Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH:15]([C:21]2[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=[CH:23][CH:22]=2)[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].I[CH3:33]>C1COCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH:15]([C:21]2[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:24]=[CH:23][CH:22]=2)[CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[CH3:33])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: CI
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(C#N)cc1)c1ccnn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)C(c1ccnn1-c1ccccc1)N(C)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a suspension of NaH (16.3 nmg, 410 μmol, 60% dispersion in mineral oil) in THF (300 μL) at 0° C. was added a solution of 4-cyano-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide (example 37, 140 mg, 340 μmol) in THF (600 μL). The reaction mixture was warmed to room temperature, and after 20 min iodomethane (45 μL, 714 μmol) was added. The mixture was allowed to stir overnight. TLC indicated that the reaction was not complete. Additional aliquots of NaH and iodomethane were added until the reaction was driven to completion. The mixture was then quenched with H2O and extracted with EtOAc twice. The organic extracts were dried (MgSO4) and concentrated. Column chromatography (EtOAc/hexanes, 1:1) provided 89 mg (57% yield) of the title compound as a glassy yellow solid. mp 37.8-54° C.; Mass Spectrum (ES): 481.1;
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)=[CH:4][CH:3]=1
Reactant: OCc1csc(Nc2ccc(F)cc2)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1csc(Nc2ccc(F)cc2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 3.03 g of 2-p-fluoroanilinothiazol-4-ylmethanol, 8.5 g of pyridine sulfur trioxide complex, 7.5 ml of triethylamine and 140 ml of dimethyl sulfoxide. giving the title compound as pale brown prisms.
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][CH2:45][CH2:44][C:43](=[O:47])[CH2:42]2)=[CH:37][CH:36]=1.[Cl:48][C:49]1[CH:59]=[C:58]([O:60][CH2:61][CH:62]=[C:63]([Cl:65])[Cl:64])[CH:57]=[C:56]([Cl:66])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54]O>O1CCCC1>[Cl:48][C:49]1[CH:59]=[C:58]([O:60][CH2:61][CH:62]=[C:63]([Cl:65])[Cl:64])[CH:57]=[C:56]([Cl:66])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54][O:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]2[CH2:46][CH2:45][CH2:44][C:43](=[O:47])[CH2:42]2)=[CH:39][CH:40]=1
Reactant: O=C1CCCC(c2ccc(O)cc2)C1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCC(c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)C1
Reaction time: 0.5 h

Procedure:
0.39 ml of azodicarboxylic acid diisopropyl ester is added at 0° C. to 0.52 g of triphenylphosphine in 20 ml of tetrahydrofuran. After 30 minutes, 289 mg of 3-(4-hydroxyphenyl)cyclohexanone and 554 mg of 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propan-1-ol in 10 ml of tetrahydrofuran are added dropwise thereto. After 24 hours at room temperature, the reaction mixture is concentrated and the residue is purified over silica gel. 3-(4-{3-[2,6-Dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-cyclohexanone is obtained in the form of a colourless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:17]1([NH:23][C:24]([O:1][CH2:2][C:3]2[CH:15]=[C:14]3[N:5]([C:6](=[O:16])[NH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=43)[N:4]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)OCc1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.0 g (0.0093 mole) of 2-(hydroxymethyl)pyrazolo[1,5-c]-quinazolin-5(6H)-one prepared as described in Example 6B and 1.55 ml (≅1.7 g or 0.014 mole) of 98% phenylisocyanate are refluxed in 20 ml of dry pyridine under N2 for 1 hour. The crude product is poured onto 200 ml of ice-water layered with ethyl acetate (50 ml) and stirred for 30 minutes. The precipitates that form are filtered off, air-dried and taken up in dioxane (150 ml). The solution is filtered while hot and the clear filtrate concentrated down to a volume of 100 ml and cooled. The precipitates are filtered off and dried in vacuo at 85°. Yield 2.45 g, 78.8% crude yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[CH2:33][N:34](C(C)C)[CH:35](C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:34]([CH3:35])[CH3:33])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (29 μL, 0.16 mmol) and PyBOP® (46 mg, 0.088 mmol). After stirring the mixture at RT for 15 minutes, dimethylamine was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by dimethylamine bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 20-45—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetamide (26 mg, 0.059 mmol, 37%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][N:38]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)ccn1
Temperature: 95 °C
Yield: 19.7 %

