Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5][N:4]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([O:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5][N:4]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(OC2CCCCO2)CC1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC1CC(OC2CCCCO2)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a solution of the product of step F (1.0 g, 3.7 mmol) in dichloromethane (20 mL) at 0° C. was added diisopropylethylamine (1.0 mL, 5.7 mmol) followed by acetyl chloride (0.32 mL, 4.4 mmol). The solution was stirred for 10 min at 0° C. followed by 45 min at ambient temperature. The reaction mixture was washed with NaHCO3 solution (3×15 mL) then NaCl solution (2×10 mL) and dried over Na2SO4. The mixture was filtered and the filtrate concentrated in vacuo to afford the crude product which was purified by flash column chromatography (SiO2, 19:1 to 4:1, hexanes/ethyl acetate) to give tert-butyl 2-(acetoxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine-1-carboxylate (701 mg, 68%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 4.69-4.51 (m, 3H), 4.22-3.83 (m, 5H), 3.53-3.48 (m, 3H), 3.23-3.18 (m, 1H), 2.05-2.03 (m, 3H), 1.84-1.55 (m, 7H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:18]([CH3:26])[CH:17]=2)[O:13][N:12]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:52]1[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][N:52]2[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]2)[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:18]([CH3:26])[CH:17]=2)[O:13][N:12]=1)[CH3:2]
Reactant: CCc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(C)c2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(CN2CC(C(=O)OC)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(C)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {6-ethyl-5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.15 g, 0.42 mmol) that was obtained in Example 29 (29a), carbon tetrabromide (0.28 g, 0.84 mmol), triphenylphosphine (0.22 g, 0.84 mmol), methyl 3-azetidinecarboxylate hydrochloride (96 mg, 0.63 mmol), and N,N-diisopropylethylamine (0.22 ml, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1) as the eluent to afford the title compound (0.13 g) in a yield of 71% as a colourless oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=1.C([O:17][C:18](=O)[CH2:19][C:20](=O)[C:21]([F:24])([F:23])[F:22])C>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18](=[O:17])[NH:13][C:11]=2[N:10]([CH3:14])[N:9]=1
Reactant: Cn1nc(-c2ccccc2F)cc1N
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: Cn1nc(-c2ccccc2F)c2c(C(F)(F)F)cc(=O)[nH]c21
Reaction time: 0.17 h
Yield: 66.6 %

Procedure:
A solution of 3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-amine (830 mg, 4.34 mmol) and 4,4,4-Trifluoro-3-oxo-butyric acid ethyl ester (960 mg, 5.21 mmol) in acetic acid (5 ml) was irradiated using a microwave at 150° C. for 1.5 h. After completion of the reaction, ice-cold water was added and the reaction mixture was stirred for 10 min. The precipitate was filtered, washed twice with pentane and dried under vacuum to yield 900 mg (67%) of the title compound. [1H-NMR (CDCl3, 300 MHz): δ 13.6 (s, 1H), 7.51-7.05 (m, 4H), 6.75 (s, 1H), 4.21 (s, 3H); LCMS RtA=1.459 min; [M+H]+=312.1]
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14]C=1C([O-])=O>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COCCCc1sc(-c2ccccc2)nc1C(=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCc1sc(-c2ccccc2)nc1C(=O)Cl
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
Oxalyl chloride (67.2 mmol, 5.9 mL) was slowly added to a room temperature solution of 5-(3-methoxypropyl)-2-phenylthiazole-4-carboxylate (22.4 mmol, 6.2 g) in CH2Cl2 (100 mL). 3 drops of DMF were added and the reaction became homogeneous over ˜20 min. The reaction was stirred for 3 h, then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (150 mL) and concentrated under reduced pressure. The crude product was dissolved in EtOAc (150 mL), washed with brine (2×100 mL), dried (MgSO4), and concentrated under reduced pressure to give 5-(3-methoxypropyl)-2-phenylthiazole-4-carbonyl chloride as a tan solid (6.6 g, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Cl.ClC1C2C(=CC(OCCCl)=C(OC)C=2)N=CN=1>CC(N(C)C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:23][CH2:22][Br:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: ClCCBr
Agent: COc1cc2c(Cl)ncnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Cl)ncnc2cc1OCCBr
Temperature: 90 °C
Yield: 62.6 %

