Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(OC)C=O.[F:8]/[C:9](=[C:13](/[CH3:19])\[CH:14]([O:17][CH3:18])[O:15][CH3:16])/[C:10]([O-])=[O:11].[H-].C([Al+]CC(C)C)C(C)C>>[F:8]/[C:9](=[C:13](/[CH3:19])\[CH:14]([O:15][CH3:16])[O:17][CH3:18])/[CH:10]=[O:11]
Reactant: COC(OC)/C(C)=C(\F)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: COC(C=O)OC
Agent: [H-]
Product: COC(OC)/C(C)=C(\F)C=O

Procedure:
The 6-fluoro octatrienoate is prepared by reacting triethyl phosphono fluoroacetate with glyoxal dimethyl acetal and the resulting reaction product, a mixture of ethyl E and Z-2-fluoro-4,4-dimethoxy-3-methyl-2-butenoate, is reduced with di-isobutyl aluminum hydride in the cold to form Z-2-fluoro-3-methyl-4,4-dimethoxy-2-buten-1-al. The latter compound is then reacted via a Horner reaction with a compound of the formula ##STR37## or via a Wittig reaction with ##STR38## wherein X is halogen to form a compound of the formula ##STR39## The latter compound is then treated with hydrochloric acid and diethyl ether to form the 6-fluoro octatrienoate depicted.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:20])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]2.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[C:25](O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]4)[N:20]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33]
Reactant: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Reactant: CCOc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OCC)c(Cl)c4)n3)ccc21
Yield: 20.6 %

Procedure:
Ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D52) (265 mg, 0.96 mmol) and 3-Chloro-4-(ethyloxy)benzoic acid (D7) (192 mg, 0.96 mmol) were stirred together in DMF (5 ml) at 80° C. and EDAC (203 mg) and HOBt (142 mg) were added. When the reaction was judged to be complete (analysis by LCMS) it was cooled and the reaction mixture was partitioned between EtOAc and aq. sodium bicarbonate solution. The organic layer was separated and washed with water, dried and evaporated and triturated with ethanol to give the crude product. Purification by flash chromatography (EtOAc/hexane 1:3 to 1:1) to afforded the title compound (87 mg) as a white solid. MS (ES): C22H2135ClN4O4 requires 440 found (MH+) 441.
Reaction SMILES: F[B-](F)(F)F.[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([N+]#N)=[C:9]([CH2:17][CH3:18])[CH:8]=1.[CH3:19][OH:20]>[Cl-].[Zn+2].[Cl-]>[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:20][CH3:19])=[C:9]([CH2:17][CH3:18])[CH:8]=1
Reactant: CO
Reactant: CCc1cc(Br)cc(CC)c1[N+]#N
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1cc(Br)cc(CC)c1OC
Temperature: 25 °C
Yield: 94 %

