Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[NH4+].[OH-].CO>C(Cl)Cl>[NH2:18][CH2:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: NCc1cccc(B(O)O)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CN)c3)nc12

Procedure:
1-[2-(3-Aminomethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and (3-aminomethylphenyl)boronic acid hydrochloride following general procedures as described in these Examples. Silica gel chromatography using 0-20% [5% NH4OH:MeOH]/DCM as eluant gave a brown solid which was washed with 1:2 Et2O/Hexanes to provide 75 mg (48%) of a pale brown solid. MP 176-178° C., M+H=309.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:5]2[C:10](Cl)=[CH:9][CH:8]=[N:7][C:6]=12.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:5]2[C:10]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: C1CCNC1
Reactant: Clc1ccnc2c(Br)c(-c3ccccc3)nn12
Solvent: CCO
Product: Brc1c(-c2ccccc2)nn2c(N3CCCC3)ccnc12
Yield: 77 %

Procedure:
3-Bromo-7-chloro-2-phenylpyrazolo[1,5-α]pyrimidine (100 mg, 0.32 mmol) was dissolved in ethanol. To this solution was added pyrrolidine (0.5 mL) and the reaction mixture heated at reflux for 10 minutes. The resulting mixture was concentrated in vacuo, then dissolved in dichloromethane and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The resulting solid was crystallized from methanol to give 85 mg (77%) of 3-bromo-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine as a solid. 1H NMR (CDCl3):δ 8.17 (m, 3H), 7.50 (m, 3H), 5.80 (d, 1H), 4.09 m (broad s, 4H), 2.10 (broad s, 4H); MS m/z 343 (M+1).
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C(C)(C)C.[OH:39][C:40]([C@H:47]1[CH2:52][CH2:51][C@H:50]([C:53]([O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:54])[CH2:49][CH2:48]1)([C:42]1[S:43][CH:44]=[CH:45][N:46]=1)[CH3:41].Br[C:61]1[N:66]=[C:65]([NH:67][C:68]2[CH:73]=[C:72]([CH3:74])[C:71]([F:75])=[CH:70][N:69]=2)[CH:64]=[C:63]([CH3:76])[CH:62]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:75][C:71]1[C:72]([CH3:74])=[CH:73][C:68]([NH:67][C:65]2[N:66]=[C:61]([C:44]3[S:43][C:42]([C:40]([C@H:47]4[CH2:52][CH2:51][C@H:50]([C:53]([O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:54])[CH2:49][CH2:48]4)([OH:39])[CH3:41])=[N:46][CH:45]=3)[CH:62]=[C:63]([CH3:76])[CH:64]=2)=[N:69][CH:70]=1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2nccs2)CC1
Reactant: Cc1cc(Br)nc(Nc2cc(C)c(F)cn2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(-c3cc(C)cc(Nc4cc(C)c(F)cn4)n3)s2)CC1
Temperature: 130 °C

Procedure:
Into a flask were added butyl diadamantyl phosphine (0.133 g, 0.37 mmol), palladium(II) acetate (0.04 g, 2.2 mmol), potassium carbonate (0.77 g, 5.6 mmol), pivalic acid (0.23 g, 2.2 mmol), butyl trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate (0.69 g, 60.0 mmol), and N-(6-bromo-4-methylpyridine-2-yl)-5-fluoro-4-methylpyridine-2-amine (0.55 g, 1.86 mmol) followed by nitrogen sparged dimethyl acetamide (4.4 mL). The slurry was evacuated and refilled with nitrogen three times and then slowly heated to 130° C. for 15 hours. The slurry was cooled to 35° C. and diluted with ethyl acetate (100 mL). The slurry was then filtered through CELITE, washed with 10% aqueous NaCl (3×100 mL) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to obtain racemic butyl trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate as a foam. 1H NMR (600 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.21 (s, 1H), 8.12 (d, J=5.8 Hz, 1H), 8.08 (s, 1H), 7.21 (s, 1H), 7.04 (s, 1H), 5.79 (s, 1H), 3.93 (t, J=6.5 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 2.14-2.05 (m, 1H), 1.93-1.80 (m, 3H), 1.65-1.60 (m, 1H), 1.53-1.47 (m, 3H), 1.45 (s, 3H), 1.31-1.16 (m, 5H), 1.08-0.99 (m, 1H), 0.83 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:21]=[CH:20][C:7]([O:8][C:9]3[CH:14]=[N:13][C:12]([CH:15]4OCC[O:16]4)=[CH:11][N:10]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CC(C)=O>[CH:1]1([C:4]2[CH:21]=[CH:20][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: c1cc(C2CC2)ccc1Oc1cnc(C2OCCO2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cnc(Oc2ccc(C3CC3)cc2)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a solution in acetone (107 mL) of the compound (2.46 g) obtained in step (3) above, p-toluenesulfonic acid monohydrate (2.04 g) was added and the mixture was stirred at 50° C. for two hours. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to it under cooling with ice and two extractions were conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate; thereafter, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-80:20) to give the titled compound as a colorless solid (0.67 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.[OH-].[Na+]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCn1ccc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c3ccn4CCC(=O)O)no2)cc1Cl
Temperature: 25 °C

