Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH:5]1([CH:11]([OH:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CCN(CC)CC>C(Cl)Cl>[C:14]1([CH:12]([C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:20])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(c1ccccc1)C(O)C1CCCCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)C1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.48 h
Yield: 85.4 %

Procedure:
DMSO (118 mL, 1.6674 mol) was added dropwise to a solution of 126.42 g (0.579 mol) of 1-cyclohexyl-2-phenylpropanol in 1737 mL of CH2Cl2 (cooled in a wet ice acetone bath). After 29 min, 147.93 g (1.0422 mol) of P2O5 was added. After 11 min, the cooling bath was removed. An aliquot quenched with Et3N showed complete reaction within 3 h at RT. The reaction mixture was cooled in a wet ice acetone bath. Et3N (282 mL, 2.0265 mol) was added dropwise to the cooled reaction mixture over a 30 min period. The cooling bath was removed and the mixture was stirred overnight at RT. The reaction mixture was quenched by dropwise addition of 500 mL of 3 N HCl (aq) (pH=0). After shaking in separatory funnel, the aqueous phase was removed. The organic phase was washed with 500 mL of 3 N HCl (aq) (pH=0), washed twice with 1 L of 10% K2CO3 (aq) (pH=12;12), washed three times with 500 mL of NaOCl (aq) solution, washed with 1L of water, washed with 1 L of 25% NaCl (aq), dried over MgSO4, gravity filtered and concentrated under vacuum with dry ice trap to collect Me2S. An amber oil of the title compound (107.01 g, 85.437%) was obtained; 1H NMR (d6-DMSO) δ 7.30-7.37 (m, 2H, phenyl CH), 7.21-7.28 (m, 3H, phenyl CH), 4.08 (q, J=6.9 Hz, 1H, —CH(CH3)Ph), 2.40-2.49 (m, 1H, cyclohexyl CH), 1.82-1.84 (m, 1H, cyclohexyl —CH2), 1.67-1.69 (m, 1H, cyclohexyl —CH2), 1.52-1.63 (m, 1H, cyclohexyl —CH2), 1.34-1.43 (m, 1H, cyclohexyl —CH2), 1.26 (d, J=6.9 Hz, 3H, —CH(CH3)Ph), 1.01-1.24 (m, 4H, cyclohexyl —CH2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@H:11]2[CH3:16])=[O:9])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[N:21]=[C:22]([Cl:24])[CH:23]=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>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:24][C:22]1[CH:23]=[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][C@H:11]3[CH3:16])=[O:9])=[CH:6][N:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[N:21]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (50 mL), 248a (330 mg, 1.5 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (446 mg, 2.0 mmol), cesium carbonate (978 mg, 3.0 mmol), Xantphos (88 mg, 0.15 mmol), and tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.075 mmol). The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 4 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (3×30 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (2:1 to 1:2) to afford 248b (430 mg, 79%) as yellow solid. MS-ESI: [M+H]+ 364.3
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[CH2:33]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C>>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[CH:35]([CH2:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[C:34](=[O:39])[CH2:33]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: O=Cc1nccs1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nccs3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 1,3-thiazole-2-carbaldehyde was substituted in place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was substituted in place of 6-[2-(3-chloro-4isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in final Step of that example. 1H NMR (CDCl3): δ 1.44-1.70 (bm, 8H), 2.0 (m, 2H), 2.40 (m, 1H), 2.60 (m, 3H), 2.76 (d, J=17.90 Hz, 1H), 3.88 (s. 3H), 4.56 (d, J=15.07 Hz, 1H), 4.76 (d, J=15.07 Hz, 1H), 6.70 (d, J=2.07 Hz, 1H), 6.98, (d, J=2.07 Hz, 1H), 7.11 (s, 1H), 7.63, (d, J=3.96 Hz, 1H), 7.87 (d, J=3.96 Hz, 1H). Anal. Calcd. For C24H28O3SNCl: C, 64.63; H, 6.33; N, 3.14. Found: C, 64.55; H, 6.64; N, 3.10.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccccc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: COC([C:5]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]2)[CH2:7][C:6]=1[OH:16])=O.[Na+].[Cl-].O>CS(C)=O>[CH2:7]1[C:8]2([CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]2)[CH2:9][CH2:10][CH2:5][C:6]1=[O:16]
Reactant: COC(=O)C1=C(O)CC2(C=CCCC2)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCC2(C=CCCC2)C1
Temperature: 160 °C
Yield: 95 %