Procedure:
A stirred solution containing 4-bromo-2,6-diethylbenzenediazonium tetrafluoroborate (17.25 g, 52.77 mmol) and freshly ground anhydrous zinc chloride (7.2 g, 52.9 mmol) in methanol (1.06 L) was refluxed for 6 h. The reaction was cooled to ambient temperature, quenched with H2O (1.2 L), saturated with solid sodium chloride and extracted with hexane. The combined organic extracts were sequentially washed with sat. aq. NaHCO3 (1×100 mL), with H2O (1×100 mL), with brine (1×100 mL), dried (Na2SO4) and concentrated to give 12.0 g (94%) of title compound. 1H NMR: consistent. mass spectrum (EI), m/z 242 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]#[N:18])[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]#[N:18])[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: N#CCC1CCNCC1
Reactant: Clc1ccc(I)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: N#CCC1CCN(c2ccc(Cl)nc2)CC1
Temperature: 105 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
2-Chloro-5-iodopyridine (0.278 g, 1.16 mmol), 2-(piperidin-4-yl)acetonitrile hydrochloride (253) [Vidaluc, J.-L. et al., Novel J. Med. Chem. 1994, 37, (5), 689-695] (0.186 g, 1.16 mmol), Pd2(dba)3 (0.0531 g, 0.0580 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0671 g, 0.116 mmol) and cesium carbonate (0.945 g, 2.90 mmol) were combined in a screw cap vial and solvated under argon atmosphere with degassed dioxane (4.5 mL). The reaction was briefly sparged with argon, then sealed and stirred at 105° C. After 3 h, the reaction was poured into water (30 mL) and extracted with 10% methanol in CH2Cl2 (3×20 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (gradient elution 10 to 50% ethyl acetate in hexanes) afforded compound 254 (0.110 g, 40.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.23-1.44 (m, J=11.98, 11.98, 11.84, 3.72 Hz, 2 H) 1.68-1.90 (m, 3H) 2.54 (d, 2 H) 2.75 (td, J=12.42, 2.15 Hz, 2 H) 3.77 (d, J=12.52 Hz, 2 H) 7.26 (d, J=9.00 Hz, 1 H) 7.42 (dd, J=8.80, 3.33 Hz, 1 H) 8.06 (d, J=3.13 Hz, 1 H) ppm.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:7][NH:6][CH:5]=1.ON=CC1NC=C(C2C=CC=C(Cl)C=2Cl)C=1>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[C:4]([C:3]#[N:2])=[CH:5][NH:6][CH:7]=1
Reactant: ON=Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Agent: ON=Cc1cc(-c2cccc(Cl)c2Cl)c[nH]1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Reaction time: 5 h

Procedure:
3.2 g of the 3-hydroxyiminomethyl-4-(2,3-dichlorophenyl)pyrrole obtained in (b) are kept for 5 hours at c. 100° C. in 50 ml of acetic anhydride, then cooled to room temperature, poured into ice/NaOH, and the resultant mixture is stirred for 2 hours. The precipitate is dissolved in ethyl acetate, washed with water, the exter phase is dried over magnesium sulfate. The residue is purified by column chromatography (silica gel; elution with a 4:1 mixture of toluence/ethyl acetate). Melting point: 149°-151° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:37](=O)[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:32][CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH2:36]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Reaction time: 3.5 h
Yield: 10.5 %

