Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23]O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]([CH3:25])([CH3:26])[CH2:22][CH2:23][N:31]3[C:27](=[O:37])[C:28]4[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30]3=[O:32])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)CCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.3 %

Procedure:
To a solution of 5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-3,3-dimethyl-4-pentyn-1-ol (F15, 75 mg), phthalimide (93 mg) and triphenylphosphine (165 mg) in tetrahydrofuran (3.5 mL), a 1.9 mol/L solution of diisopropyl azodicarboxylate in toluene (332 μL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 92 to 52% hexane in ethyl acetate) to obtain 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-3,3-dimethyl-4-pentyn-1-yl)isoindoline-1,3-dione (F16, 129 mg) as pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:34])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][Cl:34])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CO)cs2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (848 mg, 2.83 mmol) and DIPEA (550 mg, 1.5 eq.) in CH2Cl2 (10 mL) was added MsCl (285 L, 1.3 eq.) dropwise. The resulting mixture was stirred overnight. The reaction solution was then concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:4) to afford the desired product as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:20]4[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Product: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@H](c3ccc4c(c3)OCO4)CC2)CC1

Procedure:
4-(1,3-Benzodioxol-5-yl)cyclohexanone and 1,1-dimethylethyl 1-piperazine carboxylate were reacted as described in example 9 to give the product (88%, mp: 121°-122° C.). Calc'd for C22H32N2O4 : C, 68.01%; H, 8.31%; N, 7.22%. Found: C, 67.61%; H, 8.24%; N, 7.07%.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[CH:29][C:30]([F:39])=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[CH:29][C:30]([F:39])=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:32]=3)[CH2:25][CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)ccc1F

Procedure:
Example 56 was prepared from diphenylacetyl chloride and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CD3OD,) δ 7.80–7.64 (m, 1H), 7.37–7.09 (m, 12H), 7.08–6.98 (m, 1H), 6.98–6.88 (br, 1H), 4.90 (s, 1H), 3.47–3.33 (m, 2H), 3.33–3.18 (m, 2H), 3.01–2.81 (m, 4H), 2.81–2.69 (m, 1H), 2.69–2.54 (m, 1H), 2.10–1.66 (m, 6H), 1.10 (d, 6H, J=6.4 Hz); ESMS m/e: 516.4 (M+H)+. Anal. Calc. For (HCl salt) C32H39ClFN3O2.0.16CHCl3: C, 67.68; H, 6.92; N, 7.36. Found: C, 67.43; H, 6.85; N, 7.17.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1.C(Cl)Cl>[C:28]1([NH:27][C:2]2[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCC(=O)c1cccnc1Cl
Reactant: Nc1ccccc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(=O)c1cccnc1Nc1ccccc1
Temperature: 70 °C
Yield: 70.4 %

Procedure:
A solution of 1-(2-chloro-pyridin-3-yl)-propan-1-one (6.0 g, 35.4 mmol) in 1,4-dioxane (59.0 mL) in a high pressure reaction tube was treated with (1S)-(+)-10-camphorsulfonic acid (20.5 g, 88.4 mmol). The resulting mixture was heated to 70° C. until all of the solids went into solution. The reaction was raised out of the heating bath, opened and treated with aniline (4.94 g, 4.84 mL, 53.1 mmol). The vessel was then re-sealed and heated at 95° C. overnight. After cooling to room temperature, the reaction was diluted with methylene chloride (75 mL) and was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL). The organics were then dried over sodium sulfate, filtered, concentrated in vacuo and dried under high vacuum. The residue was then recrystallized from methanol. Collection by filtration (washing with 10 mL of methanol and 30 mL of hexanes) afforded 1-(2-phenylamino-pyridin-3-yl)-propan-1-one (5.64 g) of the desired product as a yellow, crystalline solid. The mother liquor was dry loaded onto silica gel. Flash chromatography (40 g, 10-25% ethyl acetate-hexanes) afforded an additional amount (1.28 g, 86% total yield) of the desired product as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.ClC1C(C(F)(F)F)=CC=CC=1C(NC(C1(N(C)C)CCCC1)C1C=CC=CC=1)=O.[CH3:46][C:47]1[C:55]([CH3:56])=[CH:54][CH:53]=[CH:52][C:48]=1[C:49](O)=[O:50].O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1([CH:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:1][C:49](=[O:50])[C:48]2[CH:52]=[CH:53][CH:54]=[C:55]([CH3:56])[C:47]=2[CH3:46])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C(=O)NC(c2ccccc2)C2(N(C)C)CCCC2)c1C
Reaction time: 20 h
Yield: 86 %