Procedure:
A mixture of 4-chloro-6-methoxyquinazolin-7-ol (5.0 g, 24 mmol), potassium carbonate (9.94 g, 72 mmol) and 1-bromo-2-chloroethane (7.98 ml, 96 mmol) in dimethyl acetamide (50 ml) was heated at 90° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and then filtered. The filtrate was purified directly by silica gel chromatography eluting with a 20 to 80% mixture of ethyl acetate in iso-hexane. The obtained product was triturated with diethyl ether to give a 3:1 mixture of 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline: 4-chloro-7-(2-bromoethoxy)-6-methoxyquinazoline (4.77 g, 73% yield) as a white solid:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])#[CH:13]>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]#[C:13][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1
Reactant: C#Cc1ccccc1F
Reactant: Cc1cc2ncc(Br)cn2n1
Product: Cc1cc2ncc(C#Cc3ccccc3F)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=252.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethynyl-2-fluoro-benzene.
Reaction SMILES: C1N(CCO)CCN([CH2:10][CH2:11]S(O)(=O)=O)C1.[F-].[K+].[CH2:18](S)[C@@H:19](O)[C@H:20](O)[CH2:21]S>>[CH3:18][C:19](=[CH:20][CH2:21][CH2:18]/[C:19](=[CH:20]/[CH2:21][CH2:10]/[C:11](=[CH:10]/[CH2:11][CH2:18]/[CH:19]=[C:20](/[CH2:21][CH2:18]/[CH:19]=[C:20](/[CH2:10][CH2:11][CH:10]=[C:10]([CH3:11])[CH3:11])\[CH3:21])\[CH3:21])/[CH3:20])/[CH3:19])[CH3:18]
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [F-]
Agent: [K+]
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C

Procedure:
Buffer mixture contains 270 mM HEPES, pH 7.5, 20 mM Potassium fluoride and 5.4 mM Dithiothreitol(DTT). 55 μL of this mixture was used per assay. The final concentrations of HEPES, KF and DTT in the assay are 150 mM, 11 I mM and 3 mM respectively.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:32]#[N:33].[Na+].O>CS(C)=O>[C:32]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:33]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: [C-]#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 18 h
Yield: 75.4 %

Procedure:
p-Toluensulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (1.0 g, 2.4 mmoles) was dissolved in dimethyl sulfoxide (10 ml), and sodium cyanide (0.3 g, 6 mmoles) was added, followed by stirring for 18 hours. To the reaction mixture was added water (100 ml) and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate-isopropyl ether (1:1) as the developing solvent to give (E)-1-cyano-7-phenyl-7-(3-pyridyl)-6-heptene (0.5 g, 76%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(C1NC=CN=1)(C1NC=CN=1)=O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc2ncoc2c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: O=C(c1ccc2ncoc2c1)N1CCCCC1

Procedure:
The amide is prepared by coupling 1,3-benzoxazol-6-carboxylic acid with piperidine by activation of the acid with carbonyl diimidazole as described for the preparation of Invention Compound V. Dilution of the reaction solution with more CH2Cl2 causes the product to precipitate. Purification is achieved by chromatography on silica gel. EMIS m/z=230 (parent), 229, 146 (base), and 118. 1H NMR δ 1.55 (br m, 4), 1.70 (br, 2), 3.4 (br, 2), 3.75 (br, 2), 7.48 (dd, 1, J=8.29, 1.22 Hz), 7.62 (d, 1, J=8.44 Hz), 7.84 (d, 1, J=1.00 Hz), and 8.15 ppm (s, 1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[NH:15][C:14](=O)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(Nc2nccc(=O)[nH]2)c1
Product: Cc1cc(C)cc(Nc2nccc(Cl)n2)c1
Temperature: 100 °C

Procedure:
2-(3,5-Dimethyl-phenylamino)-3H-pyrimidin-4-one (2.01 g, 9.34 mmol) was dissolved in POCl3 (8.70 ml, 93.4 mmol) and the mixture was heated to 100° C. in a round bottom flask equipped with a reflux condenser and a drying tube. After 5 hours the reaction was cooled to room temperature and concentrated in vacuo. The residue was quenched by the addition of sat NaHCO3 (aq) and was extracted 3× with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (dissolved sample in DCM, eluted with 85:15 hexane/EtOAc) to afford 4-chloro-N-(3,5-dimethylphenyl)pyrimidin-2-amine (4-3).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:13]=1.B1([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C2CCCC1CCC2>C1COCC1.O.C1COCC1.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>[CH2:36]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
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: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cc3ccccc3)cn2)CC1

