Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:10]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]/[CH:27]=[CH:26]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCCC/C=C\CCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCC/C=C\CCCCCC

Procedure:
Compound VI-6 (231 mg, 48.0%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 146 mg, 0.753 mmol) and (Z)-hexadec-9-enyl methanesulfonate (Nu-Chek Prep, Inc; 600 mg, 1.88 mmol).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=O.[CH2:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:11]([NH:14][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:12][CH3:13]
Reactant: CCCN
Reactant: O=C(O)CCC(=O)C(=O)O
Product: CCCNC(=O)C(=O)CCC(=O)O

Procedure:
Using 1.46 g of 2-oxoglutaric acid and 0.828 ml of n-propylamine, there was obtained 496 mg of the subject Compound (85), by conducting a reaction and treatment analogous to Example 83, as pale yellow crystals, m.p. 79°-81° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:28]([F:37])[C:29]([F:36])=[C:30]([C:32](=[O:35])[CH2:33]Cl)[CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:46]1[CH:50]=[N:49][CH:48]=[N:47]1>C(#N)C>[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:28]([F:37])[C:29]([F:36])=[C:30]([C:32](=[O:35])[CH2:33][N:46]2[CH:50]=[N:49][CH:48]=[N:47]2)[CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)CCl)c(F)c2F)C[C@H](C)O1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)Cn3cncn3)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (1208 mg, 8.74 mmol) was added to a mixture of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-chloroethanone (Intermediate 127, 500 mg, 0.87 mmol) and 1H-1,2,4-triazole (66.4 mg, 0.96 mmol) dissolved in 15 ml of Acetonitrile. The mixture was stirred at room temperature for 3 hours. Potassium carbonate was filtered from the mixture, and the filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The organic phases were combined, dried (Na2SO4), and concentrated. The crude residue (482 mg, 91%) contained mainly desired title compound and was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][Cl:23])[P:5]([N:14]([CH2:18][CH2:19][Cl:20])[CH2:15][CH2:16][Cl:17])(=[O:13])[O:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].[Cl:24][CH2:25][CH2:26][N:27]([CH2:38][CH2:39][Cl:40])[P:28](Cl)([N:30]([CH2:34][CH2:35][Cl:36])[CH2:31][CH2:32][Cl:33])=[O:29].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([P:5]([N:14]([CH2:15][CH2:16][Cl:17])[CH2:18][CH2:19][Cl:20])([O:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][O:12][P:28]([N:27]([CH2:26][CH2:25][Cl:24])[CH2:38][CH2:39][Cl:40])([N:30]([CH2:31][CH2:32][Cl:33])[CH2:34][CH2:35][Cl:36])=[O:29])=[O:13])[CH2:21][CH2:22][Cl:23]
Reactant: O=P(OCCSCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: O=P(Cl)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=P(OCCSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
5-Hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate, 174 mg (0.387 mmol), and N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidoyl chloride, 363 mg (0.996 mmol), were dissolved in 15 mL anhydrous tetrahydrofuran and cooled to 0-5° C. in an ice-water bath. Potassium tert-butoxide, 0.4 mL of 1 M solution in tetrahydrofuran (0.4 mmol), was added over a 10-15 minute period, and the reaction mixture kept at 0-5° C. for another 30 minutes under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 43 hours. Additional potassium tert-butoxide and N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidoyl chloride were added over the next 4 days to drive the reaction to completion. After 4.5 days, the reaction mixture was diluted with ethyl acetate; and the ethyl acetate layer separated, washed with water and brine, then dried over anhydrous magnesium sulfate, and the ethyl acetate removed under vacuum. The crude di[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfide, 630 mg, was twice purified by preparative HPLC, and the product fractions combined and lyophilized, giving di[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfide, compound 1CC, as a colorless oil, compound 1CC, 56 mg (18% yield), identified by HPLC and 1H and 31P NMR. Mass spectrum: 779 (C20H40Cl8N4O4P2S+4+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=3[F:19])[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:24][B:23](B2OC(C)(C)C(C)(C)O2)[O:22]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:19][C:12]1[C:13]([F:18])=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[C:3]2[CH:10]=[N:9]1