Procedure:
To a solution of the relevant 2-hydroxy-spiro[5.5]undecan-2,7-diene-3-carboxylic acid methyl ester isomer (9) or (9′) (19.0 g, 85.0 mmol) in DMSO (66 mL) was added NaCl (5.5 g, 93.5 mmol) and H2O (4.6 mL, 255 mmol). The reaction mixture was heated at 160° C. for 6 hours then cooled and poured into H2O (100 mL). The aqueous layer was extracted with Et2O (5×) and the combined organic layers dried over anhydrous MgSO4. The solvent was removed in vacuo and the resulting residue purified over silica (n-pentane/Et2O, 95:5) to afford 13.3 g (95% yield) of the desired product as a colorless oil which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([CH2:21][OH:22])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH3:27].Cl>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([CH2:21][O:22][CH2:24][CH2:25][O:26][CH3:27])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(CO)nn1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: COCCBr
Agent: Cl
Solvent: CN(C)C=O
Product: COCCOCc1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 80 °C

Procedure:
To a solution of 500 mg of 2-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-2H-pyrazole-3-carboxylic acid in 5 ml DMF 480 mg Cs2CO3 and 204 mg 1-Bromo-2-methoxy-ethane were added and the mixture was heated to 80° C. for 5 h. Then the mixture was acidified to pH 4 with aqueous HCl and filtered through a Chem Elut® cartridge by elution with ethyl acetate. After concentration the crude product was directly subjected to the next reaction step.
Reaction SMILES: OC1CCNCC1.BrC1OC(C=O)=CC=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:28]/[C:26]2[O:27][C:23]([N:20]3[CH2:19][CH2:18][CH:17]([OH:16])[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: O=Cc1ccc(N2CCC(O)CC2)o1
Reactant: COc1ccc(CC#N)cc1OC
Agent: O=Cc1ccc(Br)o1
Agent: OC1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)o2)cc1OC
Yield: 64.7 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 4-hydroxypiperidine (1.52 g) was introduced into 5-bromo-2-furaldehyde (875 mg), to thereby yield 5-(4-hydroxy-piperidin-1-yl)-furan-2-carbaldehyde (yield: 660 mg, 68%). The produced 5-(4-hydroxy-piperidin-1-yl)-furan-2-carbaldehyde (390 mg) was condensed with 3,4-dimethoxybenzyl cyanide (354 mg) through Method A (production step 2), to thereby yield the target product (yield: 458 mg, 65%).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[S:42]([NH2:45])(=[O:44])=[O:43]>>[CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:33]3[CH:34]=[CH:35][C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=3)(=[O:43])=[O:44])=[O:31])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 2-naphtylsulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:31]#[C:30][CH2:29][OH:32]
Reactant: C#CCO
Reactant: Clc1cccc(I)c1Cl
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OCC#Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A mixture of 2,3-dichloroiodobenzene (5.00 g), copper(I) iodide (69.8 mg), triphenylphosphine (240 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (378 mg), propargyl alcohol (1.19 ml), diisopropylethylamine (12.8 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 25 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (3.12 g) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(N(C(C)C)CC)(C)C.CS(C)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](CO)N2C(=O)OC(C)(C)C)ccc1OC
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](C=O)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: -5 °C
Yield: 80.4 %