Procedure:
Ethyl 3-[4-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]propanoate (D62) (1.1 g, 2.418 mmol) was dissolved in a mixture of 1,4-dioxane (100 ml) and ethanol (100 ml). Water (50.0 ml) was added followed by 2N sodium hydroxide (2.418 ml, 4.84 mmol). The mixture was stirred at RT for one and a half hours to give a single product. Evaporated off most of the solvent, acidified with glacial acetic acid, added water (50 ml) and extracted product into EtOAc (200 ml). Washed with water (30 ml) and dried over MgSO4. The solvent was evaporated off until a white precipitate was formed. The solid was filtered off and washed with ether. Mass of title compound obtained was 780 mg. δH (400 MHz, d6-DMSO) 1.38 (6H, d), 2.81 (2H, t), 4.50 (2H, t), 5.41-5.51 (1H, m), 7.07 (1H, dd), 7.36 (1H, t), 7.59 (1H, d), 7.81 (1H, d), 7.94 (1H, dd), 8.58 (1H, d), 8.96 (1H, d), 12.40 (1H, broad s). MS (ES) C21H1935ClN4O4 requires 426; found 427 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16](C(F)(F)F)=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([O:26]CC)=[O:25].C(N1CCN(C2SC(C(OCC)=O)=C(C)C=2)C1=O)C1C=CC=CC=1>>[CH2:12]([N:9]1[CH2:10][CH2:11][N:7]([C:5]2[S:4][C:3]([C:24]([OH:26])=[O:25])=[C:2]([CH3:1])[CH:6]=2)[C:8]1=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)cc1C
Product: Cc1cc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Yield: 91 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 5-(3-benzyl-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate, the title compound was obtained as a colorless solid in 91% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.36 (br s, 1H), 7.41-7.26 (m, 5H), 6.29 (s, 1H), 4.40 (s, 2H), 3.87-3.80 (m, 2H), 3.48-3.41 (m, 2H), 2.40 (s, 3H); MS (ES+) m/z 317.2 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH3:12][O:13][C@H:14]1[C@@H:19]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:13][C@H:14]1[C@@H:19]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17][N:16]([CH2:2][CH2:3][CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:6])[CH2:15]1
Reactant: O=C(CCCCl)N1CCCC1
Reactant: CO[C@@H]1CNCC[C@@H]1NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1NCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A mixture of 43.9 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine, 55.1 parts of cis-3-methoxy-N-(phenylmethyl)-4-piperidinamine, 37.8 parts of N,N-diethylethanamine and 900 parts of N,N-dimethylformamide was stirred overnight at 70° C. Another portion of 4.4 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine was added and stirring was continued overnight at 70° C. The reaction mixture was evaporated and the residue was taken up in a mixture of water and sodium carbonate. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 53.1 parts (59.0%) of cis-1-[4-[3-methoxy-4-[(phenylmethyl)amino]-1 piperidinyl]-1-oxobutyl]pyrrolidine as a residue (int. 42).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][C:7]([C:11]#[CH:12])([OH:10])[CH2:6][CH2:5]1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].[ClH:23]>CS(C)=O.O>[ClH:23].[CH3:3][N:4]1[CH2:9][CH2:8][C:7]([C:11]#[CH:12])([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C#CC1(O)CCN(C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.8 %

