Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11]([NH:14][C:15]1[S:16][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][N:19]=1)(=[O:13])[CH3:12].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:20]([C:17]1[S:16][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[N:19][CH:18]=1)(=[O:21])=[O:22])=[O:10]
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(NC(C)=O)s1
Temperature: 25 °C

Procedure:
A mixture of L-proline methylester hydrochloride (15 mmol), 2-acetylamino-thiazole-5-sulfonyl chloride (12 mmol) (prepared as described in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (35 mmol) in DCM (50 mL) was stirred at room temperature over night. Addition of water and 1N HCl to pH 2. Isolation of the organic phase which was washed with water and brine, dried and concentrated to give (S)-1-(2-acetylamino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as brown crystals. These were suspended in EtOH (15 mL) and added 4N HCl in dioxane (15 mL) and heated for 3H at 80° C. and then cooled to room temperature. Addition of aqueous NaHCO3 to neutral pH. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo to give (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as colourless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[H-].[Na+].S([O:20][CH3:21])(OC)(=O)=O.[CH3:22]N(C=O)C>>[CH3:22][O:11][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:20][CH3:21])[CH:1]=2)[CH:6]=1
Reactant: CN(C)C=O
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cc(OC)ccc2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
Naphthalene-2,6-diol (16.0 g, 0.1 mol) and NaH (6.0 g, 0.25 mol) was combined together in a 500 mL flask under argon. The mixture was cooled to −78° C. before the addition of anhydrous DMF (200 mL) by injection. The mixture emitted a significant amount o gas. Stirring was continued at room temperature for 2 hours. Dimethyl sulfate (31.5 g, 0.25 mol) was added dropwise after the mixture was cooled to −78° C. again. The reaction was continued overnight at room temperature before 200 mL of anhydrous DMF was added. 2,6-Dimethoxy-naphthalene (16.0 g, ˜85.1% yield) was collected as a white powder by filtration and washed with water and methanol before drying under vacuum. 1H NMR (CDCl3, 500 MHz): δ 7.67 (d, 2H, J=8.5 Hz), δ 7.17 (d×d, 2H, J=8.5 Hz×2.5 Hz), δ 7.13 (d, 2H, J=2.5 Hz), δ 7.13 (d, 2H, J=2.5 Hz), δ 3.93 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[NH2:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: CC1(C)CC(c2ccccc2Br)Nc2ccc(C#N)cc21
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1ccccc1C1CC(C)(C)c2cc(C#N)ccc2N1)C(=O)O
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of 2-(2-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (341 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (235 mg, 4.0 mmol) and potassium carbonate (420 mg, 3.0 mmol) in dimethyl sulfoxide (4.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (120.1 mg, 33.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 364.2.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[C:3]#N.C[OH:15].CC[O:18][CH2:19]C>>[CH3:19][O:18][C:3](=[O:15])[CH:2]([OH:1])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: CCOCC
Reactant: CO
Reactant: N#CC(O)c1cccc([N+](=O)[O-])c1
Product: COC(=O)C(O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 76 %

Procedure:
To a solution of α-hydroxy-3-nitrobenzeneacetonitrile (27.8 g, 156.1 mmol) in 500 mL of ether was added methanol (7.6 mL, 187.3 mmol). Hydrogen chloride gas was bubbled into the solution until it was saturated. The solution changed to a heterogeneous solution. The solution was cooled to 0° C. and filtered to collect the solid. The filtrate was extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated to afford 25.0 g (76%) of 2-hydroxy-2-(3-nitrophenyl)ethanoic acid methyl ester, a compound of formula (S), as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19]3([C:24](O)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:11]2[C:10]([C:27]([O:29][CH3:30])=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:41]2[CH:42]=[CH:43][CH:44]=[N:45][C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:40]1([NH:45][C:24]([C:19]2([NH:18][CH2:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:11]=34)[CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:25])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CNC3(C(=O)O)CCCC3)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CNC3(C(=O)NC4CCCC4)CCCC3)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To 1-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)cyclopentanecarboxylic acid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C26H36N4O5, 485; found, 485.4.
Reaction SMILES: C(OC(NC(C1NC(C2C=CC=C3C=2N=C(NCC(F)(F)F)C(C)=N3)=CC=1C(OCC)=O)C)=O)(C)(C)C.Br[CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=[O:41].[C:59]([O:63][C:64]([NH:66][C@H:67]([CH3:76])[C:68](=[O:75])[CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:65])([CH3:62])([CH3:61])[CH3:60].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCO.CC(O)=O>[C:59]([O:63][C:64]([NH:66][CH:67]([CH3:76])[C:68](=[O:75])[CH:69]([CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=[O:41])[C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:65])([CH3:61])([CH3:62])[CH3:60]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC(C)(C)C
Reactant: CCOC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(C)NC(=O)OC(C)(C)C
Yield: 66 %

