Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:50][C@@H:51]([CH2:55][OH:56])[C@H:52]([CH3:54])[OH:53]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:50][C@@H:51]([CH2:55][OH:56])[C@H:52]([CH3:54])[OH:53])=[O:26])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)[C@H](CO)NC(=O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 23 °C
Reaction time: 8 h

Procedure:
N-Fmoc-6-aminocaproic acid (10 g, 28.30 mmol) was dissolved in DMF (50 ml) and N-hydroxysuccinimide (3.26 g, 28.30 mmol) and 1,3-dicyclohexylcarbodiimide (5.84 g, 28.3 mmol) were added to the solution. The reaction mixture was stirred at RT (about 23° C.) overnight and the precipitated 1,3-dicyclohexylurea filtered off. To the filtrate D-threoninol (2.98 g, 28.30 mmol) was added and the reaction mixture stirred at RT overnight. The solution was reduced to ca half the volume in vacuo, the residue diluted with about m ml of ethyl acetate and extracted with about x ml of 5% NaHCO3, followed by washing with brine. The organic layer was dried (Na2SO4), evaporated to a syrup and chromatographed by silica gel column chromatography using 1-10% gradient of methanol in ethyl acetate. Fractions containing the product were pooled and evaporated to a white solid (9.94 g, 80%). 1H-NMR (DMSO-d6-D2O) 7.97-7.30 (m, 8H, aromatic), 4.34 (d, J=6.80, 2H, Fm), 4.26 (t, J=6.80, 1H, Fm), 3.9 (m, 1H, H3 Thr), 3.69 (m, 1H, H2 Thr), 3.49 (dd, J=10.6, J=7.0, 1H, H1 Thr), 3.35 (dd, J=10.6, J=6.2, 1H, H1′ Thr), 3.01 (m, 2H, CH2CO Acp), 2.17 (m, 2H, CH2NH Acp), 1.54 (m, 2H, CH2 Acp), 1.45 (m, 2H, CH2 Acp), 1.27 (m, 2H, CH2 Acp), 1.04 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 441.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][N:8]=2)[N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2ncc(I)cc2n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a solution of 2-chloro-7-iodo-1,5-naphthyridine (D-17) (586 mg, 2.02 mmol, 1.0 eq) in 1,4-dioxane (20 mL), tert-butyl piperazine-1-carboxylate (372 mg, 2.00 mmol, 1.0 eq), cesium carbonate (922 mg, 2.83 mmol, 1.4 eq), tris(benzylideneacetone)dipalladium (37 mg, 0.04 mmol, 0.02 eq) and Xantphos (35 mg, 0.06 mmol, 0.03 eq) were added. The mixture was stirred at reflux for 16 h under an argon atmosphere. After the reaction mixture was cooled to RT, it was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (15% ethyl acetate/petroether) to afford the desired product, tert-butyl 4-(6-chloro-1,5-naphthyridin-3-yl)piperazine-1-carboxylate (D-18) (207 mg, 29.4% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3-d6) δ: 8.79 (d, J=2.7 Hz, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 3.64 (m, 4H), 3.34 (m, 4H), 1.49 (s, 9H); ESI-MS m/z: 349.13[M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:28])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:9]([C:26]#[N:27])[CH:8]=1)=[O:5].[C:29](OCC)(OCC)(OCC)[CH3:30]>>[CH2:14]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:28])[N:1]=[C:29]2[CH3:30])=[CH:8][C:9]=1[C:26]#[N:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1C#N
Product: CCCCCCN(CCCCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1C#N
Temperature: 150 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
A mixture of (Z)-3-amino-N-(3-cyano-4-(dihexylamino)phenyl)but-2-enamide (1.30 g, 3.38 mmol) and triethyl orthoacetate (30 mL) was stirred at 150° C. overnight. The mixture was then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=50:1) to give the title compound as pale yellow oil (60 mg, 4%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH3:14])[C:7]=1[C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:5]>CO>[CH2:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH3:14])[C:7]=1[C:15](=[O:21])[C:16]([NH:2][NH2:3])=[O:17])[CH3:5]
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Reactant: NN
Solvent: CO
Solvent: O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Temperature: 2 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a 100 ml volume four-necked flask, methanol (22.91 g) and hydrazine hydrate (1.93 g) were added at room temperature, and cooled. Ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate (9-a) (5.01 g) diluted with methanol (10.02 g) was added dropwise at 1° C. over 5 minutes. The resulting mixture was stirred at 2° C. for 4 hours, then the mixture was filtered. The resulting filtrate was concentrated, added tert-butyl methyl ether (41 g), and washed with brine (14 g). The resulting organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel: 40 g, hexane: ethyl acetate=1:1) to gave 1.88 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39).
Reaction SMILES: N1([C:6]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[CH2:8][C:7]=2[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:19])CCCC1.Cl.C(O)(=[O:33])C>>[OH:33][C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8][C:7]=1[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C1=C(N2CCCC2)c2ccccc2S(=O)(=O)C1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C1=C(O)c2ccccc2S(=O)(=O)C1
Temperature: 0 °C

