Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25][NH2:26].CN(C=O)C>O>[O:10]1[C:9]2[CH:14]=[CH:15][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:7][C:8]=2[O:13][CH2:12][CH2:11]1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCCO2
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCNCC(=O)Nc1ccc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of 2-chloro-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide (2 mmol), potassium carbonate (10 mmol), 2-methoxyethylamine (2 mmol) and anhydrous DMF (4 mL) was stirred for 2 hours at 100° C. (monitored by TLC). The mixture was cooled to room temperature, treated with cold water (30 mL). The precipitate was collected by filtration, washed with diethyl ether and dried to afford N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-methoxy-ethylamino)-acetamide (Compound XIa, 96 mg, 36%). 1H NMR (300 MHz, CDCl3/TMS): δ=9.29 (s, 1H), 7.24 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=8.7, 2.4 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.32-4.15 (m, 4H), 3.46 (t, 2H, J=4.8 Hz), 3.36 (s, 3H), 3.34 (s, 2H), 2.82 (t, 2H, J=4.8 Hz), 2.17 (s, 1H). 13C NMR (75 MHz, CDCl3/CD3OD/TMS): δ=169.48, 143.16, 139.87, 131.43, 116.84, 112.74, 108.89, 71.41, 64.28, 64.12, 58.68, 52.57, 49.35.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:35]([O:38][P:39]([CH2:45]Br)(=[O:44])[O:40][CH:41]([CH3:43])[CH3:42])([CH3:37])[CH3:36]>CC#N>[CH:41]([O:40][P:39]([CH2:45][NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:3]=1[C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=[O:44])[O:38][CH:35]([CH3:37])[CH3:36])([CH3:43])[CH3:42]
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Sc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1NC(=O)c1c(NCP(=O)(OC(C)C)OC(C)C)cccc1Sc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 41 %

Procedure:
Compound 25 (1.0 equiv.) was dissolved in MeCN (40 mL) and treated with anhydrous potassium carbonate (2.0 equiv.) at room temperature. To this mixture diisopropyl(bromomethyl)phosphonate (1.2 equiv.) was added via a micro syringe. After being stirred for 4 Hours at 60° C., the reaction mixture was concentrated under reduced pressure. The crude residue was diluted by ethyl acetate (50 mL), and washed with water (2×10 mL). Then it was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:4 v/v ethyl acetate/petroleum ether) to provide a yellow solid (235.2 mg, 41% yield).
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9](=[O:30])[CH2:10][N:11]([CH3:29])[C:12]([N:14]1[CH2:28][CH2:27][CH2:26][C@H:15]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:13])=O)C.Cl.C(OCC)(=O)C.N1CCC[C@H]1C(OCC1C=CC=CC=1)=O.C(Cl)(Cl)Cl>C(O)(=O)C.CO>[NH2:7][C@@H:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9](=[O:30])[CH2:10][N:11]([CH3:29])[C:12]([N:14]1[CH2:28][CH2:27][CH2:26][C@H:15]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:13]
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN(CC(=O)[C@@H](N)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
A solution of 1-[[[(S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester (7.12 g., 13.6 mmole) is stirred in a saturated solution of hydrochloric acid/ethyl acetate for one hour. The resulting precipitate is collected and washed with ethyl acetate to give 5.63 g. of 1-[[(S)-3-amino-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester; m.p. 174°-175°; [α]D25 =+16.20°. TLC (silica gel; chloroform:methanol:acetic acid, 4:1:1) Rf =0.60.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:39])[O:11][C@@H:12]2[CH2:28][C@@H:27]3[C@@:15]([CH3:38])([C@@H:16]4[C@@H:24]([CH2:25][CH2:26]3)[C@:23]3(O)[C@@:19]([CH3:37])([C@@H:20]([C:30]5[CH:31]=[CH:32][C:33](=[O:36])[O:34][CH:35]=5)[CH2:21][CH2:22]3)[CH2:18][CH2:17]4)[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.O=S(Cl)Cl>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:39])[O:11][C@@H:12]2[CH2:28][C@@H:27]3[C@@:15]([CH3:38])([C@@H:16]4[C@@H:24]([CH2:25][CH2:26]3)[C:23]3[C@@:19]([CH3:37])([C@@H:20]([C:30]5[CH:31]=[CH:32][C:33](=[O:36])[O:34][CH:35]=5)[CH2:21][CH:22]=3)[CH2:18][CH2:17]4)[CH2:14][CH2:13]2)[CH2:3][CH2:2]1
Reactant: C[C@]12CC[C@H](OC(=O)NCCN3CCOCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C[C@]12CC[C@H](OC(=O)NCCN3CCOCC3)C[C@H]1CC[C@H]1C3=CC[C@H](c4ccc(=O)oc4)[C@@]3(C)CC[C@@H]12
Reaction time: 2 h
Yield: 47.6 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-morpholinoethylcarbamate (43.7 mg, 0.08 mmol, 1 eq) in pyridine (3 mL) was added SOCl2 (57.1 mg, 0.48 mmol) at 0° C. The mixture was stirred at this temperature for about 2 h, quenched with saturated NaHCO3, and extracted with EtOAc. The organic layers were combined, dried with Na2SO4, concentrated and purified via Preparative TLC to afford (3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-morpholinoethylcarbamate (20 mg, 47.6%). LCMS (M+H+) m/z calculated 524.33. found 526.0. 1H NMR (CD3OD, 400 MHz) δ 7.64 (m, 2 H), 6.38 (m, 1 H), 5.37 (m, 1 H), 4.98 (m, 1 H), 3.78 (m, 4 H), 3.34 (m, 2H), 2.92 (m, 1 H), 2.90 (m, 7H), 2.50-1.30 (m, 18 H), 1.10(s, 3 H), 0.83 (s, 3 H).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[CH3:19][NH2:20]>>[N+:1]([CH:4]=[C:5]([NH:20][CH3:19])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCCCCc1ccccn1
Product: CNC(=C[N+](=O)[O-])NCCCCc1ccccn1

