Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH:24]=[CH2:25])([CH3:22])[C:11]1=[O:26])=[O:4].B1C2CCCC1CCC2.[OH-:42].[Na+].OO>C1COCC1.CCO>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:30])[CH3:31])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[C:11](=[O:26])[C@:12]([CH2:23][CH2:24][CH2:25][OH:42])([CH3:22])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CC[C@@]1(C)OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@@](C)(CCCO)OC[C@H]2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-((2R,5R)-2-allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (50 mg, 0.11 mmol, 1.0 equiv) in THF (1.0 mL) was added 9-BBN (0.5 M solution in THF, 0.55 ml, 0.27 mmol, 2.5 equiv) at 0° C. The reaction mixture was then stirred at room temperature for 2 hours. To the solution was then cooled in an ice water bath and was added EtOH, followed by aq. NaOH solution and H2O2 aq. solution. During addition the reaction internal temperature was kept between 5° C. and 10° C. The reaction mixture was then heated to reflux for 90 minutes. After cooled at room temperature, the reaction mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the product 26 mg. MW: 462.2 [M+H]+. 1H-NMR (400 MHz, MeOD): δ 6.91 (s, 1H), 4.23 (d, 1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45 (s, 3H), 1.32 (s, 9H), 1.21 (m, 4H), 1.05 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12](=O)N(C)C)=[C:7]([Cl:17])[CH:6]=1.C[O-].[Na+].BrC[CH2:24][CH2:25][O:26][C:27]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]2[C:30]([CH:31]=[C:32]([CH2:41][CH3:42])[C:33](=[O:40])[O:34]2)=[CH:29][CH:28]=1>CO>[Cl:17][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[CH:10]=[CH:9][C:8]=1[S:11][CH2:12][CH2:24][CH2:25][O:26][C:27]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]2[C:30]([CH:31]=[C:32]([CH2:41][CH3:42])[C:33](=[O:40])[O:34]2)=[CH:29][CH:28]=1
Reactant: CCCc1c(OCCCBr)ccc2cc(CC)c(=O)oc12
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2cc(CC)c(=O)oc12
Temperature: 70 °C

Procedure:
To a solution of 3-chloro-4-dimethylcarbamoylthiophenylacetic acid methyl ester (54 mg, 0.1656 mmol) in 0.50 mL methanol was added a 0.5M solution of sodium methoxide (0.33 mL, 0.1656 mmol) in methanol. This mixture was heated to 70° C. for 90 minutes. After cooling to ambient temperature, a solution of 7-(3-bromopropoxy)-3-ethyl-8-propylcoumarin (Step D; 54 mg, 0.1656 mmol) in 1.2 mL methanol was added dropwise. The mixture was heated to 70° C. for several hours. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic mixture was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]([OH:19])[CH3:18])=[O:14])=[CH:9][CH:8]=1)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:19])[CH3:18])=[O:14])=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(O)C(NC(=O)c1ccc(NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)C(NC(=O)c1ccc(NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
a mixture of 2-chloro-N-(4-(((2-hydroxy-1-phenylpropyl)amino) carbonyl)phenyl)benzamide (294 mg, 719 μmol) and Dess-Martin periodinane (335 mg, 791 μmol) in 5 mL dichloromethane+1 mL DMF was stirred at room temperature for 2 hours then diluted with 20 mL ethyl acetate and washed with 10 mL each water and brine. The organic layer was stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow solid. The solid was slurried in hot ethyl acetate and left to equilibrate to room temperature. After 48 h, the solid was collected by filtration, rinsing with ethyl acetate and drying over a stream of air (200 mg, 68%). ESI+ m/z=407.0 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH2:13])[CH:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][C:20](Cl)=[O:21].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:20](=[O:21])[CH2:19][C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOc1nc(N)cc(N)c1C#N
Solvent: O
Solvent: c1ccncc1
Product: CCOc1nc(NC(=O)Cc2cccs2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.4 %