Procedure:
A mixture of 7.0 g of p-nitrophenyl 4-(1-pyrrolidinyl)-2H-1-benzothiopyran-3-carboxylate 1,1-dioxide, 50 ml of glacial acetic acid, and 100 ml of 1N hydrochloric acid was heated on a steam bath for 20 min and diluted with ice-water. The resulting precipitate was collected and recrystallized from tetrahydrofuran-isopropyl ether to give 5.5 g of product, mp 206°-209° dec.
Reaction SMILES: O.O[CH:3]1[C:20]2[CH:19]3[CH2:21][CH2:22][CH:16]([CH:17]=[CH:18]3)[C:15]=2[CH:14](O)[C:13]2[C:4]1=[CH:5][C:6]1[S:10][C:9](=[S:11])[S:8][C:7]=1[CH:12]=2>N1C=CC=CC=1>[S:8]1[C:7]2[CH:12]=[C:13]3[C:4](=[CH:5][C:6]=2[S:10][C:9]1=[S:11])[CH:3]=[C:20]1[C:15]([CH:16]2[CH2:22][CH2:21][CH:19]1[CH:18]=[CH:17]2)=[CH:14]3
Reactant: OC1C2=C(C3C=CC2CC3)C(O)c2cc3sc(=S)sc3cc21
Solvent: c1ccncc1
Solvent: O
Product: S=c1sc2cc3cc4c(cc3cc2s1)C1C=CC4CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In pyridine (30 mL), the 5,10-dihydroxy-5,10-dihydro-6,9-dihydro-6,9-ethanoanthra[2,3-d] [1,3]dithiol-2-thione: 1-6 (1.03 g) was dissolved, and cooled to 0° C. in an ice bath. Thereafter, phosphonyl chloride (0.81 mL) was added in the cooled mixture, and stirred for 2 hours. After completion of the reaction, the mixture was poured into iced water, and then the obtained precipitate was recovered through filtration.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Br:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][C:17]=1[CH3:24]>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[S:20][C:16]([Br:15])=[C:17]([CH3:24])[CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: Cc1cc(C(=O)O)sc1Br
Product: Cc1cc(C(=O)NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)sc1Br

Procedure:
57.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-bromo-4-methyl-thiophene-2-carboxylic acid (prepared according to M. Nemec et al., Collection of Czechoslovak Chemical Communications, 1974, 39, 3527) to give (R)-3-{[(5-bromo-4-methyl-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 403.3 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:7](=[O:17])[CH2:6][CH2:5]2.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.CCOCC>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:17]
Reactant: CN(C)CCN1C(=O)CCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 18 h