Procedure:
A mixture of K2CO3 (6 gm, 43.5 mmol, 3 equiv) and Pd(PPh3)4 (1 gm, 0.86 mmol) were stirred at room temperature in 20 mL THF/water (1:1) for 30 minutes. Tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5 gm, 14.5 mmol, 1 equiv) was then added with B-benzyl-9-BBN (2 equiv, 49 ml of a 0.5 M solution in THF). The resulting mixture was heated with stirring under argon atmosphere in an oil bath adjusted at 100-110° C. until the reaction had reached completion, as monitored by TLC. The reaction mixture was extracted with CHCl3 (3×200 mL). The combined organic layers were then dried with anhydrous Na2SO4. Chloroform was evaporated under reduced pressure and the residue was purified using flash column chromatography (initially with 4:1 hexane/ethyl acetate and finally with 1:1 hexane/ethyl acetate). Tert-butyl 4-(5-benzylpyrimidin-2-yl)piperazine-1-carboxylate was obtained as a yellow solid (3.8 gm, 74% yield); mp: 121-123° C. 1H-NMR (DMSO-d6): δ 1.47 (s, 9H), 3.47 (t, J=4.68 Hz, 4H), 3.75 (t, J=4.68 Hz, 4H), 3.78 (s, 2H), 7.14-7.29 (m, 5H), 8.16 (s, 2H). 13C-NMR (DMSO-d6): δ 28.4, 35.61, 43.70, 79.92, 122.29, 126.41, 128.51, 128.66, 140.02, 154.84, 157.87, 160.69. MS: calcd 354.21 for C20H26N4O2 [M]+. found, 355.21 [M+1]+. b) 3.7 gm of the obtained product from step a was then deprotected using HCl/MeOH as described above in the preparation of 1. As a result, compound 2 was obtained as a pale yellow solid (2.2 gm, 80% yield); mp: 108-110° C. 1H-NMR (DMSO-d6): δ 1.89 (s, 1H), 2.93 (t, J=4.8 Hz, 4H), 3.76 (t, J=4.8 Hz, 4H), 3.79 (s, 2H), 7.17-7.29 (m, 5H), 8.18 (s, 2H). 13C-NMR (DMSO-d6): δ 35.59, 44.96, 45.92, 121.79, 126.34, 128.48, 128.6, 140.1, 157.8, 160.5. MS: calcd 254.15 for C15H18N4 [M]+. found, 255.15 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CCOc1ccc(F)cc1B(O)O
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and commercially available 2-ethoxy-5-fluoro-phenyl-boronic acid the title compound is obtained as pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(OC([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][O:14][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH2:22])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccccc1OCC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 236.4 %

Procedure:
To a solution of 1-(4-pyridyl)piperidin-4-ylmethanol (357 mg) and 2-tert-butyloxycarbonylaminophenol (328 mg) in tetrahydrofuran (15 ml) was added triphenylphosphine (447 mg) followed by diethyl azodicarboxylate (0.27 ml). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to a gum which was purified by column chromatography on silica eluting with methanol/dichloromethane (10:90) to give the tert-butyloxycarbonyl protected derivative of 2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline (1.05 g);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([N:34]=[C:35]=[O:36])([CH3:33])[CH3:32]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][C:35]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:36])([CH3:24])[CH3:25])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)N
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
2-(7-Benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine (1.88 g, 4.65 mmol) and dichloromethane (50 mL) were combined and cooled to 0° C. Isopropyl isocyanate (0.50 mL, 5.11 mmol) was added and the reaction was stirred for 30 minutes. The cooling bath was removed and the reaction was stirred overnight. The volatiles were removed under reduced pressure to give a brown solid. The solid was purified by flash column chromatography on silica gel (eluting with 6% methanol in dichloromethane) to yield 1.96 g of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea as a cream colored solid.
Reaction SMILES: CNCCN(C)C.[Li].[CH2:9]([Li])[CH2:10][CH2:11]C.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cu](C#N)C#N.C(Br)C=C>O1CCCC1>[CH2:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]=[O:21])[CH:10]=[CH2:9]
Reactant: [Li]CCCC
Reactant: O=Cc1ccccc1
Agent: N#C[Cu]C#N
Agent: CNCCN(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1ccccc1C=O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a stirred solution of 20.2 g (198.0mmol) of lithium trimethylethylenediamine in 500 ml of dry tetrahydrofuran (THF) under nitrogen at -30° C. was added 79 ml (198.0 mmol) of 2.5M butyllithium (nBuLi) in hexanes dropwise over 15 minutes. The solution became pale yellow and was stirred at -30° C. for 30 minutes. To this solution was added 20.0 g (188.5 mmol) of benzaldehyde dropwise over 30 minutes. The solution became cloudy as the complex was formed and was stirred 1 hour. To this slurry was added 113 ml (283 mmol) of 2.5M nBuLi hexanes dropwise over 1 hour. This slurry was stirred for 24 hours and gradually cleared. The solution was then transferred via cannula into a slurry of 50.6 g (565 mmol) of copper cyanide in 500 ml of dry tetrahydrofuran under nitrogen at -78° C. The mixture was allowed to warm to -30° C. and stirred for 30 minutes. To this slurry was added 49 ml (565 mmol) of allyl bromide. The mixture instantly darkened upon addition. The reaction was quenched after 30 minutes with 3% aqueous ammonium hydroxide and saturated ammonium chloride. This biphasic solution was stirred overnight to ensure complete copper removal. The aqueous layer was extracted repetitively with ether to remove all product. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by distillation at 62° C. at 0.03 torr affording 15.32 g (56%) of o-allylbenzaldehyde. 1H NMR: ε3.82 (d; 2H, J=6.17 Hz, CH2CH=CH2), 4.99 (d; 1H, J=17.1 Hz, one of CH=CH2), 5.09 (d; 1H, J=10.2 Hz, one of CH=CH2), 6.04 (m, 1H CH=CH2), 7.3 (d; 1H, J=7.8 Hz, aryl H), 7.40 (dd; 1H, J=7.6 Hz, aryl H), 7.54 (dd; 1H, J=7.4 Hz, 7.8 Hz, aryl H), 7.86 (d; 1H, J=7.6 Hz, aryl H), 10.26 (s; 1H aldehyde H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Br.O>O1CCCC1>[CH3:21][O:22][CH2:23][N:11]([CH2:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12](=[O:15])[O:13][CH3:14]
Reactant: COCBr
Reactant: COC(=O)NCc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCN(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Reaction time: 8 h
Yield: 76.1 %

