Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=1.C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[N:15]=[C:16]([NH:12][C@H:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:11])[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Reactant: Brc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2cc3ccccc3c(-c3cccc4ccccc34)c2P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cccc(Br)n1)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 32.6 %

Procedure:
A mixture of (1S)-1-(3-nitrophenyl)ethanamine (365 mg, 2.2 mmol), 2,6-dibromopyridine (474 mg, 2 mmol), tris(dibenzylidene)dipalladium(0) (92 mg, 0.1 mmol), (+/−)-bis(diphenyphosphino)-1,1′-binaphthalene (125 mg, 0.2 mmol) and sodium tert-butoxide (270 mg, 2.8 mmol) in anhydrous toluene (4 mL) was heated at 80° C. for 17 hours. The mixture was cooled, diluted with ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate (3×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure to give a black oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give 6-bromo-N-[(1S)-1-(3-nitrophenyl)ethyl]pyridin-2-amine (210 mg, 33%) and the di-addition product (205 mg, 50%) both as yellow oils.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[C@H:12]([C:33]([OH:35])=[O:34])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH:38]1[CH2:40][CH2:39]1>>[CH:38]1([CH2:37][NH:36][C:33]([C@@H:12]2[CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:14][N:13]2[CH2:15][C:16](=[O:32])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])=[CH:20][C:19]=2[F:31])=[O:35])[CH2:40][CH2:39]1.[CH:38]1([CH2:37][NH:36][C:33]([C@H:12]2[CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:14][N:13]2[CH2:15][C:16](=[O:32])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])=[CH:20][C:19]=2[F:31])=[O:34])[CH2:40][CH2:39]1
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)O)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: NCC1CC1
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@@H]1C(=O)NCC1CC1)Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)NCC1CC1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
Using general procedure D (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (example 12) was coupled with aminomethylcyclopropane to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]—1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid cyclopropylmethyl-amide and (2R,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid cyclopropylmethyl-amide. White solid (both products). MS 572.3 ([M+H]+)
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)=[O:19])[CH2:24]1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: CC1CCCNC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CCCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)C1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 3-methylpiperidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from isopropyl ether, 3-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]piperidine (1 g), melting at 116° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:32]#[N:33])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:8]=[C:7]2[CH:30]=[CH2:31].C(N(CC)CC)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Br[C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:32]#[N:33])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:8]=[C:7]2/[CH:30]=[CH:31]/[C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1
Reactant: Brc1cccnc1
Reactant: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c(F)cc(C#N)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, 2.59 g of 7-fluoro-1-trityl-3-vinyl-1H-indazole-5-carbonitrile was dissolved in 50 mL of acetonitrile, added with 10 mL of triethylamine, 271 mg of palladium acetate (II), 450 mg of 2-(di-tert-butylphosphino)biphenyl and 726 μl of 3-bromo pyridine, and refluxed overnight. The solution was cooled to room temperature, added with 10 g of silica gel, the solvent was evaporated, followed by purification by silica gel column chromatography, to afford 2.00 g of the title compound as yellow crystals.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([C:24]#[N:25])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].BrCC1CC1>C1COCC1>[C:24]([C:22]1([CH2:8][CH:9]2[CH2:11][CH2:10]2)[CH2:23][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH2:21]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: [Li]CCCC
Agent: BrCC1CC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CC(C#N)(CC2CC2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (3.33 g 4.64 ml; 32.92 mmol) in THF (60 ml) at 0° C. was added n-butyllithium (2.5M in hexanes; 13.17 ml; 32.92 mmol). The solution was stirred for 30 minutes then cooled to −78° C. A solution of 3-cyanoazetidine-1-carboxylic acid tert-butyl ester (5 g; 27.43 mmol) in THF (40 ml) was added and the solution stirred for 1 hour. (Bromomethyl)cyclopropane (4.81 g 3.42 ml; 35.67 mmol) was then added dropwise with stirring and the solution stirred for 30 minutes at −78° C., then allowed to warm to ambient temperature, and stirred for 3 hours. The reaction was cooled in an ice bath and quenched with saturated aqueous ammonium chloride. The solvent was evaporated and the residue was partitioned between EtOAc (300 ml) and water (100 ml). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. The crude product was passed through a silica gel plug eluted with 15% EtOAc DCM to give the product as a pale yellow oil. (5.25 g)
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][C:24]([CH3:27])([NH2:26])[CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][C:24]([NH:26][S:29]([CH3:28])(=[O:31])=[O:30])([CH3:27])[CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
