Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2NC=CC=2C(N2CCC[C@@H](NC(=O)C(NC3C=C(Cl)C=C(Cl)C=3)C3COC3)C2)=N[CH:2]=1.[NH2:33][CH:34]([CH:38]1[CH2:41][O:40][CH2:39]1)[C:35]([OH:37])=[O:36].N1C2NC=CC=2C(N2CCC[C@@H](N)C2)=NC=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:33][CH:34]([CH:38]1[CH2:41][O:40][CH2:39]1)[C:35]([O:37][CH3:2])=[O:36]
Reactant: O=C(N[C@@H]1CCCN(c2ncnc3[nH]ccc23)C1)C(Nc1cc(Cl)cc(Cl)c1)C1COC1
Reactant: NC(C(=O)O)C1COC1
Agent: CCN=C=NCCCN(C)C
Agent: N[C@@H]1CCCN(c2ncnc3[nH]ccc23)C1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(N)C1COC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(N—((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3,5-dichlorophenylamino)-2-(oxetan-3-yl)acetamide). To a solution of 2-amino-2-(oxetan-3-yl)acetic acid (0.3 mmol) and (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (0.3 mmol) in DMF (2 mL) was added DIEA (0.9 mmol), EDCI (0.33 mmol), and HOBt (0.33 mmol). The resulting solution was then stirred at rt for 1 h. The solvent was removed in vacuo to afford a residue, which was purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1% TFA to afford the title compound. 1H NMR (400 MHz, MeOD) δ 8.08 (s, 1H), 7.03 (d, J=3.51 Hz, 1H), 6.55 (d, J=3.51 Hz, 1H), 6.41 (t, J=1.76 Hz, 1H), 6.37 (d, J=1.76 Hz, 1H), 4.64-4.69 (m, 1H), 4.54-4.60 (m, 1H), 4.42 (t, J=6.27 Hz, 1H), 4.07 (d, J=9.29 Hz, 1H), 3.71-3.97 (m, 3H), 1.83-1.93 (m, 1H), 1.76 (br. s., 1H), 1.62 (br. s., 1H). EIMS (m/z): calcd. for C22H24Cl2N6O2(M+1H) 475. found 475.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)[N:7]=1
Reactant: Nc1ccc(CO)cc1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CO)cc2)n1
Yield: 62 %

Procedure:
The reaction of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine and 4-aminobenzyl alcohol using the method described in Example 37 provided the title compound (50 mg, 62% yield). 1H NMR (DMSO-d6) 9.52 (br s, 1H), 7.77 (s, 1H), 7.70 (s, 2H), 7.42 (d, 1H), 7.33 (d, 1H), 7.24 (m, 4H), 5.07 (m, 1H), 4.45 (d, J=5.7 Hz, 2H), 2.52 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH3:28]>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)C(CN)c1cccc(O)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cccc(C(CN)C(=O)OC(C)(C)C)c1

Procedure:
To a solution in acetone (240 ml), of 2-(3-hydroxyphenyl)-(tert-butoxycarbonyl)ethylamine obtained in Step 1, K2CO3 (19.8 g) and 1-bromobutane (15 ml) were added. The suspension was refluxed for 3 days and the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (200 ml) and extracted with CH2Cl2 (2×200 ml). The solvent was eliminated under reduced pressure and the residue was purified by flash chromatography (petroleum ether/EtOAc 85:15) affording 1 (11.3 g, 81% over 3 steps) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:46])=[O:37]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])=[O:37])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.103 g, 0.27 mmol) and triethylamine (0.06 mL, 0.40 mmol) in CH2Cl2 (1 mL) was added 2-chlorobenzyl chloroformate (0.06 mL, 0.40 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, decanted, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl-].[NH4+]>C(O)(C)C.O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: Nc1cc(Br)cnc1N
Temperature: 90 °C
Yield: 94.7 %