Procedure:
A mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (0.102 g, 0.47 mmol), 2,3-dimethylbenzoic acid (0.100 g, 0.67 mmol), 1-hydroxybenzotriazole hydrate (0.092 g, 0.6 mmol) and PS-DCC (0.63 g of 1.3 mmol/g loading, 0.82 mmol) in DCM (7 ml) was shaken for 20 h. The mixture was filtered and the resin washed with DCM (2×4 ml). Combined organics were washed with saturated sodium hydrogen carbonate (20 ml), the layers separated and the organic layer applied to a 2 g SCX cartridge. The cartridge was washed with DCM (2 volumes), 50% methanol in DCM (1 volume) and methanol (2 volumes). Elution with 1M ammonia in methanol (2 volumes) and evaporation of the solvent afforded a colourless gum. Chromatography on silica gel (10 g) eluting with 0-100% ethyl acetate in pentane gradient afforded the title compound as a colourless solid (0.14 g; 86%). 1H NMR (CDCl3) δ: 0.90-1.15 (1H, m), 1.20-1.38 (1H, m), 1.40-1.55 (2H, m), 1.60-1.75 (2H, m), 1.79-1.90 (2H, m), 2.22 (6H, s), 2.28 (6H, s), 5.15 (1H, d, J=6 Hz), 6.98 (1H, d, J=6 Hz), 7.10-7.15 (1H, m), 7.19-7.27 (3H, m), 7.29-7.35 (2H, m), 7.39-7.43 (2H, m). Mass spectrum (Electrospray LC/MS), ES+: Found 351 (MH+). C23H30N2O requires 350. Ret. time 1.90 min. The title product was converted to the corresponding hydrochloride salt (0.150 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:16])=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:16][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:7]=2)=[CH:14][N:13]=[C:12]([NH2:15])[CH:11]=1
Reactant: Cc1cc(N)ncc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 60.7 %

Procedure:
5-(2-chloropyridin-4-yloxy)-4-methylpyridin-2-amine (0.116 g, 0.492 mmol) was dissolved in DMF (2 ml) and 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (0.154 g, 0.738 mmol) was added, followed by cesium carbonate (0.481 g, 1.477 mmol) and water (0.667 ml). Argon was bubbled through the mixture for several minutes, and then palladium tetrakistriphenylphosphine (0.028 g, 0.025 mmol) was added. The flask was fitted with a reflux condenser, flushed with argon, and heated under a balloon of argon at 90° C. for 16 hours. The mixture was then cooled to RT, and the solution was diluted with a 4:1 mix of ethyl acetate and THF (70 mL). It was washed with 10% aqueous LiCl (2×50 mL) and brine (50 mL), dried (MgSO4), evaporated in vacuo and purified via silica gel chromatography (DCM/MeOH) to yield 4-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amine as a clear oil (0.084 g, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.11 (d, 1H), 6.50 (dd, 1H), 6.38 (s, 1H), 5.89 (s, 2H), 3.84 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CC(=O)CC>[CH2:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 6.5 h

Procedure:
4-hydroxybenzophenone (186.7 g, 940 mmol, Fluka Chemical) was dissolved in 2-butanone (700 mL, Fisher Scientific) in a 2L four-necked flask equipped with a mechanical stirrer, reflux condenser, addition funnel and internal temperature probe. K2CO3 (195 g, 1.41 mol, Aldrich Chemical) was added to the reactor, and the contents was placed under a slow N2 purge. Allyl bromide (123 mL, 1.41 mol, Aldrich Chemical) was charged to the addition funnel. The pot temperature was raised to 65° C., at which point the allyl bromide was added over the course of 30 minutes. The reaction was stirred for 6.5 h at 65° C. after the addition was completed. At this point no starting material was present as determined by GC analysis.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:22][C:23](=[O:26])[CH2:24][CH3:25].O>CN(C=O)C>[Br:7][C:8]1[C:18]([O:19][CH2:22][C:23]([CH2:24][CH3:25])=[O:26])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC(=O)CC)c1Br
Temperature: 80 °C