Triethylamine (1.77 mL, 12.7 mmol) was added to a solution of N1-(2-chloro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine (2.5 g, 8.5 mmol) in dichloromethane (25 mL), and the resulting solution was cooled to 0° C. and stirred for five minutes. Methanesulfonyl chloride (1.07 g, 9.33 mmol) was added in portions over a period of five minutes, and the reaction was allowed to warm to ambient temperature and stirred overnight. An analysis by high-performance liquid chromatography (HPLC) indicated the reaction was incomplete, and additional methanesulfonyl chloride (0.5 equivalent) was added. The reaction was stirred for two hours and again determined to be incomplete. Additional methanesulfonyl chloride (0.5 equivalent) and triethylamine (1.5 equivalents) were added, and the reaction was stirred for two hours and then diluted with dichloromethane. The resulting solution was washed twice with brine and twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 3.1 g of N-{2-[(2-chloro-3-nitroquinolin-4-yl)amino]-1,1-dimethylethyl}methanesulfonamide as a yellow solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cnc(-c2ccc(F)cc2)s1
Temperature: 85 °C
Yield: 3.7 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (5.0 g, 26.04 mmol) in toluene (150 mL) and ethanol (75 mL) was added (4-fluorophenyl)boronic acid (7.29 g, 52.08 mmol), 2M sodium carbonate solution (73.58 mL), Pd(PPh3)4 (1.5 g, 1.3 mmol) under argon atmosphere. The resulting mixture was heated at 85° C. for 6 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (150 mL), and extracted with ethyl acetate (5×500 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressures to obtain crude product. The crude product was purified by Combiflash® chromatography (Mobile phase: 10% ethyl acetate in hexane) to give 2-(4-fluorophenyl)thiazole-5-carbaldehyde as off-white solid (200 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 8.74 (s, 1H), 8.14-8.11 (m, 2H), 7.39 (t, 2H); LC-MS m/z calculated for [M+H]+ 208.02, found 207.9.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.NN>C(O)CO>[CH3:12][C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccn1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1cccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A mixture of 1-phenylpyrrole-2-carbaldehyde (700 mg, 4.1 mmol), potassium hydroxide (490 mg, 12.3 mmol) and hydrazine hydrate (0.8 mL, 12.3 mmol) in ethylene glycol (15 mL) was stirred at ambient temperature for 30 min and then slowly heated to 150° C. and maintained for 2 h. The reaction mixture was allowed to cool to ambient temperature, poured into ice-water and extracted with diethyl ether. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over silica gel (60-120 mesh) using petroleum ether as eluent to afford 2-methyl-1-phenyl-pyrrole (430 mg, 66%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:18])[C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:13](=[O:14])[C:12]([N:11]([CH3:18])[CH3:10])([CH3:17])[CH3:16])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN(C)C(C)(C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(C)(C)C(=O)NNc1ccc(F)cn1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (200 mg, 1.57 mmol) in DMF (10.0 mL) was added 2-dimethylamino-2-methyl-propionic acid (206 mg, 1.57 mmol), EDC (332 mg, 1.73 mmol) and HOBt.H2O (21.0 mg, 0.16 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (195 mg, 51%). 1H NMR (300 MHz, CDCl3): 1.25 (6H, s), 2.28 (6H, s), 6.44 (1H, br s), 6.62 (1H, dd, J 9.1, 3.6), 7.27 (1H, ddd, J 9.1, 8.0, 3.1), 8.03 (1H, d, J 2.9), 9.04 (1H, br s).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[S:7][C:6]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:5][CH:4]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[ClH:1].[Cl:2][C:3]1[S:7][C:6]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:5][CH:4]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
4.0M hydrogen chloride in 1,4-dioxane (2.508 mL) was added to a solution of tert-butyl (S)-2-(5-chlorothiophen-2-yl)-3-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylisopropylcarbamate (283 mg, 0.502 mmol) in 1,4-dioxane (2.5 mL) and methylene chloride (2.5 mL) at 0° C. The mixture was allowed to warm up to room temperature and stirred for 1 hour. The mixture was concentrated in vacuo. The residue was then dissolved in a minimum volume of DCM (1 mL) and added dropwise to ether (10 mL) at 0° C. with stirring. A white solid precipitated. The solvents were evaporated with a rotovap in a 25° C. bath. The off-white solid was dried under high vacuum overnight to give (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (537 mg, 99.9%). MS (APCI+) [M+H]+ 464.1. 1H NMR (D20, 400 MHz) δ 8.53 (s, 1H), 6.97 (d, J=4.0 Hz, 1H), 6.96 (d, J=4.0 Hz, 1H), 5.40 (t, J=8.0 Hz, 1H), 4.78-4.71 (m, 1H), 4.31-4.27 (m, 1H), 4.09-3.97 (m, 2H), 3.84-3.42 (m, 10H), 2.36-2.30 (m, 1H), 2.21-2.13 (M, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H), 1.14 (d, J=6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][N:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.C([O:48][C:49](=O)[C@H:50]([OH:69])[CH2:51][N:52]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:62]=2[F:68])=[CH:57][CH:56]=1)[NH2:53])C.CCN(C(C)C)C(C)C.[CH2:80]([OH:84])[CH:81]([CH3:83])[CH3:82].Cl.O1CCOCC1>>[CH2:80]([O:84][C:49](=[O:48])[C@H:50]([OH:69])[CH2:51][N:52]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:62]=2[F:68])=[CH:57][CH:56]=1)[NH:53][C:13]([C:11]1[O:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:12]=1)=[O:15])[CH:81]([CH3:83])[CH3:82]
