Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COCCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COCCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 24 h

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide (110 mg, 0.348 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (279 mg, 1.39 mmol) in n-BuOH (5 mL) was stirred at 160° C. for 24 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (1×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase chromatography (Biotage 25M+ column) on Biotage SP4 unit eluting with 10-85% CH3CN gradient (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate as a solid. This material was dissolved in TFA (3 mL) and stirred at room temperature for 20 minutes. TFA was then removed in vacuo, and the residue was dissolved in a few drops of methanol and purified by C-18 reverse phase chromatography (Biotage C-18, 12M+ column) on Biotage SP4 unit eluting with 1-50% CH3CN/water gradient (14 CV). The product isolated was dissolved in CH2Cl2 (1 mL), and 2M HCl in ether (2 mL) was added. The solid was dissolved in MeOH, evaporated from CH2Cl2 (3×2 mL) and dried under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide hydrochloride (28 mg, 20% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.80 (s, 1H), 9.34 (s, 1H), 8.23 (br s, 4H), 7.57 (br s, 1H), 3.64 (t, 2H), 3.55-3.49 (m, 2H), 3.42-3.55 (m, 2H), 3.27 (s, 3H), 3.08-3.03 (m, 1H), 2.62 (t, 2H), 2.15-2.09 (m, 1H), 1.88-1.81 (m, 1H), 1.75-1.67 (m, 1H), 1.53-1.45 (m, 1H); LCMS (APCI+) m/z 396, 398 (M+H)+, Retention time=2.09 minutes (Method 2).
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]([Mg]Cl)[CH2:27][CH3:28]>C1COCC1>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([OH:25])[CH2:26][CH2:27][CH3:28])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC[Mg]Cl
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C=O)n2)cc1
Solvent: C1CCOC1
Product: CCCC(O)/C=C/c1cccc(/C(=C/CN2CCCC2)c2ccc(C)cc2)n1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A stirred solution of 3-(6-[3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enal (925 mg, 2.78 mmol) in anhydrous THF (30 ml) at -78° C. was treated dropwise with a solution of n-propyl magnesium chloride (1.53 ml, 2.0 M in diethylether, 3.06 mmol). The reaction mixture was allowed to warm slowly to room temperature (~2 hours). The reaction was quenched with water (3 ml) and THF removed under reduced pressure. The residue was taken up in 1M HCl and then basified with solid sodium bicarbonate to pH 8. The product was extracted with ethyl acetate (×3). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography eluting with 5-8% methanol in DCM. Product containing fractions were combined and solvent removed to provide 1-(6-[3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-hex-1E-en-3-ol as a pale pink foam (593 mg, 57%). 1H-NMR; δ (CDCl3), 7.44 (1H, t, J=7.7 Hz), 7.24-7.18 (3H, m), 7.12-7.07 (3H, m), 6.89 (1H, dd, J=15.7, 6.2 Hz), 6.68 (2H, m), 4.38 (1H, m), 3.35 (2H, d, J=7.1 Hz), 2.41 (4H, bs), 1.86 (3H, s), 1.71-1.61 (2H, m), 1.58-1.42 (2H, m), 1.47 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:24]([CH3:26])[CH3:25])C(OCC[Si](C)(C)C)=O)[C@H:10]([CH2:27][N:28]([CH:38]2[CH2:40][CH2:39]2)[C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:24]([CH3:25])[CH3:26])[C@H:10]([CH2:27][N:28]([CH:38]2[CH2:39][CH2:40]2)[C:29](=[O:37])[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)Cc1ccccc1)C1CC1)C(=O)OCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)Cc1ccccc1)C1CC1
Reaction time: 8 h

Procedure:
To a solution of (3R,4S)-3-[(cyclopropyl-phenylacetyl-amino)-methyl]-4-{[isopropyl-(2-trimethylsilanyl-ethoxycarbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (2.55 g, 4.44 mmol) in CH3CN (30 mL) is added tetrabutylammonium fluoride trihydrate (4.34 g, 13.33 mmol) under a nitrogen atmosphere. The reaction mixture is stirred overnight at reflux. The solvent is removed under vacuum and Water and CH2Cl2 are added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH/NH4OH 98:2:1) to give the title product. TLC, Rf (CH2Cl2/MeOH/NH4OH 98:2:1)=0.11. MS (LC-MS): 430.2 [M+H]+; tR (HPLC, C18 column, 20-100% CH3CN/H2O/16 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.90 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)(Cl)Cl>O>[O:25]=[C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)N1CCOCC1