Procedure:
A mixture of Example C1 (0.250 g, 0.598 mmol), K2CO3 (0.165 g, 1.197 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.157 g, 0.718 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.069 g, 0.060 mmol), sparged again with Ar and heated at 95° C. for 36 h. The mixture was cooled to RT, treated with satd. NaHCO3 and extracted with EtOAc (4×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (56 mg, 20%). 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1 H), 8.59 (d, J=5.6 Hz, 1 H), 8.52 (d, J=5.2 Hz, 1H), 8.27 (d, J=3.0 Hz, 1 H), 8.08 (d, J=9.1 Hz, 1 H), 7.89 (s, 1 H), 7.81-7.74 (m, 2 H), 7.70 (d, J=2.4 Hz, 1 H), 6.97 (dd, J=5.6, 2.4 Hz, 1 H), 3.93-3.78 (m, 5 H), 3.49-3.35 (m, 4 H), 2.52 (s, 3 H), 1.77-1.65 (m, 2 H), 1.62-1.56 (m, 2H); MS (ESI) m/z: 475.2 (M+H+).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.S(=[N:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)=O>N1C=CC=CC=1>[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]2=[O:8])=[O:24])=[CH:21][CH:20]=1
Reactant: O=S=Nc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCCCN1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Nc1ccc(C(=O)N2CCCCCC2=O)cc1

Procedure:
Into a 3000 mL three-neck reactor were charged caprolactam (150 g, 0.703 mol), toluene (1300 mL), and pyridine (680 mL); the reactor was then purged with nitrogen. Under ice bath, p-sulfinylaminobenzoyl chloride (147.1 g, 0.730 mol) was added with stirring to the above mixture. After removing the ice-bath, the reaction mixture was stirred at room temperature for 14 hours. After this, pyridine chloride was removed by filtration and the filtrate was washed with 5% sodium bicarbonate solution two times, and then concentrated to remove the solvent. The residue was recrystallized from ethyl acetate to give N-(p-aminobenzoyl)caprolactam, a polymerizable lactam monomer.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc([N+](=O)[O-])cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: -70 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (25 mg, 0.074 mmol) (from Example 5 supra) and Et3N (20 μL , 0.150 mmol) in 3 mL of chloroform was cooled to −70° C. and then treated with 4-nitrobenzoyl chloride (16 mg, 0.085 mmol) (Aldrich). The reaction mixture was stirred at −70° C. for 1 hr and then stirred at room temperature for 15 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate-hexanes elution) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-nitrobenzamide (yield: 24 mg, 72%) as a yellow-brown solid (mp 157-159° C.).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.CN(C)[CH:15]([CH3:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[OH:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[CH2:24][CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CC(C(=O)c1ccccc1)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCc1c(O)c2ccccc2oc1=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.81 g (5.0 mmol) of 4-hydroxycoumarin, 1.07 g (5.0 mmol) of 2-dimethylaminopropiophenone, and 20 mL of acetonitrile was treated with 0.2 mL (5.0 mmol) of triethylamine and then refluxed for 4 hours. The mixture was cooled to room temperature and poured into 5% sodium hydroxide. The aqueous solution was extracted with ether and acidified to pH 3 with 6N hydrochloric acid. The mixture was extracted with chloroform, and the extract was washed with water, dried, and concentrated to give the title compound, m.p. 149°-151° C. NMR (CDCl3) δ2.99 (m, 2H), 3.52 (m, 2H), 7.26 (m, 2H), 7.48 (m, 3H), 7.60 (m, 1H), 7.94 (dd, 1H), 8.02 (d, 2H), 10.65 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC1(C)CC(=O)c2ccc(Br)cc2O1
Product: CC1(C)C=C(C(C)(C)C)c2ccc(Br)cc2O1

