Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
4-Bromo-6-chloro-2H-pyridazin-3-one (5.02 g, 23.97 mmol) was dissolved in 40 ml dimethylformamide. Cesium carbonate (9.37 g, 28.76 mmol) was added. After 5 min, iodomethane (5.103 g, 35.95 mmol) was added dropwise over 20 min. The reaction mixture was stirred 3 hours at room temperature. The precipitate was filtered off and concentrated and the resulting residue was treated with 20 ml dichloromethane. The insoluble material was filtered off again and washed with dichloromethane. The filtrate was concentrated in vacuo to yield 4-Bromo-6-chloro-2-methyl-2H-pyridazine-3-one (5.223 g, 23.37 mmol). MS (ESI) 224.9 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:14]([O:13][C:11](=[O:12])[C@H:10]([CH3:16])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)[C@H](C)Nc1ccc(Cl)cc1

Procedure:
This compound was prepared in a manner analagous to the process described in synthesis example 14, except using 4-chloroaniline and ethyl 2-bromoproprionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].CN(C)C=O.Br[CH2:34][F:35]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH2:34][F:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)cc1OC
Reactant: FCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=COCF)c2ccc(Cl)cc2)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
One gram (1.00 g) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl) acrylamide (2.66 mmol), 130 mg (3.25 mmol) of 60% sodium hydride and 10 ml of anhydrous N,N-dimethylformamide were mixed and 0.46 g of bromofluoromethane was added thereto at −15° C. The mixture was stirred at −15° C. for 30 minutes and then stirred at 0° C. for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with 5% hydrochloric acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=1:1) to give 100 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(4-chlorophenyl)acrylamide (the present compound 1016).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(C)cccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.039 g, 63%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.084 g, 0.205 mmol) and methylamine (1.86 g, 60.0 mmol). mp >250° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](C(O)=O)[CH:9]=2)[N:4]=1.C([O:18][C:19](C1C=C2C(C=CC=[N+]2[O-])=CC=1)=[O:20])C>>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:19]([OH:20])=[O:18])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CNc1ccc2cc(C(=O)O)ccc2n1
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Product: CNc1ccc2ccc(C(=O)O)cc2n1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 20, using 7-(ethoxycarbonyl)quinoline 1-oxide. 1H NMR (400 MHz, DMSO-d6, δ): 8.08 (s, 1H), 7.90 (d, 1H), 7.71-7.62 (m, 2H), 7.21 (s, 1H), 6.84 (d, 1H), 2.91 (d, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([OH:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH:11]1(O)[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:10][C:8]2[CH:9]=[C:4]3[CH:3]=[CH:2][NH:1][C:5]3=[N:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCCC1
Reactant: Oc1cnc2[nH]ccc2c1
Product: c1cc2cc(OC3CCCC3)cnc2[nH]1

Procedure:
5-cyclopentyloxy-1H-pyrrolo[2,3-b]pyridine P-0001 was synthesized in one step from 1H-Pyrrolo[2,3-b]pyridin-5-ol 6 and cyclopentanol 7 as shown in Scheme 2.
Reaction SMILES: OO.[CH2:3]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]3[N+:17]([O-:18])=[N:16][C:15]([NH2:19])=[N:14][C:10]=3[CH:11]=2)[CH2:6]1)[CH3:4].C(O)(C(F)(F)F)=[O:21].O>N>[CH2:3]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]3[N+:17]([O-:18])=[N:16][C:15]([NH2:19])=[N+:14]([O-:21])[C:10]=3[CH:11]=2)[CH2:6]1)[CH3:4]
Reactant: CCN1Cc2cc3nc(N)n[n+]([O-])c3cc2C1
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: O
Product: CCN1Cc2cc3c(cc2C1)[n+]([O-])c(N)n[n+]3[O-]
Temperature: 20 °C
Reaction time: 28 h
Yield: 19 %