Procedure:
A suspension of 0.58 g of sodium hydride (59% in oil; washed three times with hexanes) in 15 ml of dimethylsulfoxide was heated at 80°-90° for 0.5 hour under nitrogen. The resultant solution was cooled in an ice bath and 2.0 g of 1-methyl-4-ethynyl-4-hydroxypiperidine was added. After five min, the mixture was cooled to 0° and a solution of 2.4 g of 2-fluoronitrobenzene was added dropwise. The mixture was stirred 1 hr at 0°, 3 hrs at room temperature, poured into water, extracted twice with ether, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of the solvent provided an oil, which was treated with ethereal hydrogen chloride to yield 2.34 g (54.8%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([Cl:22])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16].N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>O>[F:34][C:33]([F:36])([F:35])[S:30]([O:21][C:19]1[CH:18]=[C:17]([Cl:22])[C:3]([CH2:4][CH:5]2[CH2:9][CH2:8][N:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:6]2=[O:16])=[C:2]([Cl:1])[CH:20]=1)(=[O:31])=[O:29]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1C(Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCCCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
Charge a flask with 3-(2,6-dichloro-4-hydroxybenzyl)-1-cyclohexylpyrrolidin-2-one (Example 175) (7.5 g, 22 mmol) dissolve with pyridine (200 mL) and cool to 0° C. under nitrogen. Add Tf2O (10 mL, 26 mmol) slowly and warm to room temperature. Stir at room temperature for 30 minutes. Pour into water (1 L) and extract with ether. Wash ether layer twice with water. Dry over sodium sulfate, filter and concentrate. Purify over silica gel (10% ethyl acetate in hexanes) to yield 8.5 g (82%) of the title compound as a white solid. Mass spectrum (apci) rn/z=474.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][N:29]=[N+]=[N-])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][NH2:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Reaction time: 2 h

Procedure:
5-(2-Azidomethyl-pyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (165 mg, 0.36 mmol) is dissolved in THF (5 mL) at 0° C. and lithium aluminum hydride (0.55 mL, 0.55 mmol, 1.0M THF solution) is added. After 2 h, the mixture is quenched with water before extraction with EtOAc. The organic layer is washed with saturated aqueous NH4Cl and then dried over anhydrous Na2SO4. Following concentration the residue is separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 427.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29-8.39 (m, 2H), 8.15 (d, J=3.8 Hz, 1H), 8.09 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.12 (dd, J=8.8, 2.5 Hz, 1H), 7.00 (s, 1H), 6.81 (d, J=3.3 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 3.76 (s, 2H).
Reaction SMILES: [C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[NH2:28]>C(O)C>[C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][NH:28][C@@H:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]2[NH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=Cc1ccccc1P(c1ccccc1)c1ccccc1
Solvent: CCO
Product: N[C@@H]1CCCC[C@H]1NCc1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution, heated to 45° C., of 2.5 g of 2-diphenylphosphanylbenzaldehyde (8.6 mmol) in 250 ml of absolute ethanol is added dropwise over a period of 16 hours to a solution of 3.3 g of (1R,2R)-cyclohexane-1,2-diamine (28 mmol) in 500 ml of absolute ethanol at 0° C. under a protective gas atmosphere. The reaction solution is stirred for one hour at 0° C. and 1.37 g of sodium hydridoborate (36 mmol) are then added. The reaction mixture is slowly allowed to rise to room temperature and stirred for a further 12 hours. The reaction is then quenched by adding 100 ml of acetone and the solvent is completely removed in a rotary evaporator. The resultant residue is completely dissolved by adding 100 ml of saturated ammonium hydrochloride solution and 100 ml of methylene chloride. The organic phase is then separated and washed three times with water. 100 ml of 10% hydrochloric acid are then poured on and the mixture shaken. After a short time in the refrigerator, the product crystallises out as a white mass (hydrochloride). After drying under a high vacuum, a yield of 2.54 g (70% of theoretical) is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])=[CH:17][CH3:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:16]=[CH:17][CH3:18]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC=Cc1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CC=Cc1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-(1-propenyl)phenol (231 μl), and 4-dimethylaminopyridine (220 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 7 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Thereafter, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (137 mg, yield 43%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>[OH-].[Na+].CCOCC>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C=C(C)C(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
D-Proline (50 g) was dissolved in 430 ml of 20% aqueous sodium hydroxide and the resultant solution was stirred with ice bath cooling as 217 ml ether was added followed by dropwise addition of 50 g of methacryloyl chloride in 400 ml ether over about 45 minutes. After another 30 minutes, the aqueous phase was removed and washed once with additional ether. The aqueous phase was then acidified with concentrated hydrochloric acid and extracted three times with ethyl acetate. These combined ethyl acetate extracts were evaporated in vacuo. The resultant residue was crystallized from a mixture of toluene and petroleum ether to yield the title compound, N-methacryloyl-D-proline, which was then recrystallized from acetone/petroleum ether to yield 51.5 g (53%) of purified material.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[N:8]=1.[F:25][C:26]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>[NH4+].[Cl-].COCCOC>[Cl:13][C:9]1[N:8]=[C:7]([C:6]2[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:3][C:2]=2[C:32]2[C:26]([F:25])=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH:12]=[CH:11][N:10]=1
Reactant: CC1(C)OB(c2cccc(N)c2F)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2cccc(N)c2F)c1-c1ccnc(Cl)n1
Yield: 36.9 %