Reactant: O=C(O)c1cc(-c2ccccc2F)no1
Reactant: CC(C)CO
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
3-(2-fluorophenyl)isoxazole-5-carboxylic acid (15.4 mg, 74 μmol) and HATU (33.9 mg, 89 μmol) were stirred in DMA (0.5 mL, 5 mmol) for 10 minutes. (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (27.3 mg, 74 μmol) and DIPEA (38.9 μL, 223 μmol) were added, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was dissolved EtOAc (20 mL) and washed with water (2×2 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The product was then mixed with isobutyl alcohol (0.5 mL, 5 mmol) and 4.0 M HCl in 1,4-dioxane (93 μL, 372 mmol), and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in 50% AcOH-water (1.5 ml), filtered, and purified by reverse phase preparative HPLC to yield the title compound (1.7 mg, purity 100%) as a TFA salt. MS m/z [M+H]+ calc'd for C30H28ClF2N3O5, 584.17. found 584.4.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1Br)([CH3:3])[CH3:2].C([Li])CCC.[C:19](=[O:21])=[O:20]>Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[C:19]([OH:21])=[O:20])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: CC(C)c1cccc(C(C)C)c1Br
Agent: Cl
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)C)c1C(=O)O
Temperature: -29 °C
Reaction time: 1 h

Procedure:
2,6-Diisopropylbromobenzene (21.58 g, 0.0895 mol) was cooled to -23° C. under nitrogen and 2.5 M n-butyl lithium in hexanes (36 mL) was added dropwise as the temperature further cooled to -29° C. When the addition was complete, the reaction mixture was warmed to 0° C. and was stirred 1 hour at zero and was then poured onto a large excess of crushed dry ice. The mixture was stirred with a glass rod. When the dry ice had sublimed, hydrochloric acid (1N, 200 mL) was added and the mixture was extracted with ethyl ether, the ether washed with brine, dried (magnesium sulfate), filtered, and concentrated to a yellow oil. The oil was taken up in ether (200 mL), the ether solution extracted with sodium hydroxide solution (1N, 200 mL), the layers separated, the aqueous layer made acidic with 1.5N hydrochloric acid, brine added, and the aqueous layer extracted with ether (200 mL). The ether layer was washed with brine (50 mL), dried (magnesium sulfate), filtered and concentrated to an oil which solidified on standing, 13.42 g, 72.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:27](=O)[CH3:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH2:27][CH3:28])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl 4-{[5-chloro-3-(methoxycarbonyl)-2-methylphenyl]amino}piperidine-1-carboxylate (125 mg, 0.33 mmol) in 1,2-dichloroethane (1.6 ml) at room temperature under nitrogen was added acetaldehyde (37 μl, 0.65 mmol) followed by acetic acid (0.11 ml, 1.96 mmol). This solution was stirred for 5 minutes before adding sodium triacetoxyborohydride (0.21 g, 0.98 mmol) at room temperature. The reaction was monitored by LCMS and after 4.5 h a further acetaldehyde (73 μl, 1.31 mmol) and sodium triacetoxyborohydride (0.28 g, 1.31 mmol) were added to the reaction mixture. The mixture was stirred for a further 18 hours after which deionized water (10 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 131 mg (98%) of the title compound as a thick colourless oil. LC-MS 98%, m/z=433.5/435.1 (M+Na), 1H NMR (500 MHz, Chloroform-d) δ ppm 7.57 (1H, d, J=2.21 Hz), 7.22 (1H, d, J=2.05 Hz), 3.97-4.14 (2H, m), 3.90 (3H, s), 3.04 (2H, q, J=6.99 Hz), 2.81-2.91 (1H, m), 2.70 (2H, br. t, J=11.50, 11.50 Hz), 2.45 (3H, s), 1.69-1.80 (2H, m), 1.47-1.56 (2H, m), 1.46 (9H, s), 0.87 (3H, t, J=7.09 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][NH:9][CH3:10].[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:9]([CH3:10])[CH3:8]
Reactant: CNC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1ncc[nH]1
Temperature: 50 °C

Procedure:
To a two-necked round-bottomed flask equipped with a reflux condenser and a pressure-equalizing addition funnel, was added 2-imidazolecarboxaldehyde (6 g, 62.5 mmol) in MeOH (60 mL). To this suspension (ambient temperature) was added a solution of dimethylamine (40% aqueous, 60 mL) at a fast dropping rate (20 min). After the addition was complete, solid sodium borohydride (7 g, 186.8 mmol,) was CAUTIOUSLY added portionwise over 45 min. Foaming occurred after each portion, and the internal temperature was allowed to maintain ˜50° C. without external cooling. The reaction mixture was then heated to 65° C. for 3 h and allowed to cool to ambient temperature for overnight. The reaction contents were concentrated in vacuo and the resultant residue was taken up in EtOAc (2×30 mL) washed with brine and with CHCl3 (4×100 mL). The EtOAc extract was discarded. The CHCl3 extract was dried over (NaSO4), filtered, and concentrated in vacuo to give 3.7 g of the desired product as a waxy solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24]([CH:25]=O)=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OP([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24](/[CH:25]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 3-[{4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.27 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) under ice-cooling. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (2E)-3-[3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]-2-propenoate as colorless crystals (0.51 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.