Procedure:
Example 1(A) was repeated using morpholine, potassium carbonate and dodecanoyl chloride in a biphasic mixture of chloroform and water followed by the usual workup to obtain the above product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:34])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=4)[CH:21]=3)[CH2:17][C:16](=[O:34])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M107) (0.23 g, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (133 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[F:10].O[CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].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>C1COCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH2:14][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH3:12])=[CH:4][C:3]=1[F:10]
Reactant: Oc1cc(F)c(Br)c(F)c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](COc1cc(F)c(Br)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of 4-bromo-3,5-difluorophenol (5.0 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (5 g) and triphenylphosphine (7.5 g) in THF (50 mL) was added diisopropyl azodicarboxylate (1.9 M in toluene, 14 mL) dropwise at room temperature. The reaction mixture was stirred at 60° C. overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the title compound (5.1 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.Br[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[NH2:22][C:20]1[CH:19]=[CH:18][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29][CH2:28]4)=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
U1 was prepared from 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate following the general procedure reported in Preparative Example 54 Step 1-2. 1H NMR (400 MHz, CDCl3, 300K) δ 1.22 (m, 2H), 1.40 (s, 9H), 1.82 (d, J=12.7 Hz, 2H), 2.10 (m, 1H), 2.69 (t, J=12.3 Hz, 2H), 3.77 (m, 2H), 3.96 (s, 3H), 3.97 (m, 2H), 4.10 (m, 2H), 6.31 (d, J=5.2 Hz, 1H), 6.46 (m, 2H), 6.96 (t, J=8.7 Hz, 1H), 7.31 (s, 1H), 7.51 (s, 1H), 8.40 (d, J=5.2 Hz, 1H). MS (ES) C27H32FN3O5 requires: 497. Found: 498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([S:29][CH2:30][CH2:31][OH:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:32][CH2:31][CH2:30][S:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: OCCSCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCSCc1ccccc1
Yield: 94 %

Procedure:
A solution of 34.7 g of 2-[4-(3,5-dichloro-2-pyridyloxy)-phenoxy]-propionyl chloride in 80 ml of toluene was added dropwise at 0° to 10° C. to a solution of 16.8 g of 2-benzylthioethanol and 10.1 g of triethylamine in 100 ml of toluene whilst stirring. After the addition was completed, the mixture was stirred further at 30° to 40° C. for 1 hour. The mixture was washed successively with a 1% aqueous solution of sodium hydroxide and water, and dried. Upon distilling off the toluene under reduced pressure, there were obtained 44.9 g of 2-benzylthioethyl 2-[4-(3,5-dichloro-2-pyridyloxy)-phenoxy]-propionate in the form of a colorless viscous oil. nD20 =1.5940.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=[C:3]([CH:18]=O)[CH:2]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1(C)C=CC=CC=1>[C:21]1([N:20]=[CH:18][C:3]2[CH:2]=[CH:1][C:11]3[CH:10]=[CH:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[S:6](=[O:17])(=[O:16])[C:5]=3[CH:4]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Solvent: O
Solvent: Cc1ccccc1
Product: O=S1(=O)c2ccccc2C=Cc2ccc(C=Nc3ccccc3)cc21
Reaction time: 0.17 h

