Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH2:21][CH3:22])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:23].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:23].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH2:21][CH3:22])[CH2:15]1)[CH2:5][OH:6]
Reactant: CCC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A suspension of 23.0 g of (3R,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-propyldihydrofuran-2-one obtained in Example (116e) (75.9 mmol), 40.0 ml of a solution of 4 N hydrochloric acid in dioxane (160 mmol) and 5.20 g of 10% palladium-carbon (50% wet) in ethanol (400 ml) was stirred under a hydrogen atmosphere at room temperature for seven hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 200 ml of ethanol. Palladium-carbon was separated by filtration and washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-propyldihydrofuran-2-one hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>CC(C)=O>[Cl:10][CH2:11][CH2:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9])=[O:14]
Reactant: Nc1ccc(O)cc1F
Reactant: O=C(Cl)CCCl
Solvent: CC(C)=O
Product: O=C(CCCl)Nc1ccc(O)cc1F
Yield: 50.7 %

Procedure:
4-Amino-3-fluorophenol (3.4 g) was mixed with 3-chloropropanoyl chloride (3.56 g) in acetone (60 mL) and heated at reflux over 3 hours. After aqueous work-up with EtOAc/water, the isolated organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified with silica gel chromatography to give the product (2.95 g) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([CH:17]([OH:20])[C:18]#[CH:19])=[C:15]3[N:10]([CH:11]=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17](=[O:20])[C:18]#[CH:19])=[C:15]3[N:10]([CH:11]=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(O)c1c(-c2cccc(Cl)c2)nn2cnccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C#CC(=O)c1c(-c2cccc(Cl)c2)nn2cnccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a cold (0° C.) solution of 1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-ol (1.41 g, 4.97 mmol) in chloroform (600 mL) was added manganese dioxide (30.3 g, 0.348 mol). The reaction mixture was stirred at 0° C. for 10 minutes then filtered through a pad of celite. The filtrate was concentrated in vacuo to provide 1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one (1.40 g, 100%) as a white solid. Rf 0.37 (2:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 9.39 (s, 1H), 8.37 (d, 1H), 8.28 (d, 1H), 7.78 (s, 1H), 7.62 (d.1H), 7.52–7.40 (m, 2H), 3.17 (s, 1H); MS m/z 282 (M+1).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[C:3]([B:7]([OH:9])[OH:8])[CH:2]=1.Br[C:14]1[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>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].CC(N(C)C)=O>[CH3:19][N:18]1[C:14]([C:1]2[CH:2]=[C:3]([B:7]([OH:9])[OH:8])[CH:4]=[CH:5][CH:6]=2)=[CH:15][N:16]=[CH:17]1
Reactant: Cn1cncc1Br
Reactant: OB(O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: Cn1cncc1-c1cccc(B(O)O)c1
Temperature: 130 °C
Yield: 45.7 %

Procedure:
1,3-Benzenediboronic acid (300 mg, 1.8 mmol), 5-bromo-1-methylimidazole (291 mg, 1.8 mmol), potassium phosphate (1.15 g, 5.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (164 mg, 0.18 mmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (142 mg, 0.36 mmol) were combined with DMA (3 mL) in a sealed tube purged with N2. The reaction was heated at 130° C. for 25 min in a microwave reactor. The solution was diluted with MeOH, filtered, and concentrated in vacuo. Purification by preparatory HPLC gave 166 mg (45%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 7.91-7.98 (m, 2H), 7.83 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 3.83 (s, 3H). [M+H] calc'd for C10H11BN2O2, 202; found, 202.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:7]=1)C.C(O)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:16]([O:15][C:13]([NH:12][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:23])=[O:3])[CH:11]=[CH:10][CH:9]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 60 °C

Procedure:
To a solution of 44.0 g (140 mmol) of ethyl(3-{[(benzyloxy)carbonyl]amino}phenyl)acetate) (from Step A) in THF, ethanol, and water (1:1:1, 1500 mL) was added solid LiOH (16.8 g, 700 mmol) and the resulting solution heated to 60° C. via oil bath for 3 h. The mixture was cooled to room temperature overnight and then 40 mL of concentrate HCl was slowly added, keeping the temperature below 25° C., until the solution was about pH of 2-3. Extract with ethyl acetate (3×750 mL) and then combine and wash organics with water and then brine. Dry organics over sodium sulfate, filter and concentrate under vacuum. The title compound (24.7 g, 87%) was used for the next step reaction without further purification. LC-MS: m/z (ES) 286 (MH)+, 308 (MNa)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[C:7](=[O:16])[N:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[O:4].[OH-].[Li+]>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:9][N:8]([S:10]([CH:13]([CH3:14])[CH3:15])(=[O:11])=[O:12])[C:7]1=[O:16]
Reactant: COC(=O)C1CN(S(=O)(=O)C(C)C)C(=O)N1c1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccccc2Cl)C1=O