Procedure:
To 50 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile in 1 mL of pyridine was added 150 μL (1.21 mmol) of 2-thiopheneacetyl chloride, dropwise. The mixture was stirred for 5 min at ambient temperature, then 1 mL of water was added. The mixture was stirred for an additional 30 minutes then concentrated under reduced pressure. The residue was taken up in 10 mL of ethyl acetate, extracted with water (2×5 mL), 1M HCl(aq.) (1×5 mL), saturated NaHCO3(aq.) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was partially purified via silica gel chromatography, eluting with 30% ethyl acetate:hexanes to provide a sticky, yellow solid. This was triturated with methanol to provide 8 mg (9%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.33 (s, 1H), 7.38 (m, 1H), 7.18 (s, 1H), 6.97 (m, 2H), 6.92 (s, 2H), 4.34 (q, 2H, J=7.1 Hz), 3.94 (s, 2H), 1.30 (t, 3H, J=7.1 Hz); MS (ESI) m/e=275 (M−Et+H)+, 303 (M+H)+, 301 (M−H)−.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)Cl)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(C)C>[C:11]([NH:4][CH2:3][CH2:1][OH:2])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Solvent: CC(C)O
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A mixture of isopropanol (750 ml), diethylaminc (75 ml), ethanolamine (98%, 62.3 g, 1 mole) and triphenylchloromethane (97%, 143.7 g, 0.50 moles) was stirred at room temperature for 3 hours. The resulting solution was then poured into ice-cold water (4 l) under continuous stirring and the resulting precipitate was filtered off and dried. The crude product was digested in toluene (340 ml), then filtered off and dried in vacuo at 60° C. Thus 130 g (85%) of the pure desired compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=O)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].C(Cl)Cl>>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[CH2:34]([O:33][C:31]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][NH:8]1)=[O:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CN[C@H](C(=O)OCc2ccccc2)C1)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
A mixture of 20 mL TFA/DCM (1:1) at 0° C. was added to (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (0.92 g, 0.17 mmol) at 0° C., the cooling bath was removed and the mixture stirred for 2 h. The mixture was concentrated and triturated with diethyl ether to give (2S,4S)-4-(9H-Fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester trifluoroacetate (0.94 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:12][N:13]([CH2:18][C:19](O)=[O:20])[CH2:14][C:15](O)=[O:16].CS(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([B:9]2[O:11][C:19](=[O:20])[CH2:18][N:13]([CH3:12])[CH2:14][C:15](=[O:16])[O:10]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CC(=O)OB(c2cc(Br)cnc2F)OC(=O)C1
Yield: 82 %

Procedure:
5-Bromo-2-fluoropyridin-3-ylboronic acid (14.87 g, 67.7 mmol) (Frontier Scientific) and 2,2′-(methylazanediyl)diacetic acid (10.95 g, 74.4 mmol) (Aldrich) were dissolved in toluene (242 mL) and DMSO (97 mL) and the resulting mixture was heated at reflux under a Dean Stark trap for 2 h. After water (>2.5 mL) was collected in the trap, the reaction mixture was concentrated in vacuo to remove toluene, and water was slowly added to the resulting solution until the desired product precipitated as a white solid. This solid was collected by vacuum filteration, washed with water, and dried in a vacuum oven to give the title compound (82% yield) as a fluffy white solid. m/z (ESI, +ve ion) 330.8/332.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:7]([CH:8]=O)[C:6]1([CH3:11])[CH3:10])=[O:4].[C:12](#[N:17])[CH2:13][CH:14]=[CH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:7](/[CH:8]=[C:13](\[C:12]#[N:17])/[CH:14]=[CH:15]/[CH3:16])[C:6]1([CH3:11])[CH3:10])=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](C=O)C1(C)C
Reactant: CC=CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C=C/C(C#N)=C/[C@@H]1[C@@H](C(=O)OC)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.5 %

