Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.CCCCCC>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[OH:14][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]#[N:6]
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: N#CC(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a stirred solution of compound (II) (0.0897 g, 16.5 mol %) and molecular sieve 4 Å (powder, 65 mg, dehydrated under the condition of 0.3 mmHg/300° C. for 24 h before use) in dichloromethane (2.5 ml) was added titanium tetraisopropoxide (0.045 ml, 15 mol %) under argon at room temperature. Stir for 1 hour. Trimethylsilyl cyanide (0.15 ml, 1.1 mmol) was added to the reaction mixture and stirred for additional 0.5 h. Then, the reaction mixture was cooled to −78° C. and benzaldehyde (0.1 ml, 1 mmol) was added to the reaction mixture. The resultant reaction mixture was stirred for 48 h. The disappearance of the aldehyde was monitored by thin layer chromatography (ethyl acetate/hexane=1/5). The reaction mixture was quenched with 1 N HCl (10 ml) and stirred vigorously at room temperature for 6 h. After filtering, the mixture was extracted with dichloromethane (2×10 ml). The combined organic extracts were washed with brine (2×10 ml) and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was distilled under reduced pressure to afford 2-hydroxyl-2-phenylacetonitrile (87%, 93.2% e.e. (enantiomeric excess)). The result is listed in table 1.
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]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=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]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@@H:10]([O:14][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@H]1CN(Cc2ccccc2)C[C@@H]1OCCCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound VI-10 (966 mg, 54.1%) was obtained in the same manner as that in Reference Example 1, by using (3S,4S)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 500 mg, 2.59 mmol) and (9Z,12Z)-octadec-9,12-dienyl methanesulfonate (Nu-Chek Prep, Inc; 2.23 g, 6.47 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Cl:1])[NH:8][C:7](=[O:11])[CH2:6]2)=[O:15]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=C(Cl)CCl
Product: O=C1Cc2cc(C(=O)CCl)c(Cl)cc2N1

Procedure:
Step a) involves acylation of a composition comprising 6-chloro-1,3-dihydro-2H-indol-2-one of Formula III with chloroacetyl chloride by Friedel-Crafts acylation to obtain 5-(2-chloroacetyl)-6-chloro-2-oxindole of Formula IV.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C1CCN2C(=NCCC2)CC1.[N+:34]([C:37]1[CH:38]=[C:39](/[CH:43]=[CH:44]\[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]>C(#N)C>[N+:34]([C:37]1[CH:38]=[C:39]([CH:43]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:44][C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C\c1cccc([N+](=O)[O-])c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cccc([N+](=O)[O-])c4)c3)ncnc21
Temperature: 67 °C

Procedure:
To 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL, 0.0016 mol) followed by addition of (2Z)-3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction mixture was heated at 67° C. for 18 hours. This was cooled to room temperature, and the mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 6:4, to give 3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+1)+: 490
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:7])[NH2:6])CC.C(CC(O)=O)#[N:9].C(O[C:18](=[O:20])[CH3:19])(=O)C>>[NH2:9][C:1]1[NH:4][C:5](=[O:7])[NH:6][C:18](=[O:20])[CH:19]=1
Reactant: CCCNC(N)=O
Reactant: N#CCC(=O)O
Reactant: CC(=O)OC(C)=O
Product: Nc1cc(=O)[nH]c(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
N-cyclopropyl, N′-propylurea (1) (14.2 g, 0.1 mole), cyanoacetic acid (9.35 g, 0.11 mole) and acetic anhydride (35 ml) were mixture together and heated at 80° C. for 2 h. The solvent was then removed under reduced pressure. The residue was dissolved in MeOH (30 ml) and 20% NaOH (10 ml) was added at 4° C. The mixture was stirred at 4° C. for 1 h and then at room temperature for another 20 min. The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography as well as C-18 column chromatography to give pure 1-propyl, 3-cyclopropyl, 6-aminouracil (2) (5.23 g, 25%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>O1CCCC1>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:10]([O-:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH:17]([NH3+:20])([CH3:19])[CH3:18]
Reactant: CC(C)N
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Solvent: C1CCOC1
Product: CC(C)[NH3+]
Product: O=C([O-])c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 300 mg of 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, 80 mg of isopropylamine and 10 ml of tetrahydrofuran was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 372 mg of isopropylammonium 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter referred to as “the present compound 7”).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1>CCO>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:34][CH2:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH:3]=1)=[O:15]
Reactant: NCc1ccncc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NCc3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 90 °C
Yield: 36.5 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (60 mg, 0.16 mmol) and (4-pyridinylmethyl)amine (0.065 ml, 0.64 mmol) in EtOH (2 mL). The vessel was sealed and the reaction mixture was heated at 90° C. overnight. An additional 1 mL of (4-pyridinylmethyl) amine was added and the mixture was heated in a microwave at 160° C. for 90 min. The EtOH solvent was removed under reduced pressure, 2 mL of NMP was added, and the mixture was then irradiated (microwave) at 180° C. for 90 min. The mixture was evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water. The crude residue was extracted with EtOAc, DCM and DCM/isopropanol (70:30). The combined organics were washed with water (2×) and brine, dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated yellow oil was treated with EtOAc and sonicated. The filtered solid was washed with hexanes and dried to afford the title compound (26 mg, 36%) as a white solid. LCMS E-S (M+H)=446.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H) 8.50 (t, J=5.18 Hz, 1H) 8.43-8.48 (m, 2H) 7.89 (t, J=5.94 Hz, 1H) 7.84 (s, 1H) 7.34 (d, J=6.06 Hz, 2H) 6.73 (s, 1H) 5.89 (s, 1H) 4.83 (quin, J=6.69 Hz, 1H) 4.58 (d, J=5.81 Hz, 2H) 4.32 (d, J=5.05 Hz, 2H) 2.21 (s, 3H) 2.13 (s, 3H) 1.32 (d, J=6.82 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][S:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N)(=O)C1C=CC=CC=1>CS(C)=O.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][S:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CSCCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CN1CCCNCC1
Agent: NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CSCCOc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 100 °C
Yield: 117.4 %