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)c(F)c1F
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle under N2 was added Intermediate 70A (169.2 mg, 0.451 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (217 mg, 0.855 mmol), potassium acetate (206 mg, 2.099 mmol) and anhydrous DMSO (4.5 mL). The reaction mixture was flushed with argon, then treated with PdCl2(dppf).CH2Cl2 (28.3 mg, 0.039 mmol). The reaction mixture was again flushed with argon, securely capped and heated at 85° C. for 1 h to give complete conversion to the desired product. LC/MS (Condition B): ret. T=3.3 min, (M+H)+ 294.03.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH2:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)=[CH2:11]>C1C=CC=CC=1>[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([N:26]=[CH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)=[CH2:11]
Reactant: C=Cc1ccc([C@@H](N)Cc2ccccc2)cc1
Reactant: Cc1cccc(C=O)n1
Solvent: c1ccccc1
Product: C=Cc1ccc([C@H](Cc2ccccc2)N=Cc2cccc(C)n2)cc1

Procedure:
A solution of 0.54 g (4.5 mmol) of 6-methyl-pyridine-2-carbaldehyde, 1.0 g (4.5 mmol) of (S)-1-(4-vinylphenyl)-2-phenyl-ethylamine and 10 ml of benzene is evaporated down at room temperature and under about 3 kPa. A further 10 ml of benzene are added in order to distill off residual water of reaction together with benzene under about 3 kPa. The process is repeated twice more.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[C:46]([O:50][C:51](=[O:54])[CH2:52][NH2:53])([CH3:49])([CH3:48])[CH3:47]>C(N(CC)CC)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:24][CH:23]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:53][CH2:52][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:54])[CH2:19][CH2:20]3)[N:14]=1)[CH2:4]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (60 mg) and glycine tert-butyl ester hydrochloride (33 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 616.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][N:16]1C(=O)C2=CC=CC=C2C1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CN>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CN
Solvent: C1CCOC1
Solvent: CCO
Product: NOCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of N-[3-(benzyloxycarbonylamino)-1-propoxy]phthalimide (1.42 g, 4.0 mmol), as prepared in the preceding step, in ethanol (20 mL) and tetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25 mmol). The solution was stirred at room temperature for 1 h. The solvent was evaporated and the residue passed through silica gel (3:1 ethyl acetate:hexane to ethyl acetate) to give the title compound as a white solid (870 mg, 97%). 1H-NMR (300 MHz, CDCl3) δ7.36 (m, 5H), 5.38 (br s, 2H), 5.09 (s, 2H), 5.08 (br s, 1H), 3.73 (t, J=5.9 Hz, 2H), 3.29 (q, J=6.2 Hz, 2H), 1.79 (pentet, J=6.2 Hz, 2H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=4[F:27])=[C:11]3[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[CH:10][C:11]=12
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ncc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
A stirred mixture of 1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (27.6 g, 70.0 mmol; obtained from Example 1, Step C) and TFA (53.9 mL, 700 mmol) was heated to reflux for 18 hours under N2. The reaction was allowed to cool to room temperature, and then concentrated in vacuo using toluene (4×100 mL) to azeotrope residual TFA. The residue was diluted with EtOAc (200 mL) and carefully neutralized (pH=8-9) with saturated aqueous NaHCO3 (100 mL). The biphasic suspension was stirred at room temperature for 30 minutes. The suspension was filtered. The resulting solid was dried by toluene azeotrope (2×200 mL) to obtain the product (18.7 g, 97%). 1H NMR (DMSO-d6, 400 MHz) δ 13.85 (br s, 1H), 8.40 (m, 2H), 8.15 (m, 1H), 7.91 (s, 1H), 7.66 (m, 1H), 6.65 (m, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccc2ccccc2n1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: c1cc(CN2CCCCC2)cc(OCCCNc2ccc3ccccc3n2)c1