Procedure:
5-Bromo-3-nitropyridin-2-amine (3 g) was dissolved in isopropyl alcohol (56 mL) and water (28 mL). Ammonium chloride (1.47 g, 2 eq) was added followed by iron powder (2.31 g, 3 eq). The reaction was heated to 90° C. for 45 minutes. The solution was then cooled, and diluted with EtOAc, filtered, and the layers were separated. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated delivering product as a solid (2.45 g, 95% yield). 1H-NMR (300 MHz, DMSO-d6) δ 7.25 (d, 1H), 6.77 (d, 1H), 5.70-5.40 (bs, 2H), 5.20-4.80 (bs, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C)C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-]>[CH3:1][NH:8][CH2:10][CH2:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(CCC(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CNCCC(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of N-benzyl-N-methyl-3,3-diphenylpropylamine (1.03 g, 3.27 mmol) in methanol (35 ml) and aq. HCl (0.27 ml, of a 12.1M aq. solution, 3.3 mmol) was purged with argon and palladium hydroxide (405 mg) added. The flask was evacuated and shaken under an atmosphere of hydrogen (50 psi) for 18 hrs. The hydrogen was replaced by argon and the catalyst removed by filtration. The filtrate was treated with aq. NaOH (100 ml of a 1M solution) and extracted into Et2O. The organic extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as an oil.
Reaction SMILES: C[C@@:2]12[C@@H:10](O)[CH2:9]C[C@H:7]1[C@@H:6]1CCC3C=C(O)C=CC=3[C@H:5]1[CH2:4][CH2:3]2.[CH3:21][C@@:22]12[C@@H:38](O)[CH2:37]C[C@H:35]1[C@H:34]1[C@@H:25](C3C=CC(O)=CC=3CC1)[CH2:24][CH2:23]2>C(OCC)(=O)C>[CH2:9]=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]=[CH:23][C:22](=[CH2:21])[CH3:35].[CH2:37]=[CH:38][C:22]1[CH:35]=[CH:34][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Solvent: CCOC(C)=O
Product: C=CC(=C)C
Product: C=Cc1ccccc1
Yield: 26277.6 %

Procedure:
In a separate operation, a solution of 20 g hydrogenated colophony glycerol ester resin (Staybelite Ester® 5E) and 8 g styrene-isoprene-styrene copolymer (Cariflex® TR 1107) is prepared in 10 g ethyl acetate and 10 g naphtha having a boiling range between 80 and 100° C.; 0.12 g 17-β-estradiol is added which dissolves completely at room temperature. Using a gap width of about 100 μm, the mass is coated on an antiadhesive polyester film such that a uniform layer having a weight per unit area of 23 g/m2 results after drying for 30 minutes at 35° C. and afterdrying for 15 minutes at 60° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:12])=O>CN(C)C=O>[CH:1]1([CH2:6][C:7]([Cl:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CC1CCCC1

Procedure:
To a solution of 50 g. of cyclopentaneacetic acid containing 2.9 ml. of N,N-dimethylformamide is added dropwise, with stirring, 51 g. of thionyl chloride over a period of 15 minutes. After stirring for an additional 60 minutes excess thionyl chloride is removed in vacuo and the residual oil is distilled to give 55.4 g. (97%) of product, b.p. 57°-58° C. (10 mm.).
Reaction SMILES: O.C[N+]1([O-])CC[O:6]CC1.[CH2:10]([O:12][C:13](=[O:26])[CH2:14][C:15]1[C:19]2[CH:20]=[CH:21]C(C=C)=[CH:23][C:18]=2[S:17][CH:16]=1)[CH3:11].[CH3:27][C:28]([CH3:30])=[O:29].CC#N>[Os](=O)(=O)(=O)=O.O>[CH2:10]([O:12][C:13](=[O:26])[CH2:14][C:15]1[C:19]2[CH:20]=[CH:21][C:27]([CH:28]([OH:29])[CH2:30][OH:6])=[CH:23][C:18]=2[S:17][CH:16]=1)[CH3:11]
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(CC(=O)OCC)csc2c1
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1csc2cc(C(O)CO)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 4-methylmorpholine 4-oxide hydrate (527 mg), ethyl(6-vinyl-1-benzothiophen-3-yl)acetate (320 mg), acetone (0.5 mL), CH3CN (0.500 mL) and water (0.500 mL) was added osmium(VIII) oxide (7% microcapsule, 472 mg) at room temperature. The mixture was stirred at room temperature for 4 d. The insoluble material was removed by filtration through Celite®, and the filtrate was concentrated in vacuo. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (200 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[C:21]([OH:22])=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[C:14]([Br:23])[N:13]=1)=[O:11].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[C:21]([O:22][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[C:14]([Br:23])[N:13]=1)=[O:11]
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Triethylamine (0.759 g, 7.50 mmol) was added to a suspension of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (6, 1.415 g, 5.000 mmol) in chloroform (5 mL) over 5 min maintaining the temperature at 20-50° C. to give a yellow suspension. p-Toluenesulfonyl chloride (1.15 g, 6.00 mmol) was added over 5 min maintaining the temperature at 20-40° C. to give a yellow solution. The mixture was aged at 40° C. for 2 h during which a crystalline solid precipitated out of the mixture and the color faded (HPLC analysis indicated <0.5% starting material remaining). The mixture was cooled to 20° C. over 15 min. MeOH (10 mL) was added over 30 min then a 1:1 mixture of MeOH:water (10 mL) was added over 30 min. The mixture was cooled to −40° C. over 30 min and aged at −40° C. for 30 min. The cold mixture was filtered and the solid was washed with 1:1 MeOH:water (10 mL), MeOH (5 mL), MTBE (10 mL) and hexanes (10 mL) all at 10-20° C. The off-white crystalline solid was dried under a stream of nitrogen to provide 2.112 g (97% yield) of 5-bromo-8-(p-toluenesulfonyloxy)-1,6-naphthyridine-7-carboxylic acid methyl ester (7).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27].Cl>C1COCC1>[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccccc1I
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1I
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxyphenylacetate (1.94 g, 8.16 mmol) in THF (20 ml) was added 2-iodophenylisocyanate (2.0 g, 8.16 mmol) and Et3 N (114 μl, 0.816 mmol). After stirring overnight, the mixture was poured into 1 N HCl (200 ml). The resulting precipitate was collected by filtration and dissolved in CHCl3 (200 ml). The solution was dried over MgSO4 and evaporated to give tert-butyl 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetate (3.93 g, quant) as a pale yellow amorphous solid. 1H-NMR (CDCl3)δ 1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.78–6.88 (m, 4 H), 7.07 (s, 1 H), 7.31–7.35 (m, 1 H), 7.76 (dd, J=7.8, 1.5 Hz, 1 H), 7.95 (d, J=8.3 Hz, 1 H), 7.99 (dd, J=8.3, 1.5 Hz, 1 H). MS (ESI), m/z 483 (M++1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>O1CCCC1>[CH3:1][N:2]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]1=[O:16]
Reactant: CNCCCCN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCCCN1C(=O)c2ccccc2C1=O)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 165 °C