Procedure:
Alternatively, to a solution of 1.1 g of the alcohol 6 in 10 mL of dichloromethane is added 0.4 g of pyridine, 1.1 g of diisopropylethylamine and 2.0 g of dimethyl sulfoxide. The mixture is cooled to −5° C. and 0.6 g of sulfur trioxide-pyridine complex is added in four portions over a period of 2 h. The reaction is quenched by addition of 2.5 mL of water and acidified by addition of 1 mL of 37% hydrochloric acid. The phases are separated and the organic phase washed with 2.5 mL of water, dried over sodium sulfate and the solvent removed in-vacuum, to afford e.g. 0.88 g of the aldehyde 7 as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:10]#[N:11])=[C:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[N+]([CH3:16])([O-])=O.N12CCCN=C1CCCCC2>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:10]#[N:11])[C:5]2([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:16]1)=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C(C#N)=C1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C1(C#N)CC12CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of cyano-cyclopentylidene-acetic acid methyl ester (20.8 g, 126 mmol) in acetonitrile (500 mL) was added nitromethane (34 mL, 630 mmol, 5 eq) followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (18.8 mL, 126 mmol). The reaction solution turned orange upon the addition of DBU. The reaction mixture was stirred at room temperature for 16 hours. Another portion of DBU (1 mL) was added and stirred for 1 hour. The reaction mixture was partitioned between ether (1 L) and 1N HCl (400 mL) and the layers separated. The organic layer was washed with 1N HCl (2×300 mL), brine (2×200 mL), dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a wet-packed silica gel column eluting with 4–6% ethyl acetate/hexanes. The appropriate fractions were combined and evaporated to furnish 14.0 g (62%) of 1-cyano-spiro[2.4]heptane-1-carboxylic acid methyl ester as a clear oil: 1H NMR (300 MHz, CDCl3) δ 1.64 (d, J=5.0 Hz, 1H), 1.70–1.88 (m, 7H), 2.14 (d, J=5.0 Hz, 1H), 2.1–2.19 (m, 1H), 3.82 (s, 3H); MS (APCI) m/z 180 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8]([C:10]2[N:11]=[CH:12][N:13]([CH3:15])[CH:14]=2)=[O:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.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.C(O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:16]([CH3:17])[CH3:18])[C:8]([C:10]2[N:11]=[CH:12][N:13]([CH3:15])[CH:14]=2)=[O:9])=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CC(C)N(Cc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1)C(=O)c1cn(C)cn1
Reactant: Brc1ccccn1
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: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccc(F)c(-c2ccccn2)c1)C(=O)c1cn(C)cn1
Temperature: 150 °C
Yield: 28.5 %

Procedure:
A mixture of N-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1-methyl-N-(propan-2-yl)-1H-imidazole-4-carboxamide (100 mg), 2-bromopyridine (47 mg), tetrakis(triphenylphosphine)palladium (29 mg), potassium carbonate (69 mg), dimethylformamide (1.0 mL) and ethanol (0.5 mL) was stirred under irradiation with microwave while heating at 150° C. for 50 min. After the mixture was diluted with ethyl acetate, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and then washed with water and brine. The organic phase was collected and dried over sodium sulfate, the desiccant was filtered off and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100) and (silica gel cartridge, chloroform:methanol=100:0-98:2) to afford the title compound (25 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OCC1C=CC=CC=1)=O)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:44])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 98.2 %

Procedure:
To a solution of 2-[3-(5-Benzyloxycarbonylamino-1-tert-butoxycarbonyl-pentyl)-ureido]-pentanedioic acid di-tert-butyl ester (630 mg, 1.0 mmol) in ethanol (20 mL) was added ammonium formate (630 mg, 10 eqv) followed by 10% Pd—C and the suspension was allowed to stand with occasional agitation overnight until complete. The reaction was filtered through celite and concentrated to afford the desired product (479 mg, 98%) as a waxy solid. 1H NMR (400 MHz, CDCl3) δ 7.15-6.0 (bm, 4H, NH's), 4.29 (m, 2H), 3.02 (m, 2H), 2.33 (m, 2H), 2.06-1.47 (m, 8H), 1.45-1.40 (m, 27H, t-Bu's). ESMS m/z: 488 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH3:6][O:7][C:8](=[O:12])[CH2:9][C:10]#[N:11].[OH-].[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:12])[C:9]([C:10]#[N:11])=[CH:1][CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CC#N
Reactant: CC(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=CC(C)C
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of isobutyraldehyde (30.0 g, 416 mmol), methyl-cyano-acetate (20.6 g, 208 mmol), ammonium hydroxide (3.2 g, 41.6 mmol) and acetic acid (5.0 g, 83.2 mmol) in 500 mL of toluene is warmed to reflux under a Dean-Stark trap for 12 hours. The mixture is cooled to room temperature and extracted with saturated NaHSO3 (3×100 mL), saturated NaHCO3 (3×100 mL), and 100 mL of brine. The organic layer is dried over Na2SO4, and the solvent is evaporated. The remaining oil is distilled under high vacuum (0.5 mm Hg, B.P.=115–120° C.) to give 28.8 g of 2-cyano-4-methyl-2-pentenoic acid methyl ester 61 as an oil (90% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(N(CC)CC)C>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[CH:8]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Solvent: CCN(CC)CC
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(=O)(=O)c3ccc(C)cc3)ccc2c1

