), 6.40 (br. s., 1H), 7.09-7.24 (m, 1H), 7.24-7.38 (m, 1H), 7.53 (br. s., 1H), 10.79 (br. s., 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:42])[CH:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:30]=2)[NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20]C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:12])=[CH:3][CH:2]=1.[ClH:43].O1CCOCC1>O1CCOCC1>[ClH:43].[ClH:43].[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:42])[CH:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:30]=2)[NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)=[O:12])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(Cc2cccc(Oc3ccccc3)c2)C(=O)Nc2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](C(=O)NC(Cc2cccc(Oc3ccccc3)c2)C(=O)Nc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (III) (1.60 g) was dissolved in dry 1,4-dioxane (5 ml) and a 4N-hydrogen chloride/1,4-dioxane solution (30 ml) was added, followed by stirring at room temperature. After one hour, the precipitated crystalline substance was recovered by filtration, followed by washing with diethylether, and after drying in vacuo, the desired N-(trans-4-aminomethylcyclohexylcarbonyl)-3-phenoxy-DL-phenylalanine 4-pyridylamide dihydrochloride (1.57 g), which was confirmed by NMR spectrum analysis, was obtained in the form of a hygroscopic white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[Cu][C:11]#[N:12]>CN(C=O)C>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[N:3][CH:4]=1)=[O:9]
Reactant: N#C[Cu]
Reactant: O=Cc1ccc(Br)nc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)cn1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
A suspension of 2-bromo-5-formylpyridine (940 mg, 5.05 mmol) and copper (I) cyanide (233 μL, 7.58 mmol) in DMF (8.4 mL) was stirred at 120° C. for 1.5 hours, cooled to RT, and partitioned between water and EtOAc. The solids were removed from the aqueous layer by filtration, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica-gel chromatography, eluting with a gradient of 40%-60% (40% ethyl acetate in heptane) in heptane, to provide the title compound (236 mg, 1.786 mmol) as white solid. LC/MS (ESI+) m/z=133 (M+H)+.