Procedure:
H2O2 (70%, 0.50 mL, ca. 10 mmol) was added dropwise to a stirred mixture of 1-oxide 249 (328 mg, 1.4 mmol), TFA (4 mL) and water (0.3 mL) at 0° C. and the mixture was stirred at 20° C. Two more aliquots of H2O2 (70%, 0.50 mL, ca. 10 mmol) were added at 3 h and 20 h. After 28 h at 20° C., the mixture was diluted with aqueous NH3 solution (20 mL) and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 250 (68 mg, 19%) as a red solid which was crystallised as the hydrochloride salt: mp (MeOH/DCM) 230° C.; 1H NMR [(CD3)2SO] δ 11.84 (br s, 1H, HCl), 8.27 (s, 1H, H-9), 8.20 (s, 1H, H-5), 8.14 (br s, 2H, NH2), 4.88-5.05 (m, 2H, CH2N), 4.50-4.73 (m, 2H, CH2N), 3.42 (q, J=7.2 Hz, 2H, CH2N), 1.32 (t, J=7.2 Hz, 3H, CH3); 13C NMR [(CD3)2SO] δ 151.4, 143.0, 138.5, 134.0, 130.6, 115.6, 111.4, 56.5, 56.1, 49.1, 10.3; HRMS (FAB+) calcd for C11H14N5O2 (MH+) m/z 248.1148, found 248.1154.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:22]([F:21])[CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)O)cc1F
Agent: Cl
Product: COc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1F

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3-fluoro-4-methoxybenzoic acid.
Reaction SMILES: C1(S([CH:10]([F:12])[F:11])(=O)=O)C=CC=CC=1.Cl[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16]>CN(C=O)C>[F:12][CH:10]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[F:11]
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=S(=O)(c1ccccc1)C(F)F
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)C(F)F
Reaction time: 4 h
Yield: 50.9 %

Procedure:
Into a mixture of 5 g (26 mmol) difluoromethyl phenyl sulfone (4), 1.9 g Mg turnings (78 mmol) and 150 mL DMF at −40° C., was slowly added 11.8 g (78 mmol) chlorotriethylsilane. The reaction mixture was then stirred at −40° C. to 10° C. during a 4 h period until 19F NMR indicated all of 4 was consumed. Similar work-up as above and fractional distillation gave 2.2 g product 19, b.p. 71° C./56 Torr, yield 51%. 1H NMR (500 MHz, CDCl3): δ0.72 (q, 3JH-H=8.0 Hz, 6H); 1.02 (t, 3JH-H=8.0 Hz, 9H); 5.95 (t, 2JH-F=46.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ0.6 (s, CH2); 6.7 (s, CH3); 124.3 (t, 1JC-F=254.8 Hz). 19F NMR (470 MHz, CDCl3): δ−137.6 (d, 2JF-H=45.8 Hz). 29Si NMR (99 MHz, CDCl3): δ3.3 (t, 2JSi-F=24.8 Hz). GC-MS (m/z): 166 (M+); 115 (Et3Si+); 51 (CF2H+).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([N:13]1CCC[CH2:15][C:14]1=O)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:9]([O:8][C:6]([N:13]1[CH2:14][CH2:15][C:3](=[CH2:4])[CH2:2][CH2:1]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (5.4 g, 15.05 mmol) in THF (100 mL) was added slowly butyl lithium (2M, 15.05 mmol) at −78° C. The mixture was allowed to stir for one hour and N-Boc-piperidinone (2 g, 10.03 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The THF was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate, filtered and concentrated. The compound was purified by column chromatography (30% Hexanes/EtOAc) to provide the title compound (1.96 g, 99%).
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[C:13]([Cl:20])=[CH:12][C:11]=2[F:21])[C:5](=[O:22])[C:4]=1[CH3:23])[CH3:2].S(OC)(O[CH3:28])(=O)=O>>[CH2:1]([C:3]1[N:8]([CH3:28])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[C:13]([Cl:20])=[CH:12][C:11]=2[F:21])[C:5](=[O:22])[C:4]=1[CH3:23])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCc1[nH]c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)c1C
Product: CCc1c(C)c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-methyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,5-dimethyl-2,4(1H,3H)-pyrimidinedione, m.p. 88°-91° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:22])=[N:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:29]([C:27]3[S:28][C:24]([CH3:23])=[CH:25][CH:26]=3)(=[O:31])=[O:30])=[N:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Solvent: c1ccncc1
Product: COc1ccc(Cn2nc(NS(=O)(=O)c3ccc(C)s3)c3c(OC)cccc32)cc1F
Reaction time: 3 h