Procedure:
1,1-dimethoxy-1-(6-methoxy-2-naphthyl)propan-2-ol is treated with a molar excess of p-toluenesulfonyl chloride in the presence of a molar excess of triethylamine in a manner similar to Example 25 to yield (S) 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl p-toluenesulfonate. That material is converted to (S) methyl 2-(6-methoxy-2-naphthyl)propionate in a manner similar to that described in Example 17.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]([O-:17])(=[O:16])[CH2:14][CH3:15].[Na+].C(OC(=O)CC)(=O)CC>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[C:14]([CH3:15])[C:13]([OH:17])=[O:16]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCC(=O)[O-]
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Product: CC(=Cc1cc([N+](=O)[O-])ccc1Cl)C(=O)O
Temperature: 90 °C

Procedure:
371 g (2 moles) of 2-chloro-5-nitrobenzaldehyde were mixed with 192 g (2 moles) of sodium propionate and 780 g (6 moles) of propionic anhydride. The stirred mixture was then heated for 6 hours at 140°-160° C., solid material going into solution. The solution was then left to cool to 90° C., 200 ml of ice water were added and the precipitated solid was isolated by filtration under suction, washed with water and recrystallized from acetone to give 318 g (66% of theory) of product of melting point 228°-230° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][N:8]=2)=[N:4][CH:3]=1>ClCCCl.O=[Mn]=O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][N:8]=2)[CH:13]=[O:14])=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2cc(CO)ccn2)s1
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: Cc1cnc(-c2cc(C=O)ccn2)s1
Temperature: 25 °C

Procedure:
A solution of (2-(5-methylthiazol-2-yl)pyridin-4-yl)methanol (1.910 g; 9.26 mmol) in anh. DCE (80 ml) was treated with MnO2 (4.025 g; 46.30 mmol), and the resulting mixture was heated at reflux, under nitrogen, for 1.5 h. After cooling to rt, the resulting reaction mixture was filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 2-(5-methylthiazol-2-yl)isonicotinaldehyde as an off-white solid. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 205.35 g/mol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]([C:15]([O:17][CH3:18])=[O:16])[NH:3]1.[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:30])=O)C=CC=CC=1>CN(C=O)C>[NH2:30][N:3]1[C:2](=[O:1])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CC(=O)N1N
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(tert-Butyl) 3-methyl 5-oxo-1,3-piperazinedicarboxylate (3.15 g) was dissolved in DMF (63 ml) and combined with sodium hydride (0.59 g, in oil) with cooling on ice. The mixture was stirred at 50° C. for 1 hour and then cooled to room temperature, combined with O-diphenylphosphinyl hydroxylamine (3.13 g), and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was combined with aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried and concentrated to obtain 1-(tert-butyl) 3-methyl 4-amino-5-oxo-1,3-piperazine dicarboxylate as a yellow oil. A mixture of this material and 1-(2-methyl-4-pyridinyl)-4-piperidone (2.3 g) in ethanol (63 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 15 hours. The reaction mixture was concentrated, and the residue was dissolved in methanol (63 ml), combined with acetic acid (1.45 ml) with cooling on ice, followed by sodium cyanoborohydride (1.53 g), and then stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried, concentrated and purified by a column chromatography on a basic silica gel (ethyl acetate:methanol=20:1) to obtain the title compound (3.4 g) as a pale yellow non-crystalline powder.