Procedure:
In a 4 mL screw-cap vial were dissolved 5-fluoro-2-[4-fluoro-2-(2-methylthioethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (131 mg, 274 μmol) and 1-methylhexahydro-1,4-diazepine (157 mg, 1.37 mmol, 5 eq) in 250 μL DMSO to give a light yellow solution. The solution was heated to 100° C. for 36 hours in a heatblock, then allowed to cool to room temperature. The resulting brown solution was diluted with 1 mL dichloromethane, washed four times with water, once with brine, then dried over sodium sulfate and concentrated. The residue was combined with that from a separate, smaller scale run (100 μmol of starting benzamide) and purified via radial chromatography with 95:5, then 9:1 dichloromethane:methanol to produce 184 mg (86%) of the title compound as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[NH:19][C:20]([NH2:22])=[NH:21])C1C=CC=CC=1.Cl.CO>CCO.[Pd]>[NH3:13].[OH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[NH:19][C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)Nc1nccc2c(OCc3ccccc3)cccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: N
Product: N=C(N)Nc1nccc2c(O)cccc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
A solution of (5-benzyloxyisoquinolin-1-yl)guanidine (290 mg, 1.0 mmol) in EtOH (10 mL) containing 10% Pd-C (60 mg) and dilute HCl (1.5 mL, 2 M, 3.0 mmol) was stirred under an atmosphere of H2 (4 atmospheres) at 60° C. for 3 d. An additional portion of catalyst (30 mg) and HCl (0.5 mL) were added and hydrogenation continued for a further 3 d. The mixture was filtered through Arbocel with EtOH rinsing, the filtrate was evaporated in vacuo and the residue purified by column chromatography upon silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1 to 84:14:2) as eluant to give (5-hydroxyisoquinolin-1-yl)guanidine (66 mg, 0.33 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[N:3]=1.[C:24]([Si:28]([CH3:34])([CH3:33])[O:29][CH2:30][C:31]#[CH:32])([CH3:27])([CH3:26])[CH3:25].C1COCC1>[Cu]I.C(N(CC)CC)C>[Si:28]([O:29][CH2:30][C:31]#[C:32][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:33])[CH3:34]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2nc(Br)c3cc([N+](=O)[O-])cnc32)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 17.1 %

