Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[OH:4].NC[C@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)O.C(N(CC)C(C)C)(C)C.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47](F)[N:46]=1>O1CCOCC1.C(OCC)(=O)C>[F:44][C:45]1[N:46]=[C:47]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[OH:4])[CH:48]=[CH:49][CH:50]=1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Reactant: Fc1cccc(F)n1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNc1cccc(F)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 100 mg (0.41 mmol) of tert-butyl (1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl (1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate and 0.07 mL (0.46 mmol) of N,N-diisopropylethylamine in 0.5 mL dioxane was added 0.042 mL (0.46 mmol) of 2,6-difluoropyridine. The reaction mixture was stirred at 45° C. for 16 h, then at 50° C. for 20 h. The reaction mixture was then allowed to cool before being diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (3:7) to afford 40 mg (29%) of tert-butyl (1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate. ES-LCMS m/z 364 (M+Na).
Reaction SMILES: CN1CCCC1=O.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Sn](C)(C)[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:39][CH:38]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:37][N:36]=2)=[CH:31][CH:30]=1.[CH3:47][C:48]([O:51][C:52]([N:54]1[CH2:59][CH:58]=[C:57](OS(C(F)(F)F)(=O)=O)[CH2:56][CH2:55]1)=[O:53])([CH3:50])[CH3:49]>C(OCC)(=O)C.O.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]>[C:42]([NH:41][CH2:40][CH:38]1[O:37][N:36]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([C:57]3[CH2:58][CH2:59][N:54]([C:52]([O:51][C:48]([CH3:50])([CH3:49])[CH3:47])=[O:53])[CH2:55][CH:56]=3)=[CH:30][CH:31]=2)[CH2:39]1)(=[O:44])[CH3:43]
Reactant: CC(=O)NCC1CC(c2ccc([Sn](C)(C)C)cc2)=NO1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)NCC1CC(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)=NO1
Reaction time: 12 h

Procedure:
To a flame dried flask containing a pre-stirred slurry of 1-methyl-2-pyrrolidinone (15 mL), tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol), triphenylarsine (4 mg, 0.12 mmol) under an inert atmosphere is added N-[[4,5-dihydro-3-[4-(trimethylstannyl)phenyl]-5-isoxazolyl]methyl]acetamide (580 mg, 1.52 mmol) and 3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (450 mg, 1.37 mmol) and stirred for 12 hours. The reaction is diluted with ethyl acetate (100 mL) and water (50 mL). The organic phase is separated, extracted with water (5×50 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with methylene chloride/methanol (99/1). The appropriate fractions are combined (Rf =0.28, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 117-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[C:5]([CH3:11])[CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:22]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH2:21][CH3:22])=[O:32])=[CH:26][CH:27]=2)=[CH:4][C:5]=1[CH3:11]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(CO)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CO)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol (Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate (Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treated with copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (20-40% EtOAc-hexanes) afforded 130.0 mg (99%) of the title compound as an orange solid.