Procedure:
1.00 g of methyl N-(3-phenylbenzyl)carbamate in tetrahydrofuran (20 ml) was stirred together with 0.22 g of 60% sodium hydride at room temperature for 30 minutes. 0.78 g of methoxymethyl bromide was added dropwise at room temperature, and the resulting solution was stirred overnight. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.90 g of methyl N-methoxymethyl-N-(3-phenylbenzyl)carbamate as a pale yellow transparent viscous liquid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10](Cl)[C:11]([CH3:13])=[CH2:12])(=[O:3])[CH3:2].C([N+]([O-:23])(CC)CC)C.O1CCOCC1>[Cu]Cl.O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH:12]=[O:23])(=[O:3])[CH3:2]
Reactant: CC[N+]([O-])(CC)CC
Reactant: C=C(C)C(Cl)CCC(C)=CCOC(C)=O
Agent: Cl[Cu]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCC=C(C)CCC=C(C)C=O
Reaction time: 10 h
Yield: 61.2 %

Procedure:
2.36 g (9.41 mmols) of 6-chloro-3,7-dimethyl-2,7-octadienyl acetate (purity: 92%), 92 mg (0.93 mmols) of copper(I) chloride and 3.65 g (29.6 mmols) of triethylamine N-oxide (purity: 95%) were placed in a flask, to which 5 ml of dioxane was added, followed by agitation of the mixture at 50° C. for 10 hours. 40 ml of water was added to the reaction mixture, after which it was extracted twice each with 70 ml of diethyl ether. The resultant extract was successively washed with each 20 ml of 3% sulfuric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated ammonium chloride aqueous solution, and dried with magnesium sulfate. The solvent was distilled off from the solution and the resultant residue was purified by column chromatography using silica gel [eluent: ethyl acetate/hexane (ratio by volume)=1/9-1/3], thereby obtaining 1.21 g of 8-acetoxy-2,6-dimethyl-2,6-octadienal. Yield: 61%. The results of the instrumental analysis were found to be substantially coincident with those obtained in Example 9(b).
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](O)=O)[CH2:14][CH2:13]1)=[O:11].CN(C=O)C>C(Cl)Cl>[C:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([C:10]([O:9][CH3:8])=[O:11])[CH2:13][CH2:14]1)#[N:5]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Chlorosulfonyl isocyanate (1.0 mL, 0.012 mol) was added to a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.00 g, 0.0107 mol) in DCM cooled to 0° C. The resulting solution was heated at reflux for 15 minutes and then cooled 0° C. and treated dropwise with DMF. The mixture was stirred at room temperature overnight then poured onto ice water and the organic phase separated and washed with a saturated solution of sodium bicarbonate. The solvent was removed in vacuo and the crude material was taken up in ethyl acetate, washed with 1N aq. NaOH (10 mL) and the ethyl acetate removed in vacua. The resulting crude product was used in subsequent steps without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.70 (4 H, m), 2.01-2.18 (4 H, m), 2.24-2.54 (2 H, m) and 3.68 (3 H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=1>>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1
Reactant: COCc1csc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Fc1cncc(Br)c1
Product: COCc1csc(NC(=O)c2nc(C)ccc2Nc2cncc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methoxymethyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 3-Bromo-5-fluoropyridine instead of 3-bromopyridine to yield the final compound as a light yellow solid, MS (ISP): m/e=374.3 (M+H+).