Procedure:
0.853 g (6.20 mmol) of K2CO3, 0.154 g (0.90 mmol) of KI and 1.000 g (3.10 mmol) of ethyl 2,4-dibromo-3-hydroxybenzoate were initially charged in 10 ml of DMF. At RT, 0.621 g (3.70 mmol) of 1-bromo-2-butanone was added, and the mixture was then heated at 80° C. for 4 h. The mixture was then poured into water and extracted with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated to dryness. Drying under oil pump vacuum gave ethyl 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoate as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CO.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10% NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88%): 1H NMR (300 MHz, DMSO-d6): δ (ppm) 7.57 (d, J=8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J=6.0 Hz, 1H), 4.46 (d, J=6.0 Hz, 2H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].[CH2:22](C1C=CC(C(Cl)=O)=CC=1)[CH2:23]CCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1)=[N+:2]=[N-:3]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 76 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-pentylbenzoyl chloride (0.283 g, 1.35 mmol) was reacted with 2-azidoethanamine (0.116 g, 1.35 mmol) and triethylamine (0.273 g, 2.69 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-pentylbenzamide (0.267 g, 76%). 1H NMR (300 MHz, CDCl3) δ 7.74 (d, 2H), δ 7.61 (t, 1H), δ 7.15 (d, 2H), δ 3.54 (q, 2H), δ 3.44 (t, 2H), δ 2.58 (t, 2H), δ 1.57 (m, 2H), δ 1.26 (m, 4H), δ 0.86 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.6, 147.2, 131.7, 128.7, 127.5, 50.8, 39.7, 35.9, 31.6, 31.1, 22.7, 14.2 ppm; HRMS (ESI) calcd for C14H20N4O (M+) 260.1637. Found 260.1632.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1.[C:39](O)(=[O:41])[CH3:40].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:39]([NH:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)O
Reactant: N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
(1R*,2R*,5S*,6R*)-6-Amino-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 475 mg, 0.89 mmol), glacial acetic acid (0.076 ml, 1.34 mmol), triethylamine (0.14 ml, 0.98 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (257 mg, 1.34 mmol) and 4-dimethylaminopyridine (2 crystals) were combined in dichloromethane (4 ml) and stirred overnight at room temperature. The reaction mixture was washed with water and extracted with dichloromethane (×3). The organics were dried (MgSO4), and concentrated in vacuo to give the title compound as a yellow oil (384 mg, 75%).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH2:31]([O:38][C:39]1[CH:44]=[C:43](Br)[CH:42]=[C:41]([F:46])[C:40]=1[F:47])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O:48]1CCOCC1>O.[OH-].[K+].CCOC(C)=O>[CH2:31]([O:38][C:39]1[CH:44]=[C:43]([OH:48])[CH:42]=[C:41]([F:46])[C:40]=1[F:47])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1F
Reactant: C1COCCO1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cc(F)c(F)c(OCc2ccccc2)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
To a solution of potassium hydroxide (2246.7 mg, 40.12 mmol) in 1,4-dioxane (5 mL) and Water (5 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (212.63 mg, 0.5015 mmol). The reaction mixture was degassed with nitrogen and then treated with tris(dibenzylideneacetone)dipalladium-[0](183.54 mg, 0.2006 mmol) and 1-benzyloxy-5-bromo-2,3-difluoro-benzene [CAS: 1035155-54-4](3 g, 10.03 mmol) the reaction was then heated at 90° C. for 16 hours. The reaction was diluted with aq. KOH solution (2M, 150 mL) and EtOAc (150 mL). The aqueous was separated, and acidified to pH 1 with aq. HCl (2M). The organics were then extracted into EtOAc (150 mL). The organics were separated, washed with brine (150 mL), dried over MgSO4, filtered and concentrated in vacuo to give crude 3-benzyloxy-4,5-difluoro-phenol ˜60% pure);
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[CH:5]=O.[CH2:11]([O:18][C:19]([NH:21][CH:22](P(OC)(OC)=O)[C:23]([O:25][CH3:26])=[O:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]([NH:21]/[C:22](=[CH:5]\[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1)/[C:23]([O:25][CH3:26])=[O:24])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.5 %