Procedure:
To a microwave vial with stir bar was added 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-1a, step 5, 0.55 g, 1.3 mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.61 g, 2.6 mmol), 2.0 M aqueous sodium carbonate solution (3.2 mL, 6.4 mmol) and DME (6.4 mL). The resulting mixture was sparged with nitrogen followed by the addition of PdCl2(dppf).DCM adduct (0.052 g, 0.06 mmol). The reaction was sealed and irradiated in microwave reactor for 20 minutes at 120° C. The reaction mixture was diluted with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered, concentrated, and adsorbed onto silica gel. Purification by flash chromatography (SiO2, 0-100% EtOAc in heptane) yielded 3-(5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-4-yl)-2-fluoroaniline (223 mg, 0.48 mmol, 38%) as a viscous yellow oil: LCMS (m/z) 460.1 (MH+), tR=0.95 minute.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]4=[N:12][C:11]3=[S:19])[C:4]=2[CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][S:19][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:10]=1[CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=2[S:6][CH:7]=1
Reactant: COC(=O)CCCBr
Reactant: S=C1N=C2C=CC=CN2C1Cc1csc2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 60 mg (0.18 mmol) of 3-(5-chloro-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridine-2-thione and 38 mg (0.21 mmol) of methyl 4-bromobutyrate and 58 mg (0.42 mmol) of potassium carbonate in 2 mL of DMF is stirred at room temperature for 18 h. The mixture is diluted with water and the product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluted with 1˜5% methanol in dichloromethane to give the desired compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[N:6]1([CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:11][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C=CCCBr
Product: C=CCCN1CCCCC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of 1-bromo-3-butene (1.35 g, 10 mmol) and piperidine (1.70 g, 20 mmol) neat was refluxed under nitrogen atmosphere for 3 h. Cooled to RT, filtered and dissolved into ethyl ether (40 mL). Then solution was washed with water (2×30 mL) and dried over anhydrous Na2SO4, filtered and evaporated to dryness to yield 1.3 g (74.15%) oily 1-piperidyl-3-butene.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.N.[NH2:22][C:23]([NH2:25])=[O:24]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=3)[CH2:11][O:24][C:23]([NH2:25])=[N:22]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: C=C(c1cccc(Br)c1)c1ccc(OC)c(C)c1
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C2(c3cccc(Br)c3)COC(N)=N2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of iodine (1.92 g, 7.59 mmol) in ethyl acetate (50 mL) was added dropwise over 25 min to a mixture of 4-[1-(3-bromo-phenyl)-vinyl]-1-methoxy-2-methyl-benzene (2.1 g, 6.9 mmol) and silver cyanate (1.24 g, 8.28 mmol) in acetonitrile (19 mL) and ethyl acetate (9 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 50 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 60° C. for 4 hours. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline, dichloromethane (40 mL) was added to the crude and the two phases were separated. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Crude was purified by silica gel chromatography eluting with dichloromethane/methanol (gradient 0-2%) to give 1.0 g of the desired product as yellow gum (40%)