Procedure:
209 mg (0.9 mmol) of 2-[4-(methylamino)butyl]-1H-isoindole-1.3(2H)-dione is solubilized in 5 ml of tetrahydrofuran, then 385 μl (2.7 mmol; 3 equivalents) of triethylamine and 254 mg (0.9 mmol; 1 equivalent) of 2-(4-bromobutyl)-1H-isoindole-1.3(2H)-dione are added to the reaction mixture which is maintained for 25 minutes under microwaves at 165° C. The precipitate obtained is filtered and the filtrate concentrated under reduced pressure. The expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:39][C@H:40]([CH2:48][O:49][CH3:50])[C:41]([N:43]1[CH2:46][CH:45]([F:47])[CH2:44]1)=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[F:47][CH:45]1[CH2:46][N:43]([C:41](=[O:42])[C@H:40]([NH:39][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=2)=[O:22])[CH2:48][O:49][CH3:50])[CH2:44]1
Reactant: COC[C@@H](N)C(=O)N1CC(F)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A 10 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (75 mg, 0.16 mmol), (R)-2-amino-1-(3-fluoro-azetidin-1-yl)-3-methoxy-propan-1-one trifluoroacetate (63 mg, 0.21 mmol), and HATU (63 mg, 0.21 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.55 mL, 3.15 mmol). The light yellow reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with dichloromethane. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-90% EtOAc) to afford 47 mg (47%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as an off-white solid. MS: [M+H]+=616.
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=[CH:39][C:32]=2[O:31][CH2:30]1.O>CCCCCC.O1CCCC1>[Cl:7][CH:8]=[C:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=[CH:39][C:32]=2[O:31][CH2:30]1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CCC(=O)CO2
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(c1)CCC(=CCl)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
0.08 ml (0.2 mmol) of a 1.9M solution of n-butyllithium in hexane is added dropwise to a suspension of 76 mg (0.22 mmol) of chloromethyltriphenylphosphonium chloride in 1.7 ml of tetrahydrofuran cooled to 0° C. The solution is stirred for one hour and then 40 mg (0.18 mmol) of methyl 3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 4, in 2.5 ml of tetrahydrofuran are added at 0° C. via a hollow tube. The solution is stirred at ambient temperature for 1 h 30 and then water is added. After concentrating the solution, dichloromethane is added. The phases are separated and then the aqueous phase is extracted with dichloromethane. The combined organic phases are then washed using brine, are then dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 10/90) to provide 11 mg (24%) of methyl 3-(chloromethylene)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of a mixture of two isomers in a Z/E ratio (70/30); 1H NMR (300 MHz, CDCl3): 2.6 (m, 2H), 2.99 (m, 2H), 3.9 (s, 3H), 4.79 (s, 2H), 6.07 (s, 1H), 7.04 (d, J=8.3 Hz, 1H), 7.84 (m, 2H).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:37][CH2:38][C@H:39]1[CH2:44][CH2:43][C@H:42]([CH2:45][N:46]2[CH2:51][CH2:50][CH:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:48][CH2:47]2)[CH2:41][CH2:40]1>C(#N)C.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:52]1([CH:49]2[CH2:48][CH2:47][N:46]([CH2:45][C@H:42]3[CH2:43][CH2:44][C@H:39]([CH2:38][NH:37][C:13]([C:5]4[S:6][C:7]5[N:12]6[C:3](=[CH:2][N:1]=[C:11]6[CH:10]=[CH:9][CH:8]=5)[CH:4]=4)=[O:15])[CH2:40][CH2:41]3)[CH2:51][CH2:50]2)[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: NC[C@H]1CC[C@H](CN2CCC(c3ccccc3)CC2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NC[C@H]1CC[C@H](CN2CCC(c3ccccc3)CC2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 1 h

