Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36]>ClCCl>[Cl:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([N:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:13][CH2:14]1)[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=1)=[O:36]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: COc1ccc(CN[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C(=O)C(C)(C)CCl)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 2 h

Procedure:
A stirred solution of 15A (200 mg, 0.598 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.208 mL, 1.495 mmol), followed by slow addition of 3-chloro-2,2-dimethyl propanoyl chloride (0.155 mL, 1.196 mmol) at room temperature. After stirring for 2 h, reaction was judged complete by LCMS. It was washed with water, and the organics were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by Isco silica column (24 g) eluted with ethyl acetate:hexane, 0%-100%. Concentration of the appropriate fractions yielded 15B (226 mg, 83% yield) as a white foam. MS (ES): m/z=453.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, 2H, J=8.5 Hz); 6.75 (d, 2H, J=8.5 Hz); 4.41 (s, 2H); 4.22-4.30 (m, 1H); 3.88-3.98 (m, 1H); 3.72 (s, 3H); 3.69 (s, 2H); 3.19-3.30 (m, 1H); 1.92-2.02 (m, 2H); 1.01-1.69 (m, 23H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]1)=[O:7].O[N:28]=[C:29]([NH2:34])[CH2:30][CH2:31][O:32][CH3:33]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[CH2:11][CH:10]([C:24]2[O:26][N:34]=[C:29]([CH2:30][CH2:31][O:32][CH3:33])[N:28]=2)[CH2:9]1)=[O:7]
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Reactant: COCCC(N)=NO
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CCOC)no2)C1

Procedure:
100 mg (0.267 mmol) of the compound from Example 105A and 78 mg (0.497 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 22 mg (17% of theory)
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][CH:4]=1>O=S(Cl)Cl>[Cl:1][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:2])[N:8]=1
Reactant: Cc1cccc(CO)n1
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(CCl)n1
Yield: 70.6 %

Procedure:
A solution of (6-methylpyridin-2-yl)methanol hydrochloride (1.0 g, 0.008 mol) in SOCl2 (3 mL) was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude product. The crude material was azeotroped with toluene and the resulting residue was filtered and dried in vacuo to afford 2-(chloromethyl)-6-methylpyridine (800 mg, 63%) as a light brown solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15](OCC)=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH2:22][NH2:23].O>CCO>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([NH:22][NH2:23])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To the solution of ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (13.6 g, 45.0 mmol) in EtOH (200 mL), NH2NH2.H2O (80%, 14 mL, 225 mmol) was added. The reaction mixture was stirred at RT overnight. The desired compound precipitated from the reaction mixture, filtered and washed with EtOH (50 mL) to afford 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide as a light yellow solid (9.7 g, 75%). MS (ES+) C10H7F3N4O3 requires: 288. found: 289 [M+H]+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:24][CH2:23][C:21]1[N:20]=[CH:19][N:18]([C:13]2[CH:12]=[C:7]3[C:8]4[C:3]([CH2:4][CH2:5][N:6]3[C:16](=[O:17])[CH2:15][N:14]=2)=[C:2]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[CH:11]=[CH:10][CH:9]=4)[CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COCc1cn(C2=NCC(=O)N3CCc4c(cccc4-c4nccs4)C3=C2)cn1
Temperature: 150 °C
Yield: 36.7 %

Procedure:
Example 71. To a degassed solution of 9-iodo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (191 mg, 0.43 mmol) and 2-(tributylstannyl)thiazole (239 mg, 0.64 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (25 mg, 0.021 mmol) and the mixture was heated in the microwave at 150° C. for 2 h. The solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: from 1% MeOH in DCM to 5% MeOH in DCM in 18 min) to yield the title compound (64 mg). UPLC-MS: MS 406.1 (M+H+); UPLC rt 0.81 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 3.18-3.31 (m, 5 H), 3.78 (t, J=6.0 Hz, 2 H), 4.30 (s, 4 H), 7.18 (s, 1 H), 7.55 (t, J=7.9 Hz, 1 H), 7.67 (s, 1 H), 7.86 (d, J=7.7 Hz, 1 H), 7.93 (d, J=3.3 Hz, 1 H), 8.04 (d, J=3.3 Hz, 1 H), 8.13 (d, J=8.1 Hz, 1 H), 8.24 (s, 1 H).
Reaction SMILES: N1(C2N=C(CC([O-])=O)NC(=O)C=2)CC[O:4]CC1.[Na+].Cl[C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:45])[N:24]2[C:29](=[O:44])[CH2:30][C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:32]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:4][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:45])[N:24]2[C:29](=[O:44])[CH2:30][C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:32]=1
Reactant: CC1Cc2c(Cl)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1Cc2c(O)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 107.5 %