Procedure:
This compound (245 mg, 46% yield) as a yellow foam was prepared according to the procedures described for 293b, using 2-bromo-1-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (605) (366 mg, 1.03 mmol), (R)-ethyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (322 mg, 1.24 mmol) and K2CO3 (357 mg, 2.58 mmol) in DMF (3.5 mL), followed by the subsequent treatment of the resulting ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (297a) (360 mg, 0.68 mmol, 65% yield, m/z 533.2 (ESI, +ve) (M+H)+) with NH4OAc (637 mg, 8.27 mmol) in 2 mL of EtOH and AcOH (1 mL). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (dd, J=9.00, 5.67 Hz, 1H), 7.32-7.36 (m, 1H), 7.20 (dd, J=11.54, 9.00 Hz, 1H), 6.97 (d, J=9.98 Hz, 1H), 5.09-5.21 (m, 1H), 4.96 (s, 1H), 4.36 (qd, J=7.14, 2.05 Hz, 2H), 2.54 (s, 3H), 1.72 (s, 9H), 1.53 (d, J=6.85 Hz, 3H), 1.36-1.46 (m, 12H). 19F NMR (376 MHz, CDCl3) δ ppm −107.07 (s, 1F). m/z 514.2 (ESI, +ve) (M+H)+.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>C(Cl)(Cl)Cl>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11]
Reactant: OCCNCCO
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Solvent: ClC(Cl)Cl
Product: CC1CCC(C(C)C)C(C(=O)N(CCO)CCO)C1
Reaction time: 2 h