Yield: 25.6 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.0 g) and 2-chloroquinoline (1.31 g) were fused at 140° C. for two hours. The oily residue was taken up in methanol/water (5:50), neutralised with solid potassium carbonate and extracted into chloroform. The chloroform extract was dried, evaporated under reduced pressure and subjected to medium pressure liquid chromatography (chloroform) to afford the title product as an oil (0.77 g). This was treated with maleic acid to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]quinoline dimaleate (0.4 g), m.p. 148°-150° C. (recrystallised from ethanol).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.[CH3:21][N:22]([CH2:24][CH2:25]O)[CH3:23].CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:21][N:22]([CH3:23])[CH2:24][CH2:25][O:17][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[CH:20][CH:19]=1
Reactant: CN(C)CCO
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a clear solution of 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid ((C38), 0.5 g, 1.75 mmol) in DMF (20 mL)were added N,N-dimethylamino ethanol (0.37 mL, 3.7 mmol) and EDCI (0.71 g, 3.7 mmol). The reaction was stirred at room temperature overnight. Then DMF was evaporated under vacuum. The residue was purified over silica gel, eluting with 5% MeOH/DCM, to afford the 0.35 g of the title compound in 56% yield. 1H NMR 400 MHz (DMSO-d6) δ: 7.97 (d, J=8.9 Hz, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.15-7.07 (m, 4H), 4.95 (s, 2H), 4.33 (t, J=5.5 Hz, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.20 (s, 6H); MS (ES) m/z: 342 (M+H)+; HPLC purity: 91.90% (220 nm), 94.99% (254 nm).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][OH:18])=[CH:21][CH:22]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(CO)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-(hydroxymethyl)-phenylboronic acid; method 1: HPLC/MS: 1.12 min, [M+H]=321;
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[F:12][C:13](I)([F:18])[C:14]([F:17])([F:16])[F:15]>CN(C)C=O.[Cu]>[F:12][C:13]([F:18])([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11])[C:14]([F:17])([F:16])[F:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1I
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Temperature: -60 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
A mixture of 2.36 g of 1-iodo-2-methyl-4-nitro-benzene and 2.2 g of powdered copper (Org. Synthesis Coll., Vol. II (1948), page 445 washed with water, acetone and dried under reduced pressure) in 10 ml of dimethylformamide under nitrogen in a sealed vessel was cooled to -60° C. and 11.5 g of pentafluoroethyl iodide were added. The mixture was stirred at 160° C. at a pressure of 3.5 bars for 16 hours and then cooled in ice and returned to room temperature. The mixture was poured into ice and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica (eluant--pentane containing 2 to 3% of dichloromethane) to obtain 1.5 g of 1-pentafluoroethyl-2-methyl-4-nitro-benzene which was hydrogenated in the presence of palladized active carbon to obtain the desired product.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](F)[CH:7]=[C:6]([F:11])[N:5]=1.[CH2:12]([OH:15])[CH:13]=[CH2:14]>>[CH2:12]([O:15][C:8]1[N:9]=[C:4]([NH2:3])[N:5]=[C:6]([F:11])[CH:7]=1)[CH:13]=[CH2:14]
Reactant: C=CCO
Reactant: Nc1nc(F)cc(F)n1
Agent: [H-]
Agent: [Na+]
Product: C=CCOc1cc(F)nc(N)n1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