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>>[C:1]1([N:7]([CH2:31][CH2:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:27][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Reactant: CCCCCCOC(=O)Cl
Product: CCCCCCOC(=O)NC(=N)c1ccc(CCc2nc3cc(C(=O)N(CCc4nnn[nH]4)c4ccccc4)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]amide and n-hexyl chloroformate.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:36])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:35])[C:18]([O:26]C(C3C=CC=CC=3)=O)=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].N(C)C.[C:40]1([CH2:46][NH2:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>C(O)C>[CH2:46]([NH:47][C:21]([C:19]1[N:20]=[C:9]2[C:8]3([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:36])[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]3)[CH2:11][N:10]2[C:17](=[O:35])[C:18]=1[OH:26])=[O:23])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Reactant: NCc1ccccc1
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccccc2)c(O)c1=O
Temperature: 50 °C
Reaction time: 0.12 h
Yield: 37.5 %

Procedure:
To a mixture of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (20 mg, 0.040 mmol) in ethanol (2 mL) was added 2M Me2NH (0.040 mL, 0.081 mmol) and the mixture heated at 50° C. for 1 h (mixture became clear after 5-10 min at 50° C. and then precepitate formed). Phenylmethanamine (0.022 mL, 0.201 mmol) followed by triethylamine (0.028 mL, 0.201 mmol) were then added and the mixture heated at 90° C. for 18 h. After work-up the crude product was purified by preparative HPLC to afford the title compound (7 mg, 0.015 mmol, 38% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 12.04 (1 H, s), 8.53 (1 H, brs), 8.29 (1 H, s), 7.35-7.39 (2 H, m), 7.28-7.34 (2 H, m), 7.24-7.27 (1 H, m), 4.57 (2 H, d, J=6.27 Hz), 4.14 (2 H, d, J=4.02 Hz), 3.26 (3 H, s), 2.87 (3 H, s), 2.44-2.58 (3 H, m), 2.01-2.10 (2 H, m), 1.86-1.99 (2 H, m), 1.64-1.75 (2 H, m). LCMS (M+H)=454.73. HPLC purity: >95%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([N:17](CC)[CH2:18]C)C.Cl.CNC>C(Cl)(Cl)Cl>[CH3:15][N:17]([CH3:18])[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[CH:11]=1)=[O:13]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Agent: CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of the resultant 2-chloroquinoline-4-carbonyl chloride in chloroform (50 ml) was treated with triethylamine (4.4 ml, 31.5 mmol), followed by solid dimethylamine hydrochloride (1.28 g, 15.7 mmol). The reaction stirred for one hour at ambient temperature at which time it was washed with 10% aqueous sodium hydroxide and 15% aqueous citric acid. Drying over anhydrous sodium sulfate, followed by evaporation under reduced pressure gave 2-chloroquinoline-4-carboxylic acid dimethylamide (1.5 g, 40%) as a tan solid. [M+H]+ 235.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[C:8]1([C:14]([C:17]2[CH:22]=[CH:21]C=[CH:19][CH:18]=2)([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1N2CN3CN(C2)CN1C3>>[CH3:16][C:14]([C:17]1[CH:22]=[CH:21][C:2]([CH:3]=[O:5])=[CH:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:15]
Reactant: CC(C)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CC(C)(c1ccccc1)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Trifluoroacetic acid (35 ml), was mixed with 3.93 g(20.0 mmol), of 2,2-diphenylpropane and 2.80 g (20.0 mmol), of hexamethylenetetramine and heated to reflux for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice water and the mixture was stirred for 1 hour. The solution was adjusted to pH=about 9 and extracted with 100 ml of diethyl ether. The organic extract was washed with saturated saline and dried with sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to obtain 3.61 g (yield: 80.5%), of the target compound as a pale yellow oily substance.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([CH2:9][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[C:5]1=[N:15][N+:16]([O-:18])=[O:17])=CC.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[O:12]1[CH2:13][CH2:14][CH:10]([CH2:9][N:6]2[CH2:7][CH2:8][NH:4][C:5]2=[N:15][N+:16]([O-:18])=[O:17])[CH2:11]1
Reactant: CC=CN1CCN(CC2CCOC2)C1=N[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])N=C1NCCN1CC1CCOC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