Procedure:
In analogy to example 1, (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed using lithium hydroxide solution to give (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid as a colorless solid. MS: 345.0 ([M−H]−)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:23][N:22]([CH3:31])[N:21]=3)=[CH:16][CH:15]=2)[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:46](=O)([O-])[O-:47].[Cs+].[Cs+]>CO.[Cu](I)I>[CH3:46][O:47][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:23][N:22]([CH3:31])[N:21]=3)=[CH:16][CH:15]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cc(Cl)c4ccccc4n3)cc2)n1
Agent: I[Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cc(COc2ccc(-c3nn(C)cc3-c3ccncc3)cc2)nc2ccccc12
Temperature: 165 °C
Yield: 59.8 %

Procedure:
To a solution of 4-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (125 mg) in methanol (4 mL) was added phenanthroline (78 mg), cesium carbonate (143 mg) and copper iodide (5 mg). The reaction mixture was heated in a microwave reactor at 165° C. with 50 W of power for 20 min. The reaction mixture was filtered through celite and concentrated. Purification via MPLC biotage chromatography, eluting with 5% methanol/1% ammonium hydroxide/methylene chloride provided the title compound (74 mg). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.4 Hz, 2 H), 8.18 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.68 (m, 1H), 7.55 (s, 1H), 7.49 (t, J=7.1 Hz, 1 H), 7.37 (d, J=9.1, Hz, 2 H), 7.15 (d, J=6.2 Hz, 2H), 7.01 (m, 3H), 5.32 (s, 2H), 4.02 (s, 3 H), 3.95 (s, 3H); MS: (M+H m/z=423.3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][NH:13][C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][N:13]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: ClCC1CC1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1F
Product: COc1ccc(-c2cc(=O)n(CC3CC3)nc2-c2ccc(OC)c(F)c2)cc1F

Procedure:
Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)c(-c2ccccc2Cl)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccccc2Cl)s1

Procedure:
5 g of the compound obtained in stage 23D) are added to 100 ml of CH2Cl2, cooling is carried out at −50° C. and 41.8 ml of 1M solution of BBr3 in CH2Cl2 are added. The temperature is allowed to return to 20° C. and then 20 ml of methanol are added. The mixture is concentrated to dryness and the residue is taken up in CH2Cl2, washed with water, dried over MgSO4 and concentrated to dryness. After purifying by chromatography on silica (heptane up to heptane/AcOEt 75/25), 4.57 g of the expected compound are obtained.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[C:5](F)=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8].Cl>CN1CCN(C)C1=O>[Cl:3][C:4]1[C:5]([OH:1])=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1ccc(F)c(Cl)c1O
Temperature: 140 °C

Procedure:
Sodium hydroxide (208 g, 5.21 mol) was added in portions to a stirred solution of 3-chloro-2,4-difluorobenzoic acid (200 g, 1.04 mol) in 1,3-dimethyl imidazolidin-2-one (1 L), and the mixture was heated to 140° C. for 2 hours. The reaction mixture was cooled to room temperature and neutralized with ice-cooled 2N HCl (350 mL) precipitating a white solid that was collected by filtration. The filtered solid was dissolved in methyl t-butyl ether (500 mL), washed with saturated brine solution (150 mL) and dried over Na2SO4. Removal of solvent under vacuum afforded the title compound as off white solid. Yield: 180 g (91%). 1H NMR (300 MHz, MeOH-d4) δ: 6.8 (t, 1H), 7.90 (dd, 1H), 11.3 (s, 1H). MS (ES) MH−: 189 for C7H4ClFO3.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][C:52]1[O:53][C:54]([C:59]2[CH2:63][C:62]([C:68]3[CH:73]=[C:72]([Cl:74])[C:71]([Cl:75])=[C:70]([Cl:76])[CH:69]=3)([C:64]([F:67])([F:66])[F:65])[O:61][N:60]=2)=[CH:55][C:56]=1[CH2:57][NH2:58]>ClCCl>[CH3:51][C:52]1[O:53][C:54]([C:59]2[CH2:63][C:62]([C:68]3[CH:73]=[C:72]([Cl:74])[C:71]([Cl:75])=[C:70]([Cl:76])[CH:69]=3)([C:64]([F:66])([F:65])[F:67])[O:61][N:60]=2)=[CH:55][C:56]=1[CH2:57][NH:58][C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(O)C1CCOC1
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)C1CCOC1
Reaction time: 24 h
Yield: 76.9 %