Procedure:
A solution of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (100 mg, 0.19 mmol) and acetaldehyde (8.4 mg, 0.19 mmol) in DMF/THF (20%, 10 mL) was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added to the reaction mixture, stirred for 3.5 hours, and concentrated in vacuo. Purification by reverse phase preparative HPLC (HPLC method 2) provided the title compound as a white solid (11 mg, 10%). MS: 553.5 (MH+); HPLC Rf: 1.7 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:32])=[C:27](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].C1COCC1>O.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>[C:18]([O:17][C:15]([NH:14][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:24]=[C:23]([Cl:22])[CH:28]=[CH:27][C:26]=2[F:32])=[CH:3][CH:4]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of (R)-4-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)butanoic acid (HBC2251, 14 g, 39 mmol) and 5-chloro-2-fluorophenylboronic acid (8.5 g, 49 mmol) in 300 mL H2O was added Na2CO3 (12.5 g, 118 mmol). This solution was warmed to 40° C. and 9 mL of THF was added followed by Pd(PPh3)2Cl2 (0.6 g, 0.86 mmol). The reaction mixture was then stirred at 60° C. for approximately 1 day. The reaction mixture was cooled to 23° C., and the THF was removed in vacuo. The resulting aqueous suspension was filtered through celite and the solids washed with H2O. The combined filtrate and H2O wash was then extracted with approximately 3:1 isopropyl acetate/acetone (400 mL). After separation, the organic layer was discarded. TBME (300 mL) was added to the aqueous layer followed by slow addition of 6N HCl (32 mL). The organic layer was then separated and filtered through celite. The solids were washed with TBME. The combined filtrate and washes were concentrated to an off-white solid (14.96 g, 36.7 mmol, 94% yield, approx. 96% UV purity by LCMS). LCMS (ES) C21H23ClFNO4: Calc.: 407.1; Found: 406.4[M−H]+.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.CCN(CC)CC.[CH3:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[C:3]=1[CH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:33]([CH3:34])[CH:32]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(CC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), Et3N (0.12 mL, 0.85 mmol), 3-methylbenzoyl chloride (0.12 mL, 0.89 mmol), CH2Cl2 (3.0 mL), acetonitrile (5.0 mL), acetone cyanohydrin (0.037 mL, 0.40 mmol), Et3N (0.24 mL, 1.8 mmol), glacial acetic acid (5.0 mL), sodium cyanoborohydride (0.16 g, 2.6 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 2% MeOH in CH2Cl2) to provide a solid (0.250 g, m.p. 53°-55° C.). 1H NMR (400 MHz, DMSO-d6) δ10.884 (bs, 1H), 7.418-7.310 (m, 5H), 7.231 (t, 2H, J=7.5 Hz), 7.148-7.122 (m, 1H), 7.071 (d, 2H, J=7 Hz), 6.929 (t, 1H, J=7.5 Hz), 6.843 (d, 1H, J=7.5 Hz), 6.587 (d, 1H, J=7.5 Hz), 6.545 (s, 1H), 3.398 (AB, 2H, JAB=15.5 Hz), 3.248 (d, 1H, J=17 Hz), 3.125 (d, 1H, J=17 Hz), 2.607-2.511 (m, 1H), 2.338-2.159 (m, 3H), 2.094 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([O:20]CC)=[O:19])=[C:4]([Cl:23])[CH:3]=1.[OH-].[Na+].C(O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([OH:20])=[O:19])=[C:4]([Cl:23])[CH:3]=1
Reactant: CCOC(=O)c1cnn(C2CCOC2)c1-c1ccc(Br)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(C2CCOC2)c1-c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 102.4 %

Procedure:
A mixture of (±)-ethyl 5-(4-bromo-2-chlorophenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (1.05 g) and a 5 M aqueous sodium hydroxide solution (1.58 mL) was stirred in a mixed solvent of ethanol (20 mL) and water (5 mL) at 60° C. for three hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. 5 M hydrochloric acid was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (1 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]([NH2:17])[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([CH2:7][CH:6]2[NH:17][C:3](=[O:2])[CH2:4][CH2:5]2)=[CH:9]1
Reactant: COC(=O)CCC(N)Cc1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCC(Cc2c[nH]c3ncccc23)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A solution of 2.5 g (0.10.1 mM) of 4-Amino-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pentanoic acid methyl ester was dissolved in 20 mL of ethyl acetate. To this solution was added 20 mL of 1N sodium carbonate, and the mixture was stirred at room temperature for 6 hours. The ethyl acetate layer was dried and evaporated. The residue was chromatographed on silica using 95:5 CHCl3 :CH3OH to yield 1.48 g of product as a white crystalline solid. MP=160-162° C. NMR (CDCl3) δ11.4 (s, 1H), 8.05 (m, 1H), 7.85 (d, 1H), 7.45 (s, 1H), 7.18 (s, 1H), 6.95 (m, 1H), 4.0 (m, 1H), 2.8-3.0 (m, 2H), 2.2-2.4 (m, 3H), 1.85 (m, 1H). 13C NMR (CDCl3) 178.6,148.9, 142.4, 127.0, 123.6, 120.1, 115.3, 109.8, 55.2, 32.6, 30.3, 26.8. Mass Spectrum: m/e=216 (p+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[C:10]=1[N:9](CC1C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=1)[C:8]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N:7]2)[CH3:2].[CH2:54]([C:56]1[C:63]2[N:59]([N:60]=[C:61]([CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66])[N:62]=2)[N:58]([CH2:70][C:71]2[CH:76]=[CH:75][C:74]([C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=3[C:83]3[N:87]([C:88]([C:101]4[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=4)([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=4)[C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=4)[N:86]=[N:85][N:84]=3)=[CH:73][CH:72]=2)[CH:57]=1)[CH3:55]>>[CH2:54]([C:56]1[C:63]2[N:59]([N:60]=[C:61]([CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66])[N:62]=2)[N:58]([CH2:70][C:71]2[CH:72]=[CH:73][C:74]([C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=3[C:83]3[N:87]([C:88]([C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=4)([C:101]4[CH:102]=[CH:103][CH:104]=[CH:105][CH:106]=4)[C:95]4[CH:96]=[CH:97][CH:98]=[CH:99][CH:100]=4)[N:86]=[N:85][N:84]=3)=[CH:75][CH:76]=2)[CH:57]=1)[CH3:55].[CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[C:10]=1[NH:9][C:8]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N:7]2)[CH3:2]
Reactant: CCOC(=O)Cc1nn2ncc(CC)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)Cc1nc2c(CC)cn(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Product: CCOC(=O)Cc1nn2ncc(CC)c2[nH]1