Procedure:
Methyl-(1R)-trans-3-formyl-2,2-dimethylcyclopropane carboxylate (2.53 g, 16.2 mmol), 3-pentenonitrile (1.90 g, 23.5 mmol) and anhydrous potassium carbonate (3.22 g, 23.3 mmol) were added to 30 mL of N,N-dimethylformamide and the mixture was stirred at room temperature for 24 hours. The reaction solution was added to 100 mL of ice water and the solution was extracted twice with each 100 mL of ethyl acetate. The obtained ethyl acetate layers were combined, washed once with 50 mL of saturated brine and then dried over magnesium sulfate. After concentration under reduced pressure condition, the residue was subjected to silica gel column chromatography to obtain 0.94 g of methyl-(1R)-trans-3-[(1Z,3E)-2-cyano-1,3-pentadienyl]-2,2-dimethylcyclopropane carboxylate represented by the following formula:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[CH:8]=1>[I-].[K+].O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[CH:8]=1
Reactant: CNCCO
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CN(CCO)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a microwave reaction tube 2-(methylamino)ethanol (1.652 g, 22 mmol), 6-chloropyrimidine-2,4(1H,3H)-dione (1.465 g, 10 mmol), potassium iodide (KI) (0.017 g, 0.1 mmol) and water (20 mL) were added. The mixture was heated to 120° C. by microwave (Biotage Initiator) and stirred for 2 h. Then the solution was concentrated in vacuo to remove all the water. EtOH (10 mL) was added to the resultant residue. The suspension was filtered and the filter cake was collected to afford the title compound as a light-yellow solid (1.390 g, 75% yield),
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.C([O:34][C:35](=[O:55])[C:36]([CH3:54])([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[C:40]([O:45][CH3:46])[CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:41]3[CH:42]=[CH:43][C:38]([CH2:37][C:36]([CH3:54])([O:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:35]([OH:55])=[O:34])=[CH:39][C:40]=3[O:45][CH3:46])[N:11]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)c(OC)c1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Solvent: CCO
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 1, Part I) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass directed HPLC to provide analytically pure material. MS (EI) 564.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:25]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: Nc1cccnc1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-aminopyridine, the desired compound was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:63])=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[C@@H:51]([CH3:62])[CH2:50]3)[CH:43]=2)[CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:54][CH2:53][NH:52][C@@H:51]([CH3:62])[CH2:50]6)[CH:43]=5)[C:39]([F:63])=[CH:38][CH:37]=4)=[O:28])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of 4-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino) carbonyl]benzoic acid (0.0452 g, 0.10 mmol) in DCM (1.0 mL) was added 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazine carboxylate (0.0414 g, 0.10 mmol), HBTU (0.0569 g, 0.15 mmol), and Et3N (0.0281 mL, 0.20 mmol). This mixture was stirred at room temperature for 1 h, concentrated, and purified using a Gilson HPLC (with TFA). TFA (1 drop in each tube ˜12 mL), was added to Fractions containing product and solvent was concentrated using a GeneVav EZ-2 evaporator. The compound was purified again using a Gilson HPLC (with TFA) and evaporating the solvent using a GeneVav EZ-2 evaporator. Then product was basified with an amine cartridge to afford 0.0234 g (31%) of the title compound. LC-MS m/z 747 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.33 (d, J=6.78 Hz, 3 H) 1.41 (t, J=7.53 Hz, 3 H) 1.50 (t, J=7.15 Hz, 3 H) 1.80-1.97 (m, 2 H) 2.06-2.15 (m, J=13.05 Hz, 2 H) 2.57-2.69 (m, 1 H) 2.75-2.88 (m, J=15.06 Hz, 1 H) 3.11-3.20 (m, 2 H) 3.33-3.39 (m, 3 H) 3.46-3.56 (m, J=13.80 Hz, 2 H) 3.64-3.74 (m, 2 H) 4.00-4.10 (m, J=3.01 Hz, 4 H) 4.31-4.42 (m, 1 H) 4.47 (q, J=7.19 Hz, 2 H) 4.58-4.64 (m, 2 H) 4.70-4.77 (m, 2 H) 7.18 (dd, J=10.54, 8.53 Hz, 1 H) 7.37-7.42 (m, 1 H) 7.43-7.47 (m, 1 H) 7.48-7.54 (m, 2 H) 7.54-7.59 (m, 1 H) 7.62-7.66 (m, 1 H) 7.93-8.01 (m, 4 H) 8.30 (s, 1 H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:43]1([CH:49](O)[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[C:43]1([CH:49]([O:2][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCC(O)c1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(OC(=O)CN1CCC[C@H]1C(=O)N(Cc1ccccc1)C(=O)[C@@H](N)[C@@H](C)CC)c1ccccc1
Yield: 40.5 %

