Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:30]([C:32](=[O:43])[CH2:33][C:34]2[C:39]3[CH:40]=[CH:41][O:42][C:38]=3[CH:37]=[CH:36][CH:35]=2)[CH3:31])[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][Si](C(C)(C)C)(C)C)[CH2:18]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6](=[O:44])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:30]([C:32](=[O:43])[CH2:33][C:34]2[C:39]3[CH:40]=[CH:41][O:42][C:38]=3[CH:37]=[CH:36][CH:35]=2)[CH3:31])[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)Cc1cccc2occc12)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C(=O)Cc1cccc2occc12)C(CC1CCC(O)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of Example 36 (0.90 g, 1.45 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) (1.45 mL, 1.45 mmol). The reaction was stirred at room temperature under argon for 2.5 hours, then half the solvent was removed in vacuo. After stirring for a further 30 minutes, the reaction was poured into water (15 mL) and brine (70 mL), and extracted with dichloromethane (3×70 mL). The organics were dried (MgSO4) and the solvent removed in vacuo. Column chromatography (ethyl acetate:methanol 4:1) gave the product as a clear oil, 1.32 mmol, 90%.
Reaction SMILES: COC1C=CC(NC2OC3C=C(C(C)C#N)C=CC=3N=2)=CC=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][C:29]=1[OH:30].C(O[C:41]([S-])=[S:42])C.[K+].C(O)C>O>[S:42]=[C:41]1[NH:23][C:24]2[CH:25]=[C:26]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][C:29]=2[O:30]1
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: COc1ccc(Nc2nc3ccc(C(C)C#N)cc3o2)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1

Procedure:
2-[2-(4-methoxyanilino)-6-benzoxazolyl]propionitrile (i) A stirred mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (8.4 g.), potassium ethylxanthate (6.33 g.), ethanol (38 ml.) and water (6.5 ml.) was heated under reflux for 4 hours. The solution was evaporated to half volume and diluted with water (65 ml.). The mixture was acidified with 2N-hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then dried with anhydrous sodium sulphate, and evaporated to give ethyl 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl)propionate as an oil. Dry chlorine was passed into a solution of the thione (9 g.) in freshly dried and distilled chloroform (150 ml.) with stirring for 4 hours. The solution was then washed with water, N-sodium hydroxide solution, then water (3x). The dried (Na2SO4) organic solution was evaporated to yield ethyl 2-(2-chloro-5-benzoxazolyl]propionate as a brown oil which was shown to be a single compound by thin layer chromatography. (j) A mixture of the 2-chloro compound (12.5 g.) of Example 3 (i