Procedure:
A solution of p-menth-3-oyl chloride (4.0 g., 0.020 moles) in chloroform (30 ml.) was added dropwise to a stirred solution of diethanolamine (4.2 g., 0.044 moles) in chloroform (50 ml.). The reaction mixture goes cloudy and a yellow oil separates out. After 2 hours at room temperature, the yellow oil (upper layer) was separated. Infra red spectographic analysis indicated this to be (HOCH2CH2)2NH2+Cl-. Removal of the chloroform left a viscous oil (6 g.). Thin layer chromatography (CHCl3 and CHCl3 +10% CH3OH) indicated it to consist of one major component and a minor component of larger Rf value. This was separated by column chromatography on neutral alumina (activity 1). Eluting with chloroform (200 ml.) removed the minor component and the major product was eluted from the column with chloroform+5% methanol. The major component was shown to be N,N-bis(2-hydroxyethyl)-p-menthane-3-carboxamide.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[CH:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH2:29][S:30][CH3:31].CN1C(=O)CCC1>O>[CH3:31][S:30][CH2:29][CH2:28][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[N:12][N:11]2[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=1
Reactant: CCCSc1nccc(-n2ncc3c(O)cccc32)n1
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCSc1nccc(-n2ncc3c(OCCSC)cccc32)n1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
1-(2-Propylsulfanyl-pyrimidin-4-yl)-1H-indazol-4-ol (600 mg), potassium carbonate (1.104 g) and 1-chloro-2-methylsulfanyl-ethane 401.9 mg) were added to NMP (6 mL), and the mixture was heated to 80° C. for three hours. The mixture was cooled, diluted with water and filtered. The collected solid was washed with water and dried under reduced pressure to give 705 mg of 4-(2-Methylsulfanyl-ethoxy)-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][C:21]([OH:23])=O)([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:39][N:40]([CH3:42])[NH2:41]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([C:17](=[O:18])[N:41]([N:40]([CH3:42])[CH3:39])[C:21](=[O:23])[CH2:20]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)N
Reactant: O=C(O)CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CN(C)N1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-benzyloxycarbonyl-4-carboxy-piperidin-4-yl)acetic acid (1.28 g) in dimethylformamide (10 ml) was added dicyclohexylcarbodiimide (0.82 g), and this was followed by 30 minutes of stirring at room temperature. 1,1-Dimethylhydrazine (0.62 ml) was then added, and this was also followed by 30 minutes of stirring at room temperature. The solvent was then evaporated under reduced pressure. To the resulting residual oily compound were added acetic anhydride (10 ml) and then anhydrous sodium acetate (0.33 g), and this was followed by stirring at 100° C. for 30 minutes. The solvents were then evaporated under reduced pressure. The resulting residual substance was dissolved in ethyl acetate (50 ml), and it was washed with a saturated aqueous solution of sodium hydrogen-carbonate and then with water. The organic layer was then dried with anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure to yield an oily substance. This oily substance was separated by silica gel column chromatography (eluent; methanol-dichloromethane=1:19 (v/v)), and the solvent for the solution containing the desired product was evaporated to obtain 0.71 g of a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[N:11]=[CH:12][N:13]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(Oc2c[nH]cn2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
To a cold (0° C.) solution of 4-(4-cyanophenyloxy)-imidazole (155 mg, 0.84 mmol) and triethylanine (0.129 mL, 0.92 mmol) in DMF (1 mL) was added trityl chloride (245 mg, 0.88 mmol). The resultant mixture was stirred at ambient temperature for 5 days. The product mixture was concentrated onto silica gel, chromatographed (Silica gel, 1:9 acetone in CHCl3) to afford the title compound as a white powder.
Reaction SMILES: ClCC([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12]2)=[CH:7][CH:6]=1)=O.[Cl:21]C1C=C(C=CC=1)C(OO)=O.F[C:33](F)(F)[C:34]([OH:36])=[O:35].[OH-].[NH4+]>C(Cl)Cl>[Cl:21][CH2:33][C:34]([O:36][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:12]2)=[CH:7][CH:6]=1)=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)Oc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 0 °C
Reaction time: 96 h
Yield: 48 %

Procedure:
Compound (5) (8.4 g, 27 mmol) was dissolved in anhydrous CH2Cl2 (58 ml) and 3-chloroperoxybenzoic acid (mCPBA) (12.3 g) was added in one portion. The suspension was cooled to 0° C., and trifluoroacetic acid (2.0 ml) was added dropwise over 5-10 min. The reaction flask was protected from light, and the mixture was stirred for 3-5 days at room temperature, poured onto water (100 ml), and neutralized with ammonium hydroxide solution. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (60 ml). After purification on a silica gel column (n-hexane/EtOAc=2:1) the title compound was obtained as a yellow oil (6) (4.24 g, 48%). TLC Rf=0.5 (n-hexane/EtOAc=3:1). 1H NMR (300 MHz, CDCl3) (NMR, Varian Gemini): δ 7.20 (t, J=7 Hz, 1H, Aryl H), 7.01-6.93 (m, 2H, 2H, Aryl Ha), 4.75 (s, 2H, Ph-CH2—N), 4.33 (s, 2H, CO—CH2—), 3.90-3.82 (m, 2H, M—CH2—), 2.97-2.92 (m, 2H, Ph-CH2—). Fast Atom Bombardment Mass Spectrometry (FABMS) m/z: 322 (M+1) (C13H11NO3ClF3).
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH2:9][C:10](Br)=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18]>O1CCCC1>[Br:8][CH2:9][C:10]([NH:18][C:17]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CBr)cc(OC)c1OC
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Add triethylamine (1.53 mL, 11.0 mmol) and bromoacetyl bromide (0.87 mL, 10.0 mmol) dropwise to a 0° C. solution of 3,4,5-trimethoxy-aniline (1.74 g, 9.5 mmol) in tetrahydrofuran (30 mL). Allow the reaction to warm to room temperature overnight. Filter the mixture, wash with tetrahydrofuran, and concentrate. Dissolve the resulting brown solid in chloroform, wash with 1N HCl, saturated aqueous sodium bicarbonate solution, brine; dry over magnesium sulfate; and concentrated. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 2.50 g of the title compound as an orange solid, 87% yield. 1H NMR: consistent with structure. MS (ion spray) 304 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:2].O.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24][CH:23]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(CCCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Yield: 92 %