Procedure:
A solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (59 mg, 0.16 mmol), 4-N,N-dimethylaminopyridine (7.9 mg, 0.06 mmol, 0.4 eq), 1,3-dicyclohexylcarbodiimide (49 mg, 0.23 mmol, 1.5 eq) in dichloromethane (5.0 mL) was treated with (±) 1-phenyl-1-propanol (28 uL, 0.20 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 32 mg (41%) of L-isoleucine, N-[1-(2-(1-phenylpropoxy)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[F:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21](=[O:23])=[O:22]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])=[C:6]([CH:7]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: Fc1ccc(Br)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 1-bromo-2,3,4-trifluorobenzene (1) (5.0 mL, 41.7 mmol) in THF (120 mL) was added LiHMDS (2.0 M solution, 21 mL, 42 mmol) at −78° C. After stirring for 1 hour at −78° C., the mixture was added to a solution of CO2 in THF (1 L). The dry-ice bath was removed and the reaction mixture stirred overnight at room temperature. The reaction mixture was quenched with 10% aqueous HCl (835 mL), concentrated, and washed with ether (250 mL). The combined organics were washed with 5% aqueous NaOH (300 mL) and water (100 mL). The aqueous layer was acidified (pH 0) with concentrated HCl. The resulting suspension was extracted with ether (2×300 mL), dried over MgSO4, filtered, concentrated under reduced pressure to afford 7.70 g (72% yield) of the desired product (2).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=1>>[C:1]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: CCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 63.8 %

Procedure:
In a manner similar to that described in Example 3, butyryl chloride (0.033 g, 0.00031 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.042 g of 4-[4-(butyrylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+264.
Reaction SMILES: Cl.O1CCOCC1.C([O:12][C:13](=[O:39])[CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:38])=[C:24]([O:26][CH:27]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=3[Cl:37])[CH3:28])[CH:25]=2)[N:17]=[CH:16]1)(C)(C)C>ClCCl>[NH2:38][C:23]1[N:22]=[CH:21][C:20]([C:18]2[N:17]=[CH:16][N:15]([CH2:14][C:13]([OH:39])=[O:12])[CH:19]=2)=[CH:25][C:24]=1[O:26][CH:27]([C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=1[Cl:37])[CH3:28]
Reactant: CC(Oc1cc(-c2cn(CC(=O)OC(C)(C)C)cn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(Oc1cc(-c2cn(CC(=O)O)cn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 48 h
Yield: 108.4 %

Procedure:
A 4 M solution of hydrochloric acid in dioxane (0.22 mL, 0.89 mmol) was added to a solution of (4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-imidazol-1-yl)-acetic acid tert-butyl ester (86 mg, 0.18 mmol) in dichloromethane (2 mL). After stirring for two days the reaction was concentrated by rotary evaporation and the residue was dissolved in a minimum amount of methanol. This solution was added dropwise to ether and the resulting mixture allowed to stand overnight. The mixture was filtered and the precipitate was washed with ether and air dried to give (4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-imidazol-1-yl)-acetic acid (83 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([SH:24])[CH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([S:24][CH2:22][CH3:23])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Reactant: CCS
Product: CCSc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A5(a) from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ethyl mercaptan. White solid. MS (m/e): 292.1 ([M+H-Me2C═CH2]+, 100%).