Procedure:
A solution of 1-{[3-fluoro-4-(methyloxy)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 80) (130 mg, 0.8 mmol) in pyridine (2 mL) was added to 5-methyl-2-thiophenesulfonyl chloride (0.24 mmol). The reaction mixture was shaken briefly and allowed to stand for 3 h at 21° C. prior to concentration by blowdown. The residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier (Method C). The solvent was evaporated in vacuo to give the title compound (76 mg) LCMS (System A) RT=1.11 min, ES+ve m/z 462 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>CCO.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:27][CH:24]2[CH2:26][CH2:25]2)[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Reactant: NC1CC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(NC3CC3)cc21
Temperature: 100 °C
Reaction time: 240 h
Yield: 23.3 %

Procedure:
A solution of Example A6 (500 mg, 1.507 mmol) and cyclopropylamine (860 mg, 15.07 mmol) in EtOH (15 mL) was heated at 100° C. in a sealed vessel. After 20 h the reaction mixture was treated with additional cyclopropylamine (860 mg, 15.07 mmol) and catalytic DMAP (10 mg) and heated at 100° C. for 23 h, then 115° C. for 10 days. The mixture was cooled to RT, concentrated to dryness and the resulting residue dissolved in EtOAc (30 mL) and washed successively with water (30 mL), satd. NaHCO3 (30 mL) and brine (30 mL). The organic phase was dried over Na2SO4, concentrated to dryness and purified by reverse phase chromatography (MeCN/H2O with 0.1% TFA). The aqueous solution was treated with satd. NaHCO3 (5 mL) and allowed to stand. A solid formed which was collected by filtration to yield 3-(5-amino-4-fluoro-2-methylphenyl)-7-(cyclopropylamino)-1-ethyl-1,6-naphthyridin-2(1H)-one (124 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 6.83 (d, 1H), 6.58 (d, 1H), 6.38 (s, 1H), 4.87 (s, 2H), 4.18-4.12 (m, 2H), 2.59 (m, 1H), 1.94 (s, 3H), 1.21 (t, 3H), 0.75 (m, 2H), 0.47 (m, 2H); MS (ES-API) m/z: 353.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:32]4[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4cc(F)cc(F)c4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,5-difluorophenyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (64%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:40])[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[N:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[C:38]([C:34]1[CH:33]=[C:32]([C:30]2[N:31]=[C:22]([N:19]3[CH2:20][CH2:21][CH:16]([O:15][CH2:14][C:13]([OH:40])=[O:12])[CH2:17][CH2:18]3)[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:37]=[CH:36][CH:35]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)COC1CCN(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2nc(N3CCC(OCC(=O)O)CC3)cc3cccnc23)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TFA (1 ml) is added to a solution of {1-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-piperidin-4-yloxy}-acetic acid tert-butyl ester (200 mg, 0.45 mmol) in CH2Cl2 (2 ml) at 0° C. The reaction mixture is stirred at 0° C. for 10 minutes then at room temperature for 1.5 hours and is then concentrated. The residue is partitioned between ethyl acetate and water and the aqueous layer is adjusted to pH 5 with 1M KOH. The aqueous layer is extracted with ethyl acetate (×3) and the combined ethyl acetate extracts are dried (MgSO4), filtered and concentrated. Purification by chromatography on silica gel, eluting with 1% MeOH in CH2Cl2 gives the product. MS (ES+) Observed [M+H]+3 89.05
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 120 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
A pressure bottle was charged with 1-chloro-2-methoxy-4-nitrobenzene (10.0 g mg, 53.3 mmol, purchased from TCI America) and morpholine (15 mL, 172.0 mmol). The reaction mixture was stirred at 120° C. for 15 hours and it was allowed to cool to room temperature by itself. The resulting solid was suspended in 20 mL of ethyl acetate, filtered, and washed with 20 mL of tert-butyl methyl ether. 8.8 g of yellow solid as the desired product AA was collected (69% yield). 1H-NMR (400 MHz, d6-DMSO): 7.83 (dd, 1H), 7.67 (d, 1H), 6.98 (d, 1H), 3.88 (s, 3H), 3.71 (m, 4H), 3.16 (m, 4H). MS (EI) CH11H14N2O4: 239 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2].[CH:12]([CH:14]=[CH2:15])=O>O1CCOCC1.[Cl-].[Zn+2].[Cl-]>[C:1]([C:3](=[CH:15][CH:14]=[CH2:12])[C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: C=CC=O
Reactant: CC(C)(C)COC(=O)CC#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: C=CC=C(C#N)C(=O)OCC(C)(C)C
Yield: 37.9 %