Procedure:
7-bromo-2,2-dimethyl-chroman-4-one (Compound 65, 1.8 g, 7 mmol) was treated by the procedure described immediately above (using t-butylmagnesium chloride) to produce the title compound as a clear oil: (500 mg, 25%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39](O)[CH2:40][C@H:41]([OH:43])[CH3:42]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[C@@H:22]3[O:43][C@H:41]([CH3:42])[CH2:40][CH2:39][O:23]3)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](O)CCO
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@H]1OCC[C@@H](C)O1
Yield: 73.5 %

Procedure:
A mixture of (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (2.01 g), p-toluenesulphonic acid monohydrate (0.316 g) and (R)-(-)-butane-1,3-diol (98%, 1.37 g) in toluene (130 ml) was heated under reflux with a Dean-Stark trap for 20 h. The mixture was concentrated to ca. 30 ml and purified by FCC eluting with System A (1:4) to give the title product (1.78 g,) as a white solid. δ(CDCl3) 1.23 (d, J 6 Hz, 3H, CH3CH--O), 1.42 (d, J 7 Hz, 6H, (CH3)2CH), 1.55-1.8 (m, 2H, OCH(CH3)CH2CH2O), 3.20 (septet, J 7 Hz, 1H, (CH3)2CH), 3.7-3.9 (m, 2H, CH2O), 4.05-4.16 (m, 1H, O--CH(CH3)), 4.95 (d, J 5 Hz, 1H, CH=CHCH(O)2), 5.32 (dd, J 15 and 5 Hz, 1H, NCH=CH), 6.76 (dd, J 15 and 1 Hz, 1H, NCH=CH), 6.89 (t, J 9 Hz, 2H, C-3 and C-5 protons of 4-(4-fluorophenyl)), 7.11 (t, J 9 Hz, 2H, C-3 and C-5 protons of 5-(4-fluorophenyl)), 7.39 and 7.27 (2 dd, J 9 and 6 Hz, 4H, C-2 and C-6 protons of both 4-fluorophenyls).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26](=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH:17][C:24](=[O:23])[CH2:25][C:26](=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1ccc(N)c(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CCOc1ccc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-phenyl)-carbamic acid tert-butyl ester (Example J14) (194 mg, 0.77 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (203 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21].N1C=CC=CC=1>O>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])=[CH:3][C:4]=2[C:16]([F:19])([F:17])[F:18])=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 10.8 %

Procedure:
5-[4-amino-2-(trifluoromethyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile (0.33 g, 1.25 mmol) was dissolved in isopropyl sulfonyl chloride (1.0 mL, 9.0 mmol), pyridine (0.5 mL) was added, and the mixture was heated to 100° C. for 6 hours. The mixture was cooled and diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)phenyl]-propane-2-sulfonamide (50 mg).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:17][OH:18].C(O)C>O>[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:17][OH:18])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(I)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A mixture of 4-iodobenzonitrile (7.69 g), anhydrous sodium carbonate (6.25 g), hydroxylamine hydrochloride (8.74 g), in water (60 ml) and sufficient ethanol to maintain a clear solution, was heated at 90°-100° C. for 4 hours. The reaction mixture was cooled to ambient temperature and evaporated until a precipitate formed. The solid was collected by filtration, washed with water and recrystallised from acetonitrile to give 4-iodobenzamidoxime (5.97 g), m.p. 155°-161° C.; microanalysis, found: C, 31.4; H, 2.7; N, 10.2%; C7H7IN2 O 0.2H2O requires: C, 31.6; H, 2.81; R, 10.5%; NMR: 5.82(2H,s), 7.46(2H,d), 7.73(2H,d), 9.69(1H,s); m/z 263(M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:22])[C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:43][C:26]([CH3:42])([CH3:25])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:22])[C:16]5=[O:23])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:24]=2)[CH:30]=[N:29]1
Reactant: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C1=O
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)C1=O
Yield: 33 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2-one was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol to give 479. Yield 33%. MS (ESI):468.2. 1H NMR (400 MHz, DMSO) δ 8.17 (d, J=8.2, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.36 (dd, J=8.2, 1.8, 1H), 7.22 (d, J=1.7, 1H), 4.73 (s, 1H), 4.31 (t, J=4.9, 2H), 4.03 (s, 2H), 3.35 (d, J=5.6, 2H), 3.19 (t, J=5.0, 2H), 2.83 (s, 3H), 1.72 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1.[CH:20](O)=[O:21]>C(OC(=O)C)(=O)C>[CH:20]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:17][CH2:18][Cl:19])[CH2:3][CH2:2][Cl:1])=[CH:16][CH:15]=1)=[O:21]
Reactant: O=CO
Reactant: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O