A mixture of 2.0 g of 1-(1-propenyl)-2-nitroimino-3-[(tetrahydro-3-furanyl)methyl]imidazolidine, 20 ml of 2N hydrochloric acid and 20 ml of ethanol was stirred at 60° C. for 3 hours. After the completion of reaction, the reaction mixture was neutralized with an aqueous solution of saturated sodium bicarbonate, followed by extraction with methylene chloride three times. Next, the extract was dried over sodium sulfate, anhydrous and then concentrated under a reduced pressure. The resultant oily substance was purified by silica gel column chromatography (ethyl acetate) to obtain 1.02 g of 1-[(tetrahydro-3furanyl)methyl]-2-(nitroimino)imidazolidine as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Yield: 66.5 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.17 g, 0.41 mmol) was reacted with NBS (0.07 g, 0.41 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.13 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:39])([F:40])[F:41])[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1OC(F)(F)F)C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Product: N[C@@H](COCc1ccccc1OC(F)(F)F)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-3-(2-(trifluoromethoxy)benzyloxy)propanoic acid, gave (S)-2-amino-N-(4-(4-fluorophenoxy)phenyl)-3-(2-(trifluoromethoxy)benzyloxy)propanamide (150 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:24])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:24][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][CH2:21]1
Reactant: COC1CCN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: ClCCl
Product: COC1CCN(CCOc2ccc(NC(=O)c3cccc(F)c3)cc2-c2c(Br)cnn2C)CC1
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy)benzenamine (0.024 g, 0.060 mmol) in CH2Cl2 (0.9 mL) was added 3-fluorobenzoyl chloride (0.0086 mL, 0.0714 mmol) and triethylamime (0.01 mL, 0.077 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.027 g, 56%). LCMS m/z (%)=531 (M+H79Br, 94), 533 (M+H81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.42 (s, 1H), 7.95 (dd, J=2.1, 8.5 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.79-7.75 (m, 1H), 7.74-7.72 (m, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.63-7.57 (m, 1H), 7.45 (dt, J=2.6, 8.3 Hz, 1H), 7.29 (dd, J=3.7, 9.1 Hz, 1H), 4.47-4.38 (m, 1H), 4.35-4.28 (m, 1H), 3.69 (s, 3H), 3.27 (s, 3H), 3.53-1.37 (m, 11H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:27])[C:6]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]2OS(C(F)(F)F)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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]>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:27])[C:6]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]2[C:32]1[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)c1c(C)cc2c(Br)cccc2c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)c1c(C)cc2c(Br)cccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
To a solution of ethyl 2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.2 g, 2.56 mmol) and 4-chlorophenylboronic acid (440 mg, 2.81 mmol) in toluene was added 2 M potassium carbonate (2.8 mL, 5.63 mmol) and PdCl2(dppf) (187 mg, 0.256 mmol) and the reaction was degassed with argon 10 minutes. The reaction was stirred at room temperature for 4 hours. The reaction was filtered, diluted with water, extracted with ethyl acetate and concentrated. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) followed by reverse phase HPLC (Gemini, 40-100% ACN/H2O+0.1% TFA). Product was lyophilized to give 670 mg of ethyl 2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (36A) as a yellow oil, 1H-NMR: 400 MHz, (CDCl3) δ: 8.20 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.85 (d, J=6.8 Hz, 1H), 7.68 (t, J=7.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 3.95 (q, J=6.8 Hz, 2H), 2.41 (s, 3H), 1.14 (t, J=7.2 Hz, 5H); and 109 mg of ethyl 2-(1,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (36B) as a white solid. 1H-NMR: 400 MHz, (CDCl3) δ: 7.72 (s, 1H), 7.59-7.56 (m, 1H), 7.50 (t, J=8.0 Hz, 2H), 7.46-7.44 (m, 5H), 7.43 (d, J=2.4 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 3.94 (q, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.14 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].I[C:7]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([CH3:28])[N:8]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:13][C:12]1[C:7]([C:18]2[CH:19]=[C:20]([CH2:1][OH:4])[CH:21]=[CH:22][CH:23]=2)=[N:8][C:9]([CH3:28])=[CH:10][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(CO)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakis-triphenylphosphine palladium (14 mg), and (3-hydroxymethyl)-phenylboronic acid (90 mg) under an argon atmosphere, and the mixture was stirred 80° C. overnight. The reaction solution was cooled to room temperature, a 1 N aqueous sodium hydroxide solution was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (20 mg, yield 43%).