Procedure:
Heat a mixture of 675 mg (2.5 mmoles) of dibenzo[b,f]thiepin-3-carboxaldehyde-5,5-dioxide and 465 mg of aniline (5 mmoles) in 20 ml of toluene, under reflux, with azetropic removal of water for 21 hours. Cool the mixture and filter the insoluble product. Stir the solid in 10 ml of ether containing a few drops of THF for 10 minutes then filter to obtain the pure product, 704 mg, mp: 184°-185°.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C:14]2[O:18][C:17]([CH:19]=[N:20]O)=[CH:16][CH:15]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:22]([O-:25])(=O)[CH3:23].[Na+].Cl.ClCCl>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1.CC(C)=O.C(Cl)(Cl)Cl>[C:2]([O:3][C@@H:2]1[C@@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@H:6]([O:7][C:8](=[O:9])[CH3:10])[C@@H:8]([CH2:10][O:11][C:22](=[O:25])[CH3:23])[O:9][C@@H:1]1[O:12][CH2:13][C:14]1[O:18][C:17]([C:19]#[N:20])=[CH:16][CH:15]=1)(=[O:3])[CH3:1]
Reactant: OC[C@H]1O[C@H](OCc2ccc(C=NO)o2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](OCc2ccc(C#N)o2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A suspension of 3.0 g (10 mmol) GMF oxime (formula 9, product of Example 9) and 1.0 g freshly-melted sodium acetate in 10 ml acetic anhydride was stirred for 30 min at room temperature. The now clear solution was then made slightly acid with mineral acid by addition of hydrochloric acid (4 ml 4N HCl, 1.3 mole equiv. based on the sodium acetate used) and heated for a short time (5-8 min) to 60° C. Stirring into ice water, extraction with dichloromethane and evaporation of the combined extracts gave 3.5 g (78%) of the nitrile of formula (14) as a chromatographically homogenous syrup with Rf =0.31 (TCL in toluene/acetone, 4:1) and [α]D20 =+135° (c=0.7, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](OC)=[O:25])=[CH:15][C:13]=2[N:14]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N+:30]=1[O-:39].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][N+:30]=3[O-:39])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(C(F)(F)F)c[n+]3[O-])c3c(c2[nH]1)CC(C)(C)O3
Yield: 27.2 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.100 g, 0.207 mmol) and 2-amino-5-trifluoromethylpyridine-N-oxide (Intermediate-41, 0.053 g, 0.301 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.030 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.25 (s, 3H), 3.13 (s, 2H), 7.26-7.33 (m, 2H), 7.43 (d, J=6.9 Hz, 1H), 7.53 (s, 1H), 7.79 (d, J=6.9 Hz, 1H), 8.68 (d, J=9.3 Hz, 1H), 8.94 (s, 1H), 9.20 (s, 1H), 11.02 (s, 1H), 12.26 (s, 1H); MS [M+H]+: 532.11.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25](CC=O)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1.[OH2:31].Cl>C1COCC1>[CH2:19]([O:31][C:13](=[O:12])/[CH:16]=[CH:17]/[CH2:18][CH:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[O:12][C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=4)=[N:15][CH:14]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O
Reactant: O=CCC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(/C=C/CC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (benzyloxycarbonylmethyl)-triphenylphosphionium bromide (315 mg, 0.642 mmol) in THF (6 mL) at 0° C. is added NaH (60% in mineral oil, 27 mg, 0.642 mmol) and the suspension is allowed to stir at 0° C. for 30 min. (4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetaldehyde (253 mg, 0.642 mmol) in THF (4 mL) is added dropwise. The reaction mixture is then stirred a 0° C. for 30 min and the at ambient temperature for 18 h. Water (10 mL) and HCl solution (1N, 15 mL) is added, and the reaction mixture is extracted with EtOAc (3×15 mL). The organic phase is washed with water (1×5 mL), brine (3×20 mL), dried and concentrated to give the title compound (279 mg) as an off-white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.14 (m, 2H) 1.34-1.49 (m, 3H) 1.59-1.73 (m, 1H) 1.80-1.87 (m, 3H) 2.11 (t, J=8.00 Hz, 2H) 2.46 (ddd, J=11.68, 9.16, 2.91 Hz, 1H) 5.11 (s, 2H) 5.82 (d, J=15.66 Hz, 1H) 6.90-6.99 (m, 1H) 7.14-7.17 (d, 8.08 Hz, 2H) 7.24-7.28 (m, 3H) 7.28-7.32 (m, 6H) 7.40 (d, J=8.08 Hz, 1H) 7.49 (s, 1H); (M+H)+527.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[C:15]([O:20][CH3:21])[C:16]([NH2:19])=[N:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1.[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]=1[C:13]1[CH:14]=[C:15]([O:20][CH3:21])[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: COc1cc(-c2csc(-c3ccc(F)cc3)n2)cnc1N
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(-c3ccc(F)cc3)sc2Br)cnc1N
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 76.6 %

Procedure:
To a solution of 5-(2-(4-fluorophenyl)thiazol-4-yl)-3-methoxypyridin-2-amine (68 mg, 0.23 mmol) in chloroform (3.6 mL) at 0° C. was added a solution of bromine (2.0 M in CHCl3, 0.17 mL, 0.34 mmol). The reaction was stirred at rt for 6-10 min and concentrated in vacuo. The resulting residue was azeotroped with 5% methanol in DCM solution (5 mL) and purified by prep TLC (SiO2, 1.0 mm, 95:5 DCM-methanol) to give 67 mg of 5-(5-bromo-2-(4-fluorophenyl)thiazol-4-yl)-3-methoxypyridin-2-amine was isolated as a tan solid: LCMS (m/z): 380.0 (MH+), tR=0.85 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][S:16][CH2:17][CH2:18][CH:19]=O.[Cl:21][C:22]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:38])[C@:31]([OH:37])([CH3:36])[C:32]([F:35])([F:34])[F:33].C(=O)([O-])O.[Na+]>ClCCCl>[Cl:21][C:22]1[CH:27]=[C:26]([NH:28][CH2:19][CH2:18][CH2:17][S:16][CH3:15])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:38])[C@:31]([OH:37])([CH3:36])[C:32]([F:34])([F:33])[F:35]
Reactant: C[C@@](O)(C(=O)Nc1ccc(N)cc1Cl)C(F)(F)F
Reactant: CSCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CSCCCNc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (0.297 g) was added to a solution of 3-methylsulphanylpropionaldehyde (0.1 ml) and (R)-N-(2-chloro-4-aminophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 208) (0.282 g) in 1,2-dichloroethane (6 ml). The mixture was stirred for 16 hours. Saturated aqueous sodium hydrogen carbonate (25 ml) was added and the mixture was extracted with ethyl acetate (40 ml). The extracts were washed with brine (15 ml) then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a Varian Isolute silica column eluting with 25% ethyl acetate/hexane. The resulting solid was triturated with ether to give the title compound (0.089 g) as a solid. NMR: 1.54 (s, 3H), 1.78 (m, 2H), 2.05 (s, 3H), 2.55 (q, 2H), 3.09 (q, 2H), 5.93 (t, 1H), 6.54 (dd, 1H), 6.65 (s, 1H), 7.46 (m, 2H), 9.33 (s, 1H); MS (ESP−): 369.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:24](=[O:26])[CH3:25])[CH2:16][CH2:15]2)=[CH:22][CH:21]=1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc([C@H]2CC[C@H](NCCCc3ccccc3)CC2)cc1
Product: CC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1