1.14 g (0.0382 mol) of 80% sodium hydride (emulsion in linseed oil) were added at 25° C. under a nitrogen atmosphere to 70 ml of allyl alcohol. To the clear solution obtained after stirring at 40° C. for 20 minutes were added 5.0 g (0.0382 mol) of 2-amino-4,6-difluoropyrimidine, and the mixture was then stirred at 97° C. for 1.5 hours. To work up, the excess alcohol was removed by distillation under reduced pressure, the residue was taken up in methylene chloride, and the solution was washed with water, dried over magnesium sulfate and then freed of solvent. The viscous oil obtained in this way crystallized on trituration with n-pentane. 4.6 g (71.2% of theory) of the title compound of melting point 62°-66° C. were obtained after filtering off, washing with water and drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[CH2:27][C:28]#[N:29]>>[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[C:27](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[C:28]#[N:29]
Reactant: COc1ccc(CC#N)c(OC)c1OC
Reactant: COc1ccc(C=O)c(OC)c1OC
Product: COc1ccc(C=C(C#N)c2ccc(OC)c(OC)c2OC)c(OC)c1OC
Yield: 93.4 %

Procedure:
Following the Procedure A, the reaction was performed with 1.96 g of 2,3,4-trimethoxybenzaldehyde (10 mmol) and 2.07 g of 2,3,4-trimethoxyphenyl-acetonitrile (10 mmol), affording 2,3-bis-(2,3,4-trimethoxy-phenyl)-acrylonitrile as yellow powder (yield 3.6 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([C:17](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].Br[CH:31]1[CH2:35]C[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:33][CH2:32][CH2:31][CH2:35]3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: BrC1CCCC1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C3CCCC3)C1)O2
Temperature: 75 °C
Yield: 87.2 %

Procedure:
A mixture of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 2, 300 mg, 0.888 mmol), bromocyclopentane (397 mg, 2.66 mmol) and K2CO3 (491 mg, 3.55 mmol) in CH3CN (40 ml) was stirred at 75° C. Further bromocyclopentane (397 mg, 2.66 mmol) and catalytical amount of KI were added over three days. The solvent was removed and the residue was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (±)-(E)-3-[1′-cyclopentyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (286 mg).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[H-].[Na+].[Br:18][C:19]1[CH:20]=[CH:21][C:22](F)=[N:23][CH:24]=1.C(=O)=O.CC(C)=O>CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([O:15][CH2:14][C:2]2([CH3:1])[O:7][C:6]3=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]3[CH2:4][CH2:3]2)=[N:23][CH:24]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC1(CO)CCn2cc([N+](=O)[O-])nc2O1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC1(COc2ccc(Br)cn2)CCn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
A solution of alcohol 149 (200 mg, 0.938 mmol) in anhydrous DMF (4 mL) under N2 at 0° C. was treated with 60% NaH (53.8 mg, 1.35 mmol), then quickly degassed and resealed under N2. 5-Bromo-2-fluoropyridine (91) (0.245 mL, 2.38 mmol) was added and the mixture was stirred at room temperature for 2.5 h, and then cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (10 mL), added to brine (40 mL), and extracted with CH2Cl2 (10×50 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 1-3% EtOAc/CH2Cl2 gave 7-{[(5-bromo-2-pyridinyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (150) (269 mg, 78%) as a cream solid: mp (CH2Cl2/pentane) 172-174° C.; 1H NMR (CDCl3) δ 8.17 (br d, J=2.2 Hz, 1H), 7.67 (dd, J=8.8, 2.5 Hz, 1H), 6.64 (dd, J=8.7, 0.4 Hz, 1H), 4.49 (d, J=11.5 Hz, 1H), 4.42 (d, J=11.4 Hz, 1H), 4.17 (dt, J=12.7, 6.1 Hz, 1H), 4.09 (ddd, J=12.6, 7.7, 5.8 Hz, 1H), 2.45 (ddd, J=14.5, 7.6, 5.9 Hz, 1H), 2.18 (dt, J=14.6, 6.1 Hz, 1H), 1.57 (s, 3H). Anal. (C13H13BrN4O4) C, H, N.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: COc1ccc(-c2cc(C(Cl)CC(C)C)c(C)o2)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)nc3)c(C)o2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (0.9 g), methyl 5-aminopyridine-2-carboxylate (0.5 g), sodium carbonate (0.5 g) and sodium iodide (0.9 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (6 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid. To the obtained 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid (395 mg) were added ethyl β-alaninate hydrochloride (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg), triethylamine (168 μL) and N,N-dimethylformamide (10 mL) was added. The obtained mixture was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (171 mg, 35%) as an amorphous compound.