Procedure:
A well stirred solution of 3,5-difluorobenzaldehyde (1.92 g, 13.5 mmol) and methyl benzyloxycarbonylamino-(dimethoxyphosphoryl)acetate (5.37 g, 16.2 mmol) in dry THF (20 mL), under N2, was cooled to 0° C. and 1,1,3,3-tetramethylgaunidine (1.38 g, 16.2 mmol) added via syringe. The reaction was allowed to warm to rt and stir for 6 h, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration, the residue was chromatographed on silica gel (elution with 20% ethyl acetate/heptane) to give methyl (Z)-2-benzyloxycarbonylamino-3-phenyl-acrylate (3.55 g) as a white solid. MS (ESI+) for C18H15F2NO4 m/z 348.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.[CH2:16]([O:23]/[N:24]=[C:25]1\[CH2:26][CH2:27][C:28]2[C:33]\1=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:16]([O:23]/[N:24]=[C:25]1\[CH2:26][CH2:27][C:28]2[C:33]\1=[CH:32][CH:31]=[C:30]([C:2]1[C:3]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1)[CH:29]=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Reactant: OCCn1cc(Br)c(-c2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCn1cc(-c2ccc3c(c2)CC/C3=N\OCc2ccccc2)c(-c2ccncc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To 2-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethanol (100 mg; Example 4, step 3) in 7 mL acetonitrile and 3 mL water, was added 136 mg (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (product of Example 2, Step 4), and 155 mg potassium carbonate. The mixture was purged with nitrogen and about 43 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The mixture was heated at 80° C. After 1 hour, the reaction mixture was filtered through celite, the filter cake washed with ethyl acetate, and filtrate evaporated under vacuum. The residue was purified by chromatography, eluting with a mixture of 8:1 ethyl acetate-methanol to afford 110 mg (69% yield) product as a white solid. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 425.2 by positive ESI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][NH:64][C:65]([C@@H:67]1[CH2:71][CH2:70][CH2:69][NH:68]1)=[O:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][C@H:67]1[C:65]([NH:64][CH3:63])=[O:66])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:20]=[CH:26][C:25]([Cl:27])=[CH:24][C:23]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CNC(=O)[C@@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CNC(=O)[C@@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-methylaminocarbonyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[NH2:18][C@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.C(=O)=O>>[NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([NH:18][C@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7])[CH2:3][OH:4]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: O=C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1

Procedure:
The dipeptide Ser-Trp was synthesized according to standard peptide technology. In a first step Z-Ser-OH and Trp-OMe were coupled via the carbonic anhydride methodology (J. Am. Chem. Soc. 1967, 5012) to yield the protected dipetide Z-Ser-Trp-OMe. To that end Trp-OMe.HCl was suspended in tetrahydrofuran (THF) and subsequently N-methylmorpholine (NMM) was added. The mixture was stirred for one hour and subsequently added to a solution of Z-Ser in tetrahydrofuran/dimethylformamide (THF/DMF). A second equivalent of NMM was added and the mixture was cooled to −15° C. Isobutyl chloroformate is added at such a rate that the internal temperature does not exceed −15° C. Subsequently, the mixture was stirred for 3 hours, the temperature was allowed to rise to ambient temperature and the precipitated NMM.HCl was removed by filtration. The filtrate was kept at 4° C. overnight after which any additional precipitate was filtered and the filtrate is concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/heptane). The combined fractions were concentrated, washed with water to remove any remaining DMF and concentrated in vacuo.