Procedure:
The product is prepared by following the procedure described in example 1c using 1.2 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.82 g of 2-methyl-2,3-dihydro-1H-indol-4-ol [reference example 1c] and 1.17 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 1.1 ml of pyridine and 25 ml of N,N-dimethylformamide. After purification of the residue by chromatography on a 90 g cartridge of 15-40 μm silica, elution being carried out with pure dichloromethane and then with 98/2 then 95/5 v/v dichloromethane/methanol mixtures at a flow rate of 80 ml/min, 0.84 g of 2-[2-(4-hydroxy-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one is obtained in the form of a very pale pink powder, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:8]([NH:11][C:12]([N:14]2[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16][CH2:15]2)=[O:13])([CH3:10])[CH3:9])[CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:23][C:5]1[CH:4]=[CH:3][C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][C:6]=1[C:8]([NH:11][C:12]([N:14]1[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(NC(=O)N1CCN2CCC1CC2)c1cc(Br)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)N1CCN2CCC1CC2)c1cc(-c2ccccc2)ccc1F
Yield: 28.3 %

Procedure:
Using general procedure E, N-(2-(5-bromo-2-fluorophenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide (100 mg, 0.261 mmol), phenyl boronic acid (30 mg, 0.25 mmol) and palladium (II) acetate gave the title compound as an off-white solid (27 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 7.56-7.51 (m, 3H), 7.41-7.37 (m, 3H), 7.32-7.30 (m, 1H), 7.03 (m, 1H), 4.90 (s, 1H), 4.00 (br s, 1H), 3.59 (m, 2H), 3.11-2.92 (m, 6H), 2.04-1.98 (m, 2H) 1.78 (s, 6H), 1.73-1.67 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 161.8, 159.4, 155.9, 140.9, 137.2, 134.6, 128.9, 127.4, 127.3, 127.2, 127.1, 127.0, 116.9, 57.9, 54.4, 48.1, 46.5, 46.5, 41.4, 29.9, 29.3, 27.5, 27.5 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.90 min; (M+1) 400.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:10].CCN(C(C)C)C(C)C>C1COCC1>[N:1]1([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
Morpholine Compound 50b (1.41 mL, 16.2 mmol) was added dropwise to a solution of 2-bromo-1-(4-nitro-phenyl)-ethanone Compound 50a (4.15 g, 16.2 mmol) in THF (50 mL) and DIPEA (3.1 mL, 17.8 mmol). The reaction was stirred for 3 hours and then extracted from 0.5 M NaH2PO4 with EtOAc. The combined extracts were dried over MgSO4, filtered and evaporated down. The residue was recrystallized from EtOAc and hexanes to give 2-morpholin-4-yl-1-(4-nitro-phenyl)-ethanone Compound 50c (2.55 g) as a yellow solid. MS 251 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.O>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (400 mg) in N,N-dimethylformamide (2.6 mL) was added cesium carbonate (957 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added (3-bromopropoxy)(tert-butyl)dimethylsilane (979 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (630 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)/C=C/c1ccnc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 13.6 %