Procedure:
Triethylamine (4 mL) was added to a solution of 3-bromo-5-nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridine (0.825 g, 3.40 mmol), tert-butyldimethyl(prop-2-ynyloxy)silane (0.89 g, 5.09 mmol) in THF (20 mL) PdCl2(PPh3)2 (0.119 g, 0.170 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 minutes before CuI (0.065 g, 0.34 mmol) was added. The reaction mixture was heated to reflux under argon for 40 hours. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1) to give 3-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.193 g, 17%) as a solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:15]=[C:14]([I:16])[C:13]([CH3:17])=[CH:12][C:10]=1[NH2:11].C([O-])(=O)C.[K+].C(O[N:29]=O)CC(C)C>C1C=CC=CC=1>[C:5]([N:11]1[C:10]2[C:9](=[CH:15][C:14]([I:16])=[C:13]([CH3:17])[CH:12]=2)[CH:8]=[N:29]1)(=[O:7])[CH3:6]
Reactant: Cc1cc(I)c(C)cc1N
Reactant: CC(C)CCON=O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CC(=O)n1ncc2cc(I)c(C)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
Acetic acid anhydride (6.9 mL, 72 mmol) was added to a slurry of 2,5-dimethyl-4-iodoaniline (6.0 g, 24 mmol) and potassium acetate (2.4 g, 24 mmol) in benzene (50 mL). The mixture was heated to 80° C. and isopentylnitrit (4.8 mL, 36 mmol) was added during 20 min. The mixture was stirred at 80° C. overnight, then cooled and filtered. The filtrate was evaporated and purified by column chromatography (SiO2, dichloromethane). Product containing fractions were pooled and concentrated. The subtitle compound (1.5 g, 21%) was obtained as crystals from ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Li+].CC([N-]C(C)C)C.CN([CH:34]=[O:35])C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH:34]=[O:35])[N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[Si](C)(C)CCOCn1cc(-c2ccc([N+](=O)[O-])cc2)nc1C=O
Yield: 29.9 %

Procedure:
Reaction of 4-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (170 mg, 0.53 mmol), 0.53 M LDA (1 mL, 0.53 mmol), and DMF (232 uL, 1.60 mmol) for 4 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (55 mg, 30%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.95 (t, 2H, J=9.0 Hz), 3.63 (t, 2H, J=9.0 Hz), 5.82 (s, 2H), 7.79 (s, 1H), 7.98 (d, 2H, J=9.0 Hz), 8.27 (d, 2H, J=9 Hz), 9.89 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH:27]([CH3:29])[CH3:28]>>[CH3:26][CH:27]([CH3:29])[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Reactant: CC(C)CBr
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(OCC(C)C)cc3)cc2o1
Yield: 27 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (32.3 mg, 0.100 mmol) obtained in Example 165 and 1-bromo-2-methylpropane (0.0225 mL, 0.200 mmol) and in the same manner as in Example 158, the title compound was obtained (10.3 mg, yield 27%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:10]=2)[C:4]=1[OH:20].[N:21]([O-])=O.[Na+].[CH3:25][C:26]1[CH2:27][C:28](=[O:41])[N:29]([C:31]2[CH:40]=[CH:39][C:38]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=3[CH:32]=2)[N:30]=1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[OH:20][C:4]1[C:3]([NH:2][N:21]=[C:27]2[C:26]([CH3:25])=[N:30][N:29]([C:31]3[CH:40]=[CH:39][C:38]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=4[CH:32]=3)[C:28]2=[O:41])=[CH:8][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:10]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Reactant: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1=NNc1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Yield: 34.9 %

Procedure:
3-Amino-3′-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (340 mg, 1.34 mmol) was dissolved in 3 mL of 1 N hydrochloric acid followed by dropwise addition of 3 mL of aqueous sodium nitrite (98 mg, 1.41 mmol) upon cooling by an ice-water bath. After the mixture was reacted for 10 minutes, 5-methyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-2,4-dihydro-pyrazol-3-one 3i (276 mg, 1.21 mmol), sodium bicarbonate (1.69 g, 20 mmol) and 3 mL of ethanol were added successively. The reaction mixture was reacted at room temperature for 18 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with 20 mL of water and then dissolved in 20 mL of water. Upon cooling by an ice-water bath, the mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid. Then the mixture was filtered and dried to obtain the title compound 4-{[2-hydroxy-3′-(1H-tetrazol-5-yl)-biphenyl-3-yl]-hydrazono}-5-methyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-2,4-dihydro-pyrazol-3-one 10 (208 mg, 31.6%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[Cl:22][C:23]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:53]C([N-]C(C)C)C>>[Cl:22][C:23]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:24]=1/[CH:25]=[CH:9]/[C:10]1[NH:11][C:12]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH3:53])=[CH:14][CH:13]=2
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3ccc([N+](=O)[O-])cc3Cl)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2-chloro-4-nitrobenzyl)(triphenyl)phosphonium bromide (559) prepared as described in example 148 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0° C., the ratio of LDA:aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (560) as a dark red-brown solid (the pure E isomer) (46%), mp 239–241° C. 1H NMR [(CD3)2SO] δ11.57 (br s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.18 (dd, J=8.8, 2.1 Hz, 1H), 8.15 (d, J=8.9 Hz, 1H), 7.59 (d, J=16.3 Hz, 1H), 7.47 (d, J=16.3 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.82 (dd, J=8.7, 2.5 Hz, 1H), 6.70 (s, 1H), 3.76 (s, 3H). Found: C, 62.14; H, 3.91; N, 8.52. C17H13ClN2O3 requires C, 62.11; H, 3.99; N, 8.52.
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[C:6](=[O:22])[N:7]([CH2:19][C:20]#[CH:21])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]=1[CH2:11][CH3:12])=O.N1C=CC=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1.CCOCC>[CH2:11]([C:10]1([CH2:24][CH3:25])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]([CH2:19][C:20]#[CH:21])[C:6](=[O:22])[CH:5]1[CH2:4][C:2]#[N:1])[CH3:12]
Reactant: c1ccncc1
Reactant: C#CCn1c(-c2ccccc2)nc(CC)c(CC(N)=O)c1=O
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: C#CCN1C(=O)C(CC#N)C(CC)(CC)N=C1c1ccccc1
Temperature: 0 °C
Yield: 49.8 %