Procedure:
Tetrahydro-furan-3-carboxylic acid (81 mg), PyBOP (268 mg) and DIPEA (0.244 ml) are added to a solution of C-{2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-yl}-methylamine (200 mg) in dichloromethane (4 ml). After 24 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are washed with a saturated solution of NaHCO3 and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield tetrahydro-furan-3-carboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide (189 mg, compound 2.3 in Table 2) as a white foam. MS (HPLC/MS): 525 (MH+). Retention time: 1.97 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH:7]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]([NH2:22])=[O:21])=[CH:11]1)[CH2:8][CH3:9].C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.[Cl-].[Na+].O.O>[CH3:1][S:2]([CH2:9][CH2:8][CH2:7][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]([NH2:22])=[O:21])=[CH:11]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)n1cc(CC(N)=O)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCCn1cc(CC(N)=O)c2ccccc21
Temperature: 0 °C
Yield: 74.2 %

Procedure:
Methanesulfonyl chloride (0.67 mL, 14.5 mmol) was added dropwise to a 0°-5° C. solution of 1-(1-hydroxypropyl)-indole-3-acetamide (1.68 g, 7.23 mmol) and triethylamine (1.41 mL, 10.1 mmol) in CH2Cl2 (20 mL) under N2. The reaction was stirred 30 minutes in the ice bath and then the reaction was worked up extractively using CH2Cl2 (200 mL), water (100 mL), aqueous saturated NH4Cl (100 mL) and brine (50 ml), and the organic layer dried (MgSO4) and the solvent removed in vacuo to give a solid that was triturated in THF (15 mL) and filtered to give 1.58 g (71%) of the above titled compound after drying. NMR. MS (FD) m/z=310 (M+, 100%). Analytical calculated for C14H18N2O3S C, 54.18; H, 5.85; N, 9.03. Found C, 54.64; H, 5.98; N, 8.97.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][N:16]2[C:22](=[O:23])[C@@H:21]([NH:24][C:25](=[O:37])[C@@H:26]([N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:29])[CH3:27])[CH2:20][O:19][C:18]3[C:38]([C:42]([O:44]C)=[O:43])=[CH:39][CH:40]=[CH:41][C:17]2=3)=[CH:7][CH:6]=1>CO>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][N:16]2[C:22](=[O:23])[C@@H:21]([NH:24][C:25](=[O:37])[C@@H:26]([N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:29])[CH3:27])[CH2:20][O:19][C:18]3[C:38]([C:42]([OH:44])=[O:43])=[CH:39][CH:40]=[CH:41][C:17]2=3)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cccc2c1OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2Cc1ccc(Br)c2ccccc12
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C[C@@H](C(=O)N[C@H]1COc2c(C(=O)O)cccc2N(Cc2ccc(Br)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
A 0.1 M solution of LiOH.H2O (8.87 mL, 887 μmol, Eq: 1.00) was added to a solution of (S)-methyl 5-((4-bromonaphthalen-1-yl)methyl)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (568 mg, 887 μmol, Eq: 1.00) in MeOH (10 mL) at 0° C. The mixture was stirred at RT for 20 min. then heated to 40° C. After 6.5 h the MeOH was removed in vacuo and the aqueous mixture diluted with sat. NaHCO3 and extracted with Et2O. The aqueous mixture was cooled 0° C., acidified to pH 3 with 3 N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound (433 mg, 78%) as a white foam which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[I-].[Na+].[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>CN(C)C=O.[Ni](Br)Br.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10])[CH:37]=[CH:36][C:35]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: FC(F)(F)c1ccc(Cl)cc1Cl
Reactant: C=CC(=O)OCC
Agent: Br[Ni]Br
Agent: [Cl-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 140 °C
Yield: 24.7 %

Procedure:
A suspension of 3.5 g of 2,4-dichlorobenzotrifluoride, 1.28 g of triphenylphosphine, 865 mg of paradium(II) chloride, 2.68 g of sodium iodide, 712 mg of nickel(II) bromide, 4.94 g of triethylamine, and 1.79 g of ethyl acrylate in 16 ml of N,N-dimethylformamide was heated at 140° C. for over night in a sealed tube. The reaction mixture was filtrated off, and the filtrate was concentrated under a reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with water, dried, and evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to give 1.12 g of ethyl 3-chloro-4-trifluoromethylcinnamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:36])[CH2:16][O:17][C:18]2[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=2[C:20]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][NH:27]3)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C=O.[C:39]([BH3-])#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:39])[CH2:14][CH:15]([OH:36])[CH2:16][O:17][C:18]2[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=2[C:20]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][NH:27]3)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNCC(O)COc2ccccc2C(=O)Nc2cccc3[nH]ccc23)cc1OC
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CCN(C)CC(O)COc2ccccc2C(=O)Nc2cccc3[nH]ccc23)cc1OC
Reaction time: 2 h
Yield: 72.9 %