Procedure:
tert-Butyl (E)-3-(2-cyano-4-pyridyl)acrylate (0.84 g, 3.2 mmol) and methyl thiosalicylate (0.74 g, 4.4 mmol) were dissolved in toluene (3 ml), and triethylamine (0.77 ml, 5.5 mmol) was added thereto. The reaction mixture was refluxed for 7 hrs and subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated. The residue was recrystallized from ethyl acetate-isopropyl ether to give the titled compound (0.16 g, 17%) as white crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[NH:6])[NH:4][OH:5].C(N(CC)CC)C.[F:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1[C:17](Cl)=O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:6]=[C:17]([C:16]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:15]=2[F:14])[O:5][N:4]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: N=C(CCl)NO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1ccc(C(F)(F)F)cc1-c1nc(CCl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
To a solution of 2-chloro-N-hydroxyethanimidamide (2.4 g, 22.1 mmol) and triethylamine (3.7 ml, 26.5 mmol) in dry toluene (35 mL) was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5 g, 22.1 mmol) at 0° C. The mixture was stirred at room temperature for 1 h and then at 100° C. overnight. The resulting solid was filtered and the filtrate was then concentrated in vacuo. The residue was purified by radial chromatography (0-30% EtOAc-hexanes gradient) to afford the title compound (1.2 g, 19% yield): MS (ES) m/z 281 (M+1) and 283 (M+1, isotope).
Reaction SMILES: [C:1]1([C:7](=[O:18])[C:8]#[C:9][CH2:10][O:11]C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CCO>[OH:11][CH2:10][C:9]#[C:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: O=C(C#CCOC1CCCCO1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: O=C(C#CCO)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of (1-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-yn-1-one (3.0 g, 12.3 mmol) in EtOH (20 mL) was added pyridinium p-toluenesulfonate (0.62 g, 2.5 mmol). The resulting solution was stirred for 1 h at 50° C. and then the reaction mixture was poured into water (150 mL), extracted with Et2O (3×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4-hydroxy-1-phenylbut-2-yn-1-one as a dark red oil (3.2 g, crude).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([CH2:25][OH:26])[CH2:19]2)([CH3:15])([CH3:14])[CH3:13]>ClCCl.CCOCC>[C:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([CH:25]=[O:26])[CH2:19]2)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc2c(c1)CC(CO)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)CC(C=O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
To a suspension of pyridinium chlorochromate (FCC, Fluka, 3.24 g, 15 mmole) in dichloromethane (20 ml), there was added at room temperature, a solution of 5-tert-butyl-2-indanmethanol (2.04 g, 10 mmole) in dichloromethane (10 ml). The mixture was stirred for 5 h at room temperature. It was diluted in ether (50 ml), filtered on CELITE®, then on a FLORISIL® column (Fluka), and concentrated. Bulb-to-bulb distillation provided 5-tert-butyl-2-indancarbaldehyde (1.47 g, purity>99%, yield 72%) as a colorless oil.
Reaction SMILES: [Mg].[CH2:2]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[O:18][B:19]([O:22]C)[O:20]C.Cl>O1CCCC1>[CH2:2]([C:10]1[CH:15]=[CH:14][C:13]([O:18][B:19]([OH:22])[OH:20])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COB(OC)OC
Reactant: CCCCCCCCc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(OB(O)O)cc1
Temperature: -78 °C

Procedure:
50 ml of THF (tetrahydrofuran) was added to 2.91 g (0.12 mol) of metallic magnesium, and the mixture was stirred. 100 ml of a solution of 26.89 g (0.1 mol) of p-octylbromobenzene in THF was added dropwise thereto, and the mixture was heated. After the initiation of the reaction was confirmed, the mixture was refluxed for one hr. The mixture was cooled to −78° C., 12.46 g (0.12 mol) of trimethylboric acid was added dropwise thereto, and the mixture was stirred for 30 min. The temperature was returned to room temperature, followed by stirring for additional one hr. Dilute hydrochloric acid was added thereto, and the mixture was stirred for one hr. The aqueous layer was extracted with ether, and the oil layer was washed with water and then with an aqueous sodium hydrogencarbonate. The oil layer was then dried over sodium sulfate, the solvent was removed by distillation, and the resultant crude product was purified by chromatography on silica gel to give p-octylphenylboric acid.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([NH2:12])=[N:10][CH:11]=1.[CH:13]1([CH2:18][N:19]([CH2:30][CH3:31])[C:20]2[C:21]([CH:28]=O)=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:13]1([CH2:18][N:19]([CH2:30][CH3:31])[C:20]2[C:21]([CH2:28][NH:12][C:9]3[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:11][N:10]=3)=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1C=O
Reactant: CSCCOc1cnc(N)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CNc1ncc(OCCSC)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
A solution of 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (1.03 g, 5.55 mmol) obtained in Step 1 and 3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypicolinaldehyde (1.60 g, 6.10 mmol) obtained in Step 3 in 1,2-dichloroethane (60 mL) was stirred at room temperature for 10 minutes, and then added with sodium triacetoxyborohydride (1.24 g, 5.83 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (1.60 g, 67%) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:23][N:24]([CH3:41])[CH2:25][CH2:26][CH2:27][N:28]([CH3:40])[C:29]1[C:30]([NH2:39])=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.C1COCC1>C(N(CC)CC)C>[CH3:41][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][N:28]([CH3:40])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:30]=1[NH:39][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(Cl)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1NC(=O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 25 °C
Reaction time: 108 h