Procedure:
A stirred suspension of 0.25 g (0.85 mmol) of 5-aminocarbonylmethyl-6-ethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 275) in 12 mL of THF was cooled in an icebath and 0.15 mL (1.9 mmol) of pyridine was added followed by 0.13 mL (0.92 mmol) of trifluoroacetic anhydride. The mixture was stirred in the ice bath for 4 h, diluted with 80 mL of ether, washed with 20 mL of saturated aqueous NaHCO3 and dried over MgSO4. Removal of the solvent left 0.24 g of crude product as a yellow solid. Flash chromatography on 30 g of silica gel, eluting sequentially with 50, 75 and 100% ether in hexanes afforded 0.13 g of 6-ethyl-5-cyanomethyl-6-ethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 277) as a white solid, m.p. 178°-180° C. 1 H-NMR (CDCl3) 1.3(3H,t), 2.4(1H,t), 2.75(2H,q), 3.75(2H,s), 4.6(2H,d), 7.55(3H,m), 7.7(2H,m).
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH:23][C@@H:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[CH:14]=[N:13]2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:36].C(OC(C)C)(C)C>C(Cl)Cl.C(O)(C)C>[ClH:36].[ClH:36].[N:1]1[C:2]([CH2:10][CH2:11][N:12]2[N:13]=[CH:14][C:15]3[C:20](=[C:19]([NH:23][C@@H:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cccc3cnn(CCc4cn5ccccc5n4)c(=O)c23)C1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: O=c1c2c(N[C@@H]3CCNC3)cccc2cnn1CCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (R)-tert-butyl 3-(3-(2-(imidazo[1,2-a]pyridin-2-yl)ethyl)-4-oxo-3,4-dihydrophthalazin-5-ylamino)pyrrolidine-1-carboxylate from Example 218 (52 mg, 0.110 mmol) in 20 mL of DCM was mixed with 1 mL of HCl containing isopropanol and the reaction mixture was stirred under nitrogen for 12 h at room temperature. The reaction mixture was mixed with diisopropyl ether and the supernatant was discharged. Then, the residue was dissolved in isopropanol and diisopropyl ether was added. The supernatant was discharged. The precipitate was dried to give 24 mg of a yellow salt as solid foam. LC-MS: m/e=357.2 (M+H)+
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32]([OH:49])[CH:33](O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].O>C1(C)C=CC=CC=1>[CH2:32]1[O:49][C:11]2([CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[O:13][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCC(O)CO
Reactant: O=C1CC(c2ccccc2)NC(c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC1COC2(CC(c3ccccc3)NC(c3ccccc3)C2)O1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of 14.6 g (58.0 mmol) of 2,6-diphenyl-4-piperidone and 12.2 g (64 mmol) of p-toluenesulfonic acid monohydrate in 500 mL of toluene is refluxed and the azeotroping water is collected in a Dean Stark trap. When 1 mL of water is collected, 15.0 g (58.0 mmol) of 1,2-hexadecanediol (Aldrich) is added and the reaction is refluxed until another 1 mL of water is collected. The reaction mixture is cooled to room temperature and made basic with 50% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous phase is extracted with toluene (2×100 mL). The combined organic phases are dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. 11.0 g (38% yield) of the title compound is isolated after purification by liquid chromatography (LC) (silica gel, ethyl acetate/hexane) followed by recrystallization from ethanol: mp 63°-70° C.