Procedure:
In a manner similar to Example 16, trans-4-[4-(3-phenylpropylanino)cyclohexyl]phenol was allowed to react with acetic anhydride to give trans-N-[4-(4-hydroxyphenyl)cyclohexyl]-N-(3-phenylpropyl) acetamide. Yield (90 mg, 2%): mp 175-180° C.; IR (KBr): 3240, 2929, 1620, 1590 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.30-7.17 (m, 5H), 7.00 (d, J=9 Hz, 2H), 6.69 (dd, J=9, 2 Hz, 2H), 3.37 (m, 1H), 3.25 (m, 4H), 2.61 (m, 2H), 2.41 (m, 1H), 2.10 (s, 3H), 1.87-1.75 (m, 4H), 1.72-1.46 (m, 4H); CI-MS (methane) (m/z): 352 [M+H]+; HRMS-API (m/z): [M+H]+ Calcd for C23H29NO2, 352.2276. found: 352.2278. HPLC: method A, 12.08 minutes (97.3%); method B, 16.36 minutes (98.9%); Anal. Calcd for C23H29NO2.0.75H2O: C, 75.67; H, 8.43; N, 3.84. Found: C, 75.40; H, 7.93; N, 3.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([NH:28][NH2:29])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:30]2[CH2:34][C@H:33]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:32]([OH:40])[C@H:31]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:42]([O:44][C:45](=[O:51])[CH:46]([CH:49]=O)[CH:47]=O)[CH3:43]>C(O)C>[CH2:42]([O:44][C:45]([C:46]1[CH:47]=[N:29][N:28]([C:26]2[N:25]=[C:24]3[C:20]([N:21]=[CH:22][N:23]3[C@@H:30]3[CH2:34][C@H:33]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:32]([OH:40])[C@H:31]3[OH:41])=[C:19]([NH:18][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:27]=2)[CH:49]=1)=[O:51])[CH3:43]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Reactant: CCOC(=O)C(C=O)C=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
To a solution of N-[(1S,2R,3S,4R)-4-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-hydrazino-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (0.1 g, 0.177 mmol) in dry ethyl alcohol (5 ml) is added 2-formyl-3-oxo-propionic acid ethyl ester (synthesised from ethyl-3,3-diethoxy-propionate, as described in: Bertz S. H., Dabbagh G. and Cotte P.; J. Org. Chem. (1982) 47, pp 2216-2217) (0.033 g, 0.231 mmol). The reaction mixture is heated at reflux for 8 hours then concentrated in vacuo. The crude residue is purified by chromatography on silica (60-120 mesh) eluting with 3% methanol in chloroform to afford the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH+ 671).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][S:18][C:12]3=[N:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.[CH:20]1([CH2:23][O:24][C:25]2[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH2:22][CH2:21]1.[O-]CC.[Na+]>C(O)C>[CH:20]1([CH2:23][O:24][C:25]2[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=2/[CH:27]=[CH:19]/[C:10]2[N:11]=[C:12]3[S:18][CH:17]=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:21][CH2:22]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: COc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2c(/C=C/c3cccc(OC)c3OCC3CC3)nc3sccn3c2=O)cc1
Yield: 43.2 %

Procedure:
The title compound was prepared by condensation of Intermediate 9 (350 mg, 1.283 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (371 mg, 1.799 mmol) in presence of sodium ethoxide (174 mg, 2.570 mmol) in ethanol (10 ml) according to the procedure of Example 24 afforded 255 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.25-0.27 (m, 2H), 0.49-0.51 (m, 2H), 1.03-1.05 (m, 1H), 3.67-3.70 (m, 2H), 3.77-3.81 (m, 3H), 6.89-6.91 (m, 2H), 6.98-7.02 (m, 4H), 7.23-7.26 (m, 2H), 7.47-7.49 (m, 1H), 7.96-8.10 (m, 1H), 8.10-8.15 (m, 1H); ESI-MS (m/z) 461.39 (M+H)+.