Procedure:
To a solution of 0.41 g (1.88 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.37 g (3.21 mM) of N-hydroxysuccinimide in acetonitrile (5 ml) was added 0.62 g (3.23 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide at room temperature, and the mixture was stirred for 1 hour. To this reaction mixture was added a suspension of 0.70 g (1.95 mM) of 1-(trans-4-aminomethyl-1-cyclohexylmethyl)-4-phenylpiperidine dihydrochloride and 1.0 ml (7.71 mM) of triethylamine in chloroform (10 ml) and the mixture was further stirred for 2 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and a small amount of ethanol and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. After concentration, the crude product obtained was purified by column chromatography (methanol/ethyl acetate 30-50%) and recrystallization from ethyl acetate to provide the title compound as red-purple crystals.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:25]=[CH:24][CH:23]=[CH:22][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9](=[O:10])[C:8]2[CH:22]=[CH:23][CH:24]=[N:25][C:7]=2[O:6][C:5]2[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)c1cccnc1Oc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1

Procedure:
To a degassed solution of 2-(4-Fluoro-phenoxy)-N-(4-nitro-benzyl)-nicotinamide (0.800 g 2.17 mmole) in ethyl acetate was added 10% palladium on carbon (0.160 g). This was shaken under 40 psi hydrogen for 30 minutes. The catalyst was removed by filtration, and the solution was concentrated to give an oil that was purified by chromatography on silica gel eluting with 4% methanol/methylene chloride. Recrystalization from ethyl acetate/hexane gave a solid. (0.562 g). 1H NMR (400 mhz, CDCl3) d 3.64 (s, 2H), 4.58 (d, J=5.60 Hz, 2H), 6.64 (d, J=8.30 Hz, 2H), 7.05 (m, 7H), 8.02 (s, broad , 1H), 8.20 (m, 1H), 8.62 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([CH:20]=C)=[CH:13][C:12]=3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl.C[OH:28]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([CH2:20][OH:28])=[CH:13][C:12]=3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=Cc1cnc2c(c1)CN(C(=O)c1ccc(F)cc1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCc2ncc(CO)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Fluorophenyl)(3-vinyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone (50 mg, 0.2 mmol; prepared as described above) was dissolved in CH2Cl2:MeOH (9:1, 15 mL) and cooled in a dry ice/acetone bath. Ozone was bubbled through the solution for 3 min and the reaction was allowed to warm to RT as then purged with an air inlet for 5 min. Sodium borohydride (65 mg, 1.7 mmol) in MeOH (10 mL) was added and the reaction allowed to stir for 1 h. The reaction mixture was concentrated, partitioned between water and EtOAc, and the water layer extracted with CH2Cl2:butanol (9:1). The volatiles were removed under reduced pressure to give 40 mg of crude product. The crude (4-fluorophenyl)(3-(hydroxymethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone was used in the next step without further purification. LC-MS (M+H)=287.2.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CO.O.[NH2:16][NH2:17]>O>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:16][N:17]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)Cc1ccc(C=NN=Cc2ccc(CC(C)C)cc2)cc1
Reaction time: 24 h

Procedure:
A 3-liter three-necked flask was charged with 638.5 g (3.94 mol) of 4-isobutylbenzaldehyde and 1 liter of methanol, which were stirred for mixing by a mechanical stirrer. While the reactor was cooled with water so as to maintain the temperature of the reaction solution below 50° C., 98.5 g (1.97 mol) of hydrazine monohydrate was slowly added dropwise. After the completion of addition, the reaction solution was heated under reflux for 30 minutes and then allowed to stand one day.