Procedure:
A solution of 4-[bis(2-chloroethyl)amino]-(L)-phenylalanine (150 mg) in formic acid (1.82 ml) and acetic anhydride (0.64 ml) is stirred at room temperature for 3 hours. The reaction mixture is concentrated to reduced volume under reduced pressure and partitioned between water (3 ml) and ethyl acetate (2×50 ml). The organic phase is dried over sodium sulphate and the solvent is evaporated under vacuum, to give N-formyl-4-[bis(2-chloroethyl)amino]-(L)-phenylalanine (160 mg) as a yellow foam, [α]D =+67° (C=2, ethanol).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:13]([NH:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([CH2:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)(=[O:23])=[O:24])[C:13]([NH:15][O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:14]
Reactant: CC(C)(C)ONC(=O)[C@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)ONC(=O)[C@@H](N)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
(R)-2-(benzyloxycarbonylamino)-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (6.0 g) obtained from Example 17 was dissolved in ethanol (100 ml) and hydrogenated at 1 atmosphere in the presence of 10% palladium on carbon (6 g) for a period of 18 hours. The catalyst was filtered off and the solvent removed from the filtrate under reduced pressure to give (R)-2-amino-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide as a glass.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[O:8][C:7]([CH2:9][OH:10])=[CH:6][CH:5]=1.[CH2:11](I)[CH3:12]>CN(C=O)C>[Br:3][C:4]1[O:8][C:7]([CH2:9][O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: CCI
Reactant: OCc1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1ccc(Br)o1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (95%, 19 mg, 0.75 mmol) was diluted in dry DMF (0.5 mL) and cooled to 0° C. A solution of (5-bromo-2-furanyl)methanol (120 mg, 0.68 mmol) was added, and the mixture was stirred for 5 minutes. Ethyl iodide (117 mg, 0.75 mmol) was added, and the mixture was stirred at it overnight. The reaction mixtures were quenched by the careful addition of water, then extracted with diethyl ether. The combined organics were dried and concentrated. The residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes. The desired fractions were combined and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH2:8][CH2:9][C:10]([CH3:12])=[O:11].[Mg].[CH:16](Br)=[CH2:17]>O1CCCC1>[CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH2:8][CH2:9][C:10]([OH:11])([CH:16]=[CH2:17])[CH3:12]
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Reactant: C=CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(O)CC/C=C(\C)CCC=C(C)C

Procedure:
According to the method reported by A. Ofner et al in Helv. Chim. Acta., 42, 2577-2584 (1959), cis- or trans-nerolidol was prepared respectively from cis- or trans-geranylacetone. That is, in 420 ml. of tetrahydrofuran were placed 12.5 g. of freshly-prepared metallic magnesium turnings and 60 g. of vinyl bromide were added dropwise thereto under water cooling to form a Grignard reagent. 50 g. cis- or trans-geranylacetone were added dropwise thereto at 25° C. The reaction mixture was neutralized with ammonium chloride and extracted with ether. The extract was dried over sodium sulfate and distilled off under reduced pressure. The residue was subjected to vacuum distillation (1.0 mmHg) in a rectifying column having about 40 theoretical plates (about 30 practical plates) with a reflux ratio of 10 ~ 20 and a bottom temperature of approximately 190° C., to give cis-nerolidol from cis-geranylacetone in a yield of 82 percent. The product was identified by the standard product obtained in Example 12. The trans-isomer was obtained in the same manner.