Procedure:
In the same manner as described in Example 66, 0.12 g of ethyl [7-ethyl-1-[[2'-(N-triphenylmethyl-tetrazol- 5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazol-2-yl]acetate (compound 76a) and 1.11 g of ethyl [7-ethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazol-2-yl]acetate (compound 76b) were obtained from 0.53 g of ethyl [7-ethyl-1H-pyrazolo[1,5-b][1,2,4]triazol-2-yl]acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[NH4+:15].[OH-]>CC#N.O>[NH2:15]/[C:4](/[O:3][CH2:1][CH3:2])=[CH:5]\[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: [NH4+]
Reactant: CCOC(=CC(=O)C(F)(F)F)OCC
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCO/C(N)=C/C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one (7.94 g, 37.4 mmol) in MeCN (30 mL) at room temperature was dropped 28% solution of NH4OH in water (7 mL). It was stirred at room temperature overnight. After solvent was removed under reduced pressure, to it was added CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one as solid (6.371 g, 93%). 1H NMR (300 MHz, CDCl3) δ 9.79 (br, 1H), 5.66 br, 1H), 5.13 (s, 1H), 4.15 (q, 2H), 1.38 (t, 3H); LC-MS (ESI) m/z 184 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([NH:4][CH2:5][C:6]1([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CC(=O)NCC1(N2CCCCC2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCNCC1(N2CCCCC2)CCCCC1
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
A solution of 1-[1-(acetamidomethyl)cyclohexyl] piperidine (5.5 g.) in dry tetrahydrofuran (50 ml) was added dropwise with stirring during 10 mins. to a suspension of lithium aluminium hydride (3.8 g.) in dry tetrahydrofuran (100 ml). The mixture was heated under reflux for 51/2 hrs. and stirred at room temperature for 16 hrs. Water (10 ml) was added dropwise to decompose excess lithium aluminium hydride (grey suspension had turned white). The suspension was filtered through hyflo, washed with ether and the combined filtrates dried (anhyd. Na2SO4). The dried filtrate was evaporated to dryness under reduced pressure and the residual oil (5 g.) was distilled under high vacuum to give 1-[1-(Ethylaminomethyl)cyclohexyl]piperidine (3.5 g.). b.p. C 138°-144° at 5.5 mm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[CH:22]=[CH2:23].CCN(CC)CC.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].O.CCOC(C)=O.CC#N>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:23]=[CH:22]/[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:3][CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2CCCC2)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCC2)c2ccc(O)cc2)cc1
Temperature: 85 °C
Yield: 74.5 %