Procedure:
A solution of 6-amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (0.280 g, 1.20 mmol) in absolute ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.684 g, 2.40 mmol) at room temperature and the resulting mixture was stirred overnight (18 h). The reaction was diluted with ether (45 mL) and the precipitate collected by vacuum filtration. The precipitate was washed from the filter with methanol and the solvent was evaporated. The residue was diluted with 1N sodium hydroxide solution (5 mL) and product was extracted into ethyl acetate (3×10 ml). The combined ethyl acetate layer was washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 1:19). Product was dried under high vacuum. Yield: 230 mg of yellow oil 3 (56%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1N)[C:9]([OH:11])=[O:10].O.Cl>C(O)CCCC>[N:1]1[C:2](=[O:3])[N:4]=[C:13]2[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[CH:6][C:14]=12
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: NC(N)=O
Agent: Cl
Solvent: CCCCCO
Solvent: O
Product: O=C1N=c2ccc(C(=O)O)cc2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Urea (1.20 g, 0.0200 mol) and 3,4-diaminobenzoic acid (3) (3.04 g, 0.0200 mol) in pentan-1-ol (10 mL) was vigorously stirred and heated to reflux under a nitrogen atmosphere. The heating was discontinued after 4 hours and on cooling to room temperature, water (30 mL) was added. The pH was adjusted to 1 with conc. HCl. The resultant dark solid was filtered off, washed with further water (2×20 mL) and dried to give 3.00 g (84% yield) of benzimidazol-2-one-5-carboxylic acid (4) as a black powder,
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Zn]CC)C.CC1(C)[C@@H]2CC[C@@]1(CSSCC13C(C)(C)C(CC1)CC3N1CCOCC1)[C@H](N1CCOCC1)C2.[C:49]1([CH3:57])[CH:54]=[CH:53][C:52]([CH:55]=[O:56])=[CH:51][CH:50]=1>[Zn].C1(C)C=CC=CC=1>[C:1]1([C@H:55]([C:52]2[CH:53]=[CH:54][C:49]([CH3:57])=[CH:50][CH:51]=2)[OH:56])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: OB(O)c1ccccc1
Agent: CC1(C)C2CCC1(CSSC[C@]13CC[C@H](C[C@H]1N1CCOCC1)C3(C)C)C(N1CCOCC1)C2
Agent: CC[Zn]CC
Agent: [Zn]
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H](O)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a toluene (4.0 mL) solution of phenylboronic acid (0.24 g, 2 mmol) was added diethylzinc (6.0 mL, 6 mmol 1.0 M in hexanes). The mixture was heated at 60° C. overnight and was then cooled to ambient temperature. The mixed zinc solution was transferred to another flask containing (1S,2R,4R)-1,2-bis((7,7-dimethyl-2-morpholinobicyclo[2.2.1]heptan-1-yl)methyl)disulfane (IIIa) (51 mg, 0.1 mmol) via syringe. After 10 minutes at ambient temperature, the mixture was cooled to 0° C. and neat p-tolualdehyde (108 μL, 1 mmol) was added dropwise. The reaction was stirred at 0° C. for 24 hours and was quenched by slow addition of sat. aq. NH4Cl (3 mL) and subsequent dilution with DCM (25 mL) and 1 N aq. HCl (30 mL). After layer separation, the aqueous solution was washed twice with DCM (20 mL). The DCM layers were combined, dried over Na2SO4, and concentrated to give a yellow oil which was purified by silica gel column chromatography (1:6 ethyl acetate:n-heptane) to give (R)-phenyl-p-tolyl-methanol as a white solid (0.147 g; 74% yield; 95.9% e.e.). The optical purity was determined by normal phase HPLC using a Chiralcel OD-H chiral column (eluted with isocratic 10:90 IPA/hexane, with 0.5 mL/minute flow rate; monitoring at 254 nm).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]3=[O:19])=[N:7][C:6]=12.CC1(C)C(C)(C)OB([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CCOC(C)=O.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]>[CH:16]([C@H:15]1[CH2:14][O:13][C:12](=[O:19])[N:11]1[C:8]1[CH:9]=[CH:10][N:5]2[N:4]=[CH:3][C:2]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[C:6]2[N:7]=1)([CH3:18])[CH3:17]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)O)cc3)c2n1
Temperature: 100 °C
Reaction time: 19 h
Yield: 45 %

Procedure:
In a vial, a mixture of (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (Example 1, Step 4; 1.82 g, 5.58 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.08 g, 8.37 mmol), and 2 M K2CO3 (8.37 mL, 16.7 mmol) in dioxane (20 mL) was degassed by bubbling N2 for 5 minutes. Pd2 dba3 (0.51 g, 0.56 mmol) and XPHOS (0.266 g, 0.558 mmol) were added and the reaction was capped under N2 and heated at 100° C. After 19 hours, the mixture was cooled to ambient temperature, diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography (0-3% MeOH in dichloromethane) to afford 0.92 g (45%) of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid. LCMS (APCI+) m/z 367.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2N([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)C3C(SC=2C=1)=CC=CC=3.N1C=CC(B(O)O)=CC=1.N1C=CC=C(B(O)O)C=1>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.CN1C(=O)CCC1.O.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:44]4[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(Cl)ccc32)CC1
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB(O)c1cccnc1
Agent: OB(O)c1ccncc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4ccncc4)ccc32)CC1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 2i, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, 4-pyridyl boronic acid for 3-pyridyl boronic acid, Cp2Fe(PtBu2)2PdCl2 for Pd(PPh3)4 and a 5:1 mixture of dioxane:water for NMP, the title compound 4-(3-pyridin-4-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 1k was obtained. MS m/z (MH+) 444.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]1[CH2:15][C:14](=[O:16])[C:13]([C:17](=O)[CH2:18][CH3:19])=[C:12]([OH:21])[CH2:11]1.Cl.[CH2:23]([O:25][NH2:26])[CH3:24]>>[CH3:9][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]1[CH2:15][C:14](=[O:16])[C:13]([C:17](=[N:26][O:25][CH2:23][CH3:24])[CH2:18][CH3:19])=[C:12]([OH:21])[CH2:11]1
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(O)cc2C)CC1=O
Reactant: CCON
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(O)cc2C)CC1=O