Procedure:
A mixture of 1-nitro-2-methylthio-2-[4-(2-pyridyl)butylamino]ethylene and 33% ethanolic methylamine were heated on a steam bath for 15 minutes. Concentration, followed by crystallisation from ethyl acetate yielded the title compound m.p. 90°-91°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(C(C)(C)C)cc2)CC1
Yield: 34 %

Procedure:
To 1-bromo-4-tert-butyl-benzene (639 mg; 3.0 mmol), [1,4]diazepane-1-carboxylic acid tert-butyl ester (500 mg; 2.5 mmol), tris-(dibenzylidenacetone)-dipalladium (0) (45 mg; 0.049 mmol), sodium tert-butoxide (360 mg; 3.75 mmol) and (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (92 mg; 0.147 mmol) is added toluene (5 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 2 hours at 100° C. Further tris-(dibenzylidenacetone)-dipalladium (0) (45 mg; 0.049 mmol) and (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (92 mg; 0.147 mmol) are added and microwave irradiation at 120° C. is continued for another hour. The reaction mixture is then diluted with ethyl acetate and filtered. The filtrate is concentrated under high vacuum and the obtained residue is purified by column chromatography on silica gel (hexanes/dichloromethane 50:50 v/v to 100) to afford the desired compound (284 mg; 0.85 mmol).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.Br[CH2:16][C:17]#[C:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCBr
Reactant: CCCc1cc(OC)c(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1cc(OC)c(OC)cc1CCC

Procedure:
Following the same procedure as in Example 7a) and 7b), 3.92 g (0.02 moles) of 1-hydroxy-6-propyl-3,4-dimethoxybenzene were reacted with 2.66 g (0.02 moles) of 1-bromo-2-butyne and 2.8 g (0.02 moles) of anhydrous potassium carbonate in 20 ml of acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:38]([C:36]4[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=4)=[O:39])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Reactant: COc1cc(C(=O)O)on1
Product: COc1cc(C(=O)NC2(C(=O)N[C@H]3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)CC2)on1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 552.2 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To a solution of the iodide 408 (4.5 g, 10.8 mmol) in dry THF (120 ml) at was added CuI (205 mg, 0.1 eq, 1.08 mmol), TEA (2.73 g, 2.5 eq, 27 mmol), ethynyltrimethylsilane (2.12 g, 2 eq, 21.6 mmol) and Pd(PPh3)2Cl2 (212 mg, 0.028 eq, 0.30 mmol) and the reaction mixture was heated to reflux for 2 hours. It was then cooled to RT and partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and adsorbed onto silica gel. Purification by column chromatography (30% EtOAc/hexane) afforded 409 (2.2 g, 53% yield). LCMS: 387.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](OC)(OC)(OC)[CH2:16][CH2:17][CH3:18].CS(O)(=O)=O.O1CCCC1>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:12][C:15]([CH2:16][CH2:17][CH3:18])=[N:14][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCC(OC)(OC)OC
Reactant: NNC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nnc(Cc2ccc([N+](=O)[O-])cc2)o1