Reaction SMILES: [N:1]([CH:4]([C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[F:12][C:11]([F:13])([F:14])[C@H:10]([CH3:15])[C@@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:1]
Reactant: [H][H]
Reactant: CCOC(=O)C(N=[N+]=[N-])[C@@H](C)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](N)[C@@H](C)C(F)(F)F
Reaction time: 8 h

Procedure:
32.8 g of crude ethyl (3R)-2-azido-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in 110 ml of ethanol and, after inertizing with argon, 6.98 g of palladium on carbon (5%) were added. The mixture was stirred overnight at standard pressure under an atmosphere of hydrogen, with the reaction vessel repeatedly being vented and filled with fresh hydrogen. The reaction mixture was then filtered off through Celite, the filter residue was washed with 50 ml of ethanol and the filtrate was concentrated under reduced pressure (up to about 20 mmHg). The slightly yellowish liquid that remained was briefly freed from residual solvent under high vacuum. This gave 23.5 g of the target compound as an about 70% pure crude product which was not purified any further (yield over three steps about 38% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH2:19][NH:20][CH2:21][CH3:22])[CH:11]=1)[CH3:2].[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:27]([CH:24]2[CH2:26][CH2:25]2)=[O:28])[CH2:21][CH3:22])[CH:11]=1)[CH3:2]
Reactant: O=C(O)C1CC1
Reactant: CCNCc1cc(F)ccc1-c1cncc(CC(=O)OCC)c1
Product: CCOC(=O)Cc1cncc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-fluoro-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and cyclopropanecarboxylic acid were reacted as described in Example 8, Step 6 to provide (5-{2-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-fluoro-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28]OC4C=CC=CC=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2].[BrH:41].CC(O)=O>C(O)(=O)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][Br:41])[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: Br
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(COc4ccccc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(phenoxymethyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (5.5 g, 9.54 mmol), in acetic acid (23.62 mL) under nitrogen atmosphere, was added 37% HBr/AcOH (47.7 mL). The reaction mixture was stirred at r.t. for 3 h. After the completion of the reaction as confirmed by TLC, the reaction mixture was cooled to 0° C. and quenched very slowly with saturated solution of potassium carbonate until effervescence ceases. The crude compound was extracted with ethyl acetate (2×300 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford crude compound which was purified by column chromatography (silica gel, 3:7 Ethyl acetate:Pet ether) to afford the title compound (4.28 g, 79%) as a white solid.
Reaction SMILES: C[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[CH:21]([C:29]([F:32])([F:31])[F:30])[N:22]([CH2:26][CH2:27][CH3:28])[O:23][C:24]=3[CH:25]=2)=[C:8]([Cl:33])[CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Li+]>CO.O>[Cl:33][C:8]1[CH:7]=[C:6]([CH2:2][C:3]([OH:5])=[O:4])[CH:11]=[CH:10][C:9]=1[S:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([C:29]([F:31])([F:30])[F:32])[N:22]([CH2:26][CH2:27][CH3:28])[O:23][C:24]=2[CH:25]=1
Reactant: CCCN1Oc2cc(OCCCSc3ccc(C(C)C(=O)O)cc3Cl)ccc2C1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN1Oc2cc(OCCCSc3ccc(CC(=O)O)cc3Cl)ccc2C1C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of methyl 3-chloro-4-(3-(2-propyl-3-trifluoromethyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylacetic acid (0.113 grams) in methanol (1.5 mL) was treated with a solution of lithium hydroxide in water (1.01 M; 0.362 mL). The reaction was refluxed 1 hour. The reaction mixture was partitioned between isopropyl acetate and 0.1N HCl. The organic was dried over magnesium sulfate, filtered and concentrated to a solid. The solid was suspended in methylene chloride/cyclohexane (1:1; 2 mL). The mixture was refluxed briefly and cooled to 0° C. The title compound was isolated by filtration.