Procedure:
Under an inert atmosphere, a solution of 0.2 g of 2[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide in 5 ml of methanol in the presence of 0.1 ml of formaldehyde with 40% of water was admixed with a solution of 26 mg of sodium cyanoborohydride and 27.2 mg of zinc chloride in 5 ml of methanol and the reaction mixture was left for 2 hours at ambient temperature. 5 ml of 0.1N sodium hydroxide were added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried, and the solvents were eliminated under reduced pressure to obtain 0.230 g of crude product. It was purified by chromatography over silica (eluent: chloroform-ethyl acetate-triethylamine, 6-3-1) to obtain 0.150 g of 2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][SiH:13](Cl)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]2[CH2:15][CH2:14][Si@H:13]([C@H:17]3[CH2:21][CH2:4][C@H:3]([CH2:2][CH2:7][CH3:6])[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCC2CC[SiH](Cl)CC2)cc1
Reactant: C1CCOC1
Product: CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](COc3ccc(F)cc3)CC2)CC1

Procedure:
4.1 g (20 mmols) of 4-n-propylcyclohexyl bromide was dropped in a mixture of 0.5 g of magnesium (21 mmols) and 50 ml of THF to obtain a Grignard reagent. Subsequently, the solution was dropped in 50 ml of a THF solution of 5.2 g (20 mmols) of 4-(4-fluorophenyloxymethyl)-1-chloro-1-silacyclohexane to obtain a crude product. This product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring and the cyclohexane ring. The product was after-treated by a usual manner and isolated through column chromatography to obtain 6.1 g (yield: 87%) of the intended trans-trans isomer product.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH:25]([CH:27]([CH3:33])[C:28](OCC)=O)=[O:26]>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:25](=[O:26])[CH:27]([CH3:33])[CH:28]=[N:10][CH2:9][CH2:8]1
Reactant: CCCCCCCCCCCCCCC(O)CNCCNCCN
Reactant: CCOC(=O)C(C)C=O
Product: CCCCCCCCCCCCCCC(O)CNCCN1CCN=CC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 339.5 g (1 mole) of N-(2-hydroxy)hexadecyldiethylenetriamine and 130.1 g of ethyl 2-formylpropionate. At 140° to 150° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-(2-hydroxyhexadecyl)aminoethyl-6-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH:31][C:2]1[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=1)=[CH:26][CH:25]=2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 2-ethoxycarbony-5-aminoindole gave N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.95 (d, 1H), 7.84 (d, 1H, J=3.9 Hz), 7.34 (s, 1H), 7.33 (d, 1H, J=1.8 Hz), 7.22–7.19 (m, 2H), 7.11–7.05 (m, 2H), 6.55 (m, 1H), 4.62 (s, 2H), 4.38 (q, 1H, J=6.9 Hz), 1.40 9t, 3H, J=7.5 Hz).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:27]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:26])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:22][CH:23]([F:25])[F:24])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]2)[N:6]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1B(O)O>>[NH2:27][C:4]1[S:3][C:2]([C:37]2[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:36]=2[F:35])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:22][CH:23]([F:24])[F:25])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]1)=[O:26]
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(CC(F)F)c3N3CCCC(O)CC3)c(N)s2)c1
Yield: 49.2 %

Procedure:
Following the procedure for Example 105 starting with tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.13 g, 0.23 mmol) and 2-fluoro-5-methylbenzeneboronic acid (53 mg, 0.35 mmol) gave 111 as a black solid (56 mg, 50% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.93 (s, 1H), 8.08 (d, J=7.4 Hz, 1H), 7.66 (s, 1H), 7.42 (s, 2H), 7.24 (d, J=8.7 Hz, 2H), 6.39 (tt, J=55.3, 4.2 Hz, 1H), 4.55 (d, J=3.8 Hz, 1H), 4.42 (td, J=14.5, 4.2 Hz, 2H), 3.86-3.80 (m, 1H), 3.29-3.03 (m, 4H), 2.37 (s, 3H), 1.94-1.84 (m, 3H), 1.77-1.55 (m, 3H). LCMS (ES+) m/z 495 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2nc(C)c(C)n2c1
Yield: 86.4 %

Procedure:
A solution of 8.0 g (24.7 mmol) ethyl 8-benzyloxy-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxylate in 80 ml ethanol is hydrogenated over 0.8 g 10% Pd/C (1 bar H2) for 24 h. The catalyst is filtered off and the filtrate is evaporated. The oily residue is crystallized from diethyl ether to give 5.0 g (86%) of the title compound as a colourless solid (m.p. 219-221° C.).