Procedure:
To a 1 liter, 3-necked glass reaction flask equipped with a mechanical stirrer, pressure compensating addition funnel and thermometer was added 1,4-dioxane (300 mls), zinc chloride (62.7 g; 0.46 moles), neopentyl cyanoacetate (116.25 g; 0.75 moles) and 1 ml of a solution of 1,4-hydroquinone, prepared by dissolving 1.22 g 1,4-hydroquinone in 100 mls 1,4-dioxane. The mixture was stirred and cooled by means of an ice bath, while a solution of acrolein (52.54 g; 0.94 moles) in 1,4-dioxane (200 mls) was added slowly from the addition funnel. The rate of addition was adjusted such that the reaction temperature did not exceed 40° C. After the reaction exotherm had subsided, the cooling bath was removed and the mixture stirred for a further 5 days. The solvent was removed by distillation under reduced pressure at 28° C. and 45 mbar and the reaction product was transferred to a 2-liter flask. Hexane (900 mls) was added and a yellow polymeric precipitate was formed. The hexane solution was decanted from the polymer and washed 3 times with 1200 ml portions of cold 0.1M hydrochloric acid solution, dried over anhydrous sodium sulfate and the solvent removed by distillation under reduced pressure to yield crude neopentyl 2-cyanopenta-2,4-dienoate (54.95 g; 38%) as a low viscosity orange colored liquid. The structure of the monomer was confirmed by proton NMR and IR analysis. The monomer was stabilized by the addition of 0.6 mg (approximately 10 ppm) of methane sulfonic acid. This monomer was used without further purification in the preparation of the BCPP-TMDS compositions.
Reaction SMILES: [O:1]1[CH:10]2[CH:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][N:6]1[CH2:7][CH2:8][CH2:9][CH:10]2[O:1][CH2:2][CH2:3][CH2:4][CH:5]12
Reactant: C1COC2CCCNC2C1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCCC2OCCCC21
Temperature: 25 °C
Yield: 30 %

Procedure:
A mixture of octahydro-2H-pyrano[3,2-b]pyridine (0.50 g), 1-bromo-3-chloropropane (0.90 mL) and K2CO3 (0.70 g) in acetone was heated to reflux for 10 h, then cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 25:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.23 g, 30.00%), HPLC: 80.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 218.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C([N-]C(C)C)(C)C.[Li+].I[CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1>[CH2:23]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1CCc2cc(OC)ccc2C1=O
Temperature: -78 °C

Procedure:
A solution of 6-methoxy-3,4-dihydro-1(2H)-naphthalenone (5.29 g, 30 mmol) in anhydrous tetrahydrofuran (THF, 150 mL) was placed under a N2 atmosphere, cooled in an ice bath, stirred, and treated with lithium diisopropylamide (90 mL of a 0.4M solution in THF, 36 mmol) dropwise over 13 minutes. The mixture was stirred at 0-5° C. for 30 minutes, then cooled in a dry ice-acetone bath to −78° C. and treated all at once with iodobutane (17.04 mL, 150 mmol). The resulting mixture was allowed to slowly warm to room temperature and stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl and concentrated under vacuum. The residue in EtOAc was washed with 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40M (4×15 cm) silica gel column, eluting successively with 1000 mL portions of 0.1%, 0.2%, 1%, 2%, and 5% EtOAc in hexane. The product-containing fractions were evaporated under vacuum to afford 2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=[O:5].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C)C=O.[Cl-].[Na+].C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:9][C:8](=[O:10])[CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(CC(=O)O)CC(=O)O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)CC(C)(C)CC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 3,3-dimethylglutaric acid (6.4 g) in dry dimethylformamide (100 ml) was added in four portions sodium hydride (50%) (1.92 g) at 30° to 40° C. under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes, and p-methoxybenzyl chloride (6.28 g) in dry dimethylformamide (20 ml) was added to the mixture. The reaction mixture was stirred at 60° to 70° l C. for 10 hours, diluted with saturated aqueous sodium chloride and ethyl acetate. The ethyl acetate layer was extracted with aqueous potassium carbonate. The aqueous layer was acidified on ice-bath with concentrated hydrochloric acid and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 3,3-dimethylglutaric acid mono-p-methoxybenzyl ester.