Procedure:
To 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoyl chloride (60 mg, 0.17 mmol) and N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (44.1 mg, 0.160 mmol) was added THF (1.0 mL). The mixture was stirred at rt for 4.5 days. The reaction was quenced with excess triethylamine, filtered and concentrated. The residue was purified by Gilson reverse-phase HPLC (0.1% TFA in water/acetonitrile). After basic workup, N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzamide was obtained as a white solid. MS m/z=558 [M+1]+. Calc'd for C28H27F4N5O3: 557.55.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CC(C)(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reaction time: 8 h

Procedure:
3-Methyl-1,3-butanediol (1.5 mL, 14.1 mmol) is suspended in dry dichloromethane (5 mL) and pyridine (1.24 mL, 15.46 mmol) is added followed by 4-toluenesulfonyl chloride (2.68 g, 14.1 mmol). The mixture is stirred overnight then washed with 1 M aqueous hydrochloric acid, dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-30% ethyl acetate in cyclohexane) to give the title compound. (Yield 970 mg). LC (METHOD 2): tR=5.67 min; Mass spectrum (ES+): m/z=258 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[NH:11][C:10]1=[O:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:11]1[CH:12]([CH:15]([CH3:16])[CH3:17])[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C1NC(=O)N(c2cc(F)ccc2Cl)C1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C1C(=O)N(c2cc(F)ccc2Cl)C(=O)N1Cc1ccccc1
Yield: 76.4 %

Procedure:
This compound was synthesized in analogy to example 155 (step A to E). In step A, 2-methyl-propionaldehyde was starting material in place of cycloheptanone and ammonium acetate in place of cyclopropylamino acetate. In step B, 2-chloro-5-fluoro-phenyl amine was used in place of 4-Amino-benzoic acid ethyl ester. The pure 3-(2-chloro-5-fluoro-phenyl)-5-isopropyl-imidazolidine-2,4-dione that resulted from this procedure was then benzylated by stirring of 300 mg (1.11 mmol) of 3-(2-Chloro-5-fluoro-phenyl)-5-isopropyl-imidazolidine-2,4-dione with 141 ml (1.16 mmol) of benzyl bromide and 51 mg (1.16 ml) of sodium hydride (55% in oil) in 5 ml DMF for 3 h at RT. The reaction mixture was then taken up in ethyl acetate and was washed with 1N HCl and water. The crude product was purified by silica gel chromatography with Ethyl acetate/Heptane 1:3 to give 306 mg of pure 1-benzyl-3-(2-chloro-5-fluoro-phenyl)-5-isopropyl-imidazolidine-2,4-dione that was reduced with the same procedure described in step D and E to give pure 3-benzyl-1-(2-chloro-5-fluoro-phenyl)-4-isopropyl-imidazolidin-2-one as a colorless viscous oil MS (ESI): 347.3 (MH+).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>C1COCC1>[N:45]1([CH2:44][CH2:43][O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A solution of 10 g of p-nitrophenol (72 mmol) in 100 mL dry THF was treated with 28.28 g (108 mmol) of triphenyl phosphine. The solution was cooled to 0° C. then treated with 18.78 g (108 mmol) diethyl azodicarboxylate. After stirring for 30 min at 0° C., 12.4 g (108 mmol) 1-(2-hydroxyethyl)pyrrolidine was added. The cooling bath was removed and the reaction allowed to stir overnight at ambient temperature. EtOAc was added (300 mL) and the mixture was extracted twice with 200 mL 1 N H2SO4. The combined extracts were washed twice with 200 mL EtOAc, made basic with 5 N NaOH and extracted three times with 150 mL EtOAc. The extracts were dried over MgSO4 and concentrated under vacuum to an oil which was purified by chromatography (SiO2 ; 1% MeOH in CHCl3) to recover 7.56 g (32 mmol, 44%) of the desired compound as a solid.