Procedure:
A mixture of 2-(4-nitrophenyl)acetohydrazide (7.0 g), trimethyl orthobutyrate (16.01 g), methanesulfonic acid (0.69 g) and tetrahydrofuran (200 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 2-(4-nitrobenzyl)-5-propyl-1,3,4-oxadiazole was obtained as a colorless oil (7.73 g, yield 87%) from a fraction eluted with hexane-ethyl acetate (3:2-1:2, v/v).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([Cl:36])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([Cl:36])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C=O)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
A mixture of {1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol (0.61 g), activated manganese dioxide (2.0 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.53 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.Br[C:23]1[S:24][CH:25]=[C:26]([Br:28])[N:27]=1>O1CCCC1.[Zn].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O>[Br:28][C:26]1[N:27]=[C:23]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[S:24][CH:25]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2nc(Br)cs2)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
1,2-Dibromoethane (0.084 mL, 0.97 mmol) was added to a mixture of zinc powder (0.520 g, 8.13 mmol) in tetrahydrofuran (2 mL), and the resulting mixture was stirred for 10 min at 80° C. and was then cooled to room temperature. A solution of chlorotrimethylsilane (0.115 mL, 1.22 mmol) in tetrahydrofuran (1 mL) was added dropwise with stirring, and the resulting mixture stirred for 45 min at room temperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.74 g, 6.15 mmol) in tetrahydrofuran (2 mL) was added, and the resulting mixture stirred for 2 h at room temperature. A solution of 2,4-dibromothiazole (0.744 g, 3.09 mmol) in tetrahydrofuran (1 mL) and tetrakis(triphenylphosphine)palladium(O) (0.354 g, 0.31 mmol) were added, and the resulting mixture stirred overnight at room temperature. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:2, ethyl acetate/petroleum ether) to afford tert-butyl 3-(4-bromothiazol-2-yl)azetidine-1-carboxylate (0.151 g, 8%) of as yellow oil. MS (ESI, pos. ion) m/z 319, 321 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:17])([CH3:19])[CH3:18])=[CH:12][CH:11]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2O)cc1
Product: COc1ccc(C(=O)Oc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 61 %

Procedure:
Using the procedure described in Example 149, Part B, N-(2-hydroxyphenyl)-4-tert-butylbenzamide (2.00 mmol) was reacted with p-anisoyl chloride to yield 494 mg (61%) of the title compound as a crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][CH:20]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cccc(OCc3ccccc3)c2)s1
Temperature: 70 °C
Reaction time: 3 h
Yield: 2.8 %

Procedure:
To a solution of the resulting 3-benzyloxy-phenol (2.6 g, 13.0 mmol) and a 5-nitrothiophene-2-carbonitrile (2.0 g, 13.0 mmol) in dimethylsulfoxide (25 mL) was added potassium carbonate (1.98 g, 14.0 mmol), and the solution was stirred at 70° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile (110 mg, 2.8%) was obtained as a pale brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH3:27][CH:28]([NH2:30])[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:30][CH:28]([CH3:29])[CH3:27])[CH2:13][CH2:14]1
Reactant: CC(C)N
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2cnccc2nc1N1CCC(Oc2ccc(F)cc2F)CC1
Yield: 70.7 %

Procedure:
A solution of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (2 g, 5.31 mmol), propan-2-amine (1.36 mL, 15.92 mmol) and DIPEA (1.85 mL, 10.62 mmol) in dioxane (10.62 mL) was heated at 95° C. overnight. After concentration, the residue was purified with silica gel column chromatography using a gradient of 0% to 100% EtOAc in heptanes to give the title compound (1.5 g, 71%) as an off-white solid. ESI-MS m/z [M+H]+ 400.00.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.CN>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:2][CH3:1])=[O:45])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. Methylamine (2M in THF, 1.0 mL, 2.0 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was triturated with MeOH to yield a white solid (0.024 g, 46% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[C:24]1([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COc2ccccc2CCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CCc2ccccc2OC[C@@H]2CNCCO2)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
0.500 g of (S)-4-t-butoxycarbonyl-2-[2-(2-phenylethyl)phenoxymethyl]morpholine [prepared as described in step (a) above] was dissolved in 2 ml of dioxane, and 4 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution, which was then allowed to stand at room temperature for 1 hour. At the end of this time, the mixture was concentrated by distillation under reduced pressure. The resulting oil was dissolved in 15 ml of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 0.345 g (yield 82%) of the title compound as colorless crystals, melting at 143°-145° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][N:13]1[C:20]2[N:16]([N:17]=[CH:18][CH:19]=2)[CH2:15][CH2:14]1)=O)C.[F-].[Na+].O>O1CCCC1>[OH:9][CH2:10][CH2:12][N:13]1[C:20]2[N:16]([N:17]=[CH:18][CH:19]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)CN1CCn2nccc21
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCN1CCn2nccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a suspension of lithium aluminum hydride (3.89 g) in tetrahydrofuran (195 ml) was added dropwise a solution of 1-ethoxycarbonylmethyl-2,3-dihydro-1H-imidazo[1,2-b]-pyrazole (20 g) in tetrahydrofuran (100 ml) at room temperature. The mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled under ice-bath To a mixture were added sodium fluoride (17.2 g) and water (5.5 ml) under ice-cooling. The insoluble material was filtered off and the filtrate was evaporated. The residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated in vacuo to give 1-(2-hydroxyethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (5.91 g).