Procedure:
4-[(4-Bromophenyl)(cyclopentylidene)methyl]phenol (3) (0.351 g, 1.07 mmol), tert-butyl acrylate (0.94 mL, 0.82 g, 6.4 mmol, 6 eq), Pd(OAc)2 (0.051 g, 0.23 mmol, 0.21 eq), Et3N (0.89 mL, 0.65 g, 6.4 mmol, 6 eq), P(o-tolyl)3 (0.139 g, 0.46 mmol, 0.43 eq), and anhydrous CH3CN (16 mL) were combined in a round-bottomed flask and the reaction mixture was heated overnight at 85° C., with stirring, under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel with the aid of EtOAc and water. The layers were separated and the organic phase washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 50:50) to give 0.30 g (74%) of compound 4 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.45 (s, 9 H), 1.60 (m, 4 H), 2.30 (m, 4 H), 6.43 (d, J=15.9 Hz, 1 H), 6.67 (d, J=8.6 Hz, 2 H), 6.90 (d, J=8.4 Hz, 2 H), 7.12 (d, J=8.2 Hz, 2 H), 7.49 (d, J=15.9 Hz, 1 H), 7.58 (d, J=8.3 Hz, 2 H), 9.32 (s, 1 H). HRMS (EI) Calcd for C25H28O3: 376.2038 (M+). Found: 376.2046.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[C:14]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])(=[O:16])[CH3:15].N1C=CC=CC=1>O>[CH3:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][C:14](=[O:16])[CH3:15])[CH:19]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2ccc(NC(=O)c3cccc(OC(C)=O)c3)nc2n1
Yield: 78.6 %

Procedure:
The procedure is similar to that described in Example 3, but starting with 2-amino-7-methoxynaphthyridine (3.5 g), 3-acetoxybenzoyl chloride (4.4 g) and anhydrous pyridine (40 cc). The reaction mixture is poured into water (400 cc) and the precipitate obtained is separated by filtration and then washed with water (6×100 cc) and dried in the air. On recrystallization from ethanol (140 cc) of the product thereby obtained, N-(7-methoxy-1,8-naphthyridin2-yl)-3-acetoxybenzamide (5.3 g), m.p. 172° C., is obtained.
Reaction SMILES: Cl.[F:2][C:3]1([F:28])[CH2:5][CH:4]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1)[CH2:12][CH2:11]2.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>C1COCC1>[F:28][C:3]1([F:2])[CH2:5][CH:4]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:27][C:32]([NH:31][CH2:29][CH3:30])=[O:33])[CH3:26])=[CH:23][CH:24]=1)[CH2:12][CH2:11]2
Reactant: CCN=C=O
Reactant: C[C@H](N)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(=O)N[C@@H](C)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Temperature: 25 °C

Procedure:
4.09 mg (10.0 μmol) (S)-1-{4-[6-(2,2-Difluoro-cyclopropylmethoxy)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-phenyl}-ethylamine hydrochloride (example XXXIII.1) and 5.62 μL (40.0 μmol) TEA in 250 μL THF are stirred at r.t. Then 3.91 μL (50.0 μmol) ethyl isocyanate are added and the resulting mixture is stirred at r.t. over night. The reaction is quenched by the addition of 25 μL aq. K2CO3 solution (c=3 mol/L), filtered over basic aluminum oxide and concentrated by evaporation.
Reaction SMILES: N[C@H](C(O)=O)C[S:4]([CH2:6][CH:7]=[CH2:8])=[O:5]>O>[CH2:8]=[CH:7][CH2:6][S:4](=[O:5])[S:4][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCS(=O)C[C@H](N)C(=O)O
Solvent: O
Product: C=CCSS(=O)CC=C
Reaction time: 3 h
Yield: 21.8 %

Procedure:
10 grams of L-Alliin was added to 200 ml of distilled water and 12 grams of fresh garlic cloves were added as described above in (Example 3). When the reaction was complete, after approximately 3 hrs., the reaction mixture was extracted with a suitable solvent such as 50 ml of diethyl ether. The ether layer was separated, dried over Magnesium Sulphate, filtered and evaporated to a straw coloured liquid yielding 1 gram of allicin. This was dissolved in distilled water (100 ml) and the 1% Allicin solution was stored at −20 C.