Procedure:
5-(2,6-Dimethyl-4-hydroxyphenyl)-2-[1-(ethoxyimino)propyl]-3-hydroxycyclohex-2-en-1-one (31) was prepared from 5-(2,6-dimethyl-4-hydroxyphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1, part (iv). The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is reported in Table 5, Example 37.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[F:31]C1C=CC=CC=1C=O>>[F:31][C:29]1[CH:30]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccccc1F
Product: O=C(NCCNCc1ccccc1F)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 2-fluorobenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 410 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46-11.56 (1H, m) 10.26 (1H, s) 8.03 (1H, t, J=5.56 Hz) 7.99 (1H, d, J=5.47 Hz) 7.75 (1H, d, J=5.47 Hz) 7.44 (1H, d, J=5.47 Hz) 7.37-7.42 (1H, m) 7.26-7.30 (1H, m) 7.19-7.26 (1H, m) 7.05-7.12 (1H, m) 6.78 (1H, d, J=5.47 Hz) 6.40 (1H, dd, J=3.61, 1.66 Hz) 3.70 (2H, s) 3.32-3.37 (2H, m) 2.62 (2H, t, J=6.54 Hz)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:20][C:16]=2[N:17]=[CH:18][N:19]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:15]3[C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[N:19][CH:18]=[N:17][C:16]=3[O:20][C:21]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCNC(=O)OC(C)(C)C)c23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCN)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 380 mg (0.76 mmol) of the compound from Stage 1 in 5 ml methylene chloride and add 0.4 ml anisole and then 5.5 ml trifluoroacetic acid. Stir for 2 h at room temperature. Dilute the mixture with dichloromethane and wash with sodium hydrogencarbonate solution until reaction is neutral. After washing the organic phase with saturated sodium chloride solution, dry over magnesium sulphate. The residue left after concentration by evaporation is dissolved in ethanol and concentrated by evaporation; this operation is repeated three times. 349 mg (82% of theor.) of the title compound is obtained as a yellowish foam.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH2:21][OH:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:29]C#N.[Na+].FC(F)(F)C(O)=O.O>C(Cl)Cl>[C:11](=[O:12])([OH:29])[NH2:15].[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH2:21][OH:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#C[O-]
Agent: COc1ccc(Cc2nc3cc(Cl)cc(CCO)c3o2)cc1OC1CCCC1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NC(=O)O
Reaction time: 8 h

Procedure:
A suspension of 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chloro-7-(2-hydroxyethyl)benzoxazole (0.6 g, 0.0015 mol) and sodium cyanate (0.2 g, 0.0030 mol) was stirred in 4 ml of CH2Cl2 and then trifluoroacetic acid (0.34 g, 0.0030 mol) was added. The mixture was stirred overnight as the initial solid dissolved and a new solid began to form. The next day CH2Cl2 (50 ml) and water (50 ml) were added. The water layer was separated and extracted with 2×50 ml of CH2Cl2. The combined CH2Cl2 layers were washed with 50 ml of water, dried and evaporated to give 0.6 g of white crystalline solid. This material was recrystallized from 6 ml of toluene to give 0.3 g of title compound as white crystals, mp 97-98° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:15][CH2:14][CH2:13][Br:12]
Reactant: Oc1ccc2ccccc2c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCCOc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 3.60 g (25 mmol) of 2-naphthol and 6.0 g (30 mmol) of 1,3-dibromopropane in dimethylformamide was added 7.25 g (52.5 mmol) of finely ground anhydrous potassium carbonate. The mixture was stirred vigorously overnight. Solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was further extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, and after filtration, the solvent was removed under reduced pressure. The residue was then chromatographed over silica gel using 10% methylene chloride/hexane as eluent to afford 1.66 g of the title compound, which was homogeneous by thin layer chromatography (5% by volume of ethyl acetate/hexane on silica gel plates).