Procedure:
A solution of 24-5 (650 mg, 1.60 mmol), water (100 mg), ammonium formate (512 mg, 8.12 mmol), and 10% palladium on carbon (75 mg) in ethanol (40 mL) was heated to 90° C. for 1 hour. The reaction mixture was filtered through celite and the filtrate evaporated in vacuo to afford the title compound 24-6 (600 mg). The crude product was used directly in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:38]([OH:45])(=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42].O>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:36][CH:37]=2)[CH2:4][CH2:3]1.[C:38]([O-:45])(=[O:44])[CH2:39][CH2:40][C:41]([O-:43])=[O:42]
Reactant: O=C(O)CCC(=O)O
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: CCO
Solvent: O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 90 °C

Procedure:
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide (4.94 g, 10 mmol) is added to a solution of butanedioic acid (succinic acid; Fluka, Buchs, Switzerland; 1.18 g, 10 mmol) is added to a solution of in ethanol (25 mL). The mixture is heated to 90° C., treated with water (0.2 g) and filtered. Upon cooling, the product crystallizes and is filtered and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, succinate as a pale-yellow crystalline solid, having the following analytical properties: Analysis found: C, 64.19; H, 6.11; N, 15.82%; H2O, 0.87%. Calculated for C33H37N7O5-0.30 H2O: C, 64.23; H, 6.14; N, 15.89%; H2O, 0.88%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-:16].[K+].[K+]>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([O:16][CH2:11][CH2:12][CH2:13][Cl:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCNCC1
Reactant: ClCCCBr
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(OCCCCl)CC1
Yield: 38.1 %

Procedure:
A mixture of 1-acetylpiperazine (1.0 g, 7.8 mmol), 1-bromo-3-chloropropane (772 μl, 7.8 mmol) and potassium carbonate (2.7 g, 19.5 mmol) in acetonitrile (150 ml) was heated at reflux for 2 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 1-acetyl-4-(3-chloropropoxy)piperazine (656 mg, 41%) as a colourless oil.
Reaction SMILES: C[C@H](CCCC(C)C)C[CH2:4][CH2:5][C@H:6]([CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[O:12])C.[O-]Cl.[Na+].CC(O)CCCCCC>C(O)(=O)C>[CH3:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:6][CH2:5][CH3:4]
Reactant: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCCCCCC(C)O
Solvent: CC(=O)O
Product: CCCCCCC(C)=O
Yield: 95 %

Procedure:
Subsequent hydrogenation (H2 /Pd-C) yields the same saturated C-18 alcohol: ##STR22## Other methods used to oxidize 2° alcohol 9 "phytone" include: (a) aqueous NaOCl (bleach) in acetic acid; such conditions give >95% yield of 2-octanone from 2-octanol. See: J. Org. Chem., 45, 2030 (1980).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1.[OH-].[Na+]>O>[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH2:5])[C:10]=2[N:24]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(N)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Temperature: 160 °C

Procedure:
Ammonium acetate (25 g) and 2,6,7-trimethyl-4-phenoxy-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridine (2.50 g, 5.80 mmol) were combined and heated at 160° C. in a sealed tube for 2 days. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). Sodium hydroxide (15%) was added and the mixture was extracted with chloroform (2×150 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2% methanol in chloroform) followed by recrystallization from methanol/dichloromethane/hexanes to provide 2,6,7-trimethyl-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridin-4-amine as an off white powder, m.p. 181–183° C.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]2=[N:4][C:3]=1[CH:13]([CH3:15])[CH3:14].[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]([OH:36])[C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]4=[N:4][C:3]=3[CH:13]([CH3:15])[CH3:14])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]
Reactant: COc1cccn2c(I)c(C(C)C)nc12
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: COc1cccn2c(C(O)c3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C(C)C)nc12
Yield: 34.6 %

Procedure:
[step 3] Using 3-iodo-2-isopropyl-8-methoxyimidazo[1,2-a]pyridine (600 mg, 1.90 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (278 mg, 0.95 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[hydroxy(2-isopropyl-8-methoxyimidazo[1,2-a]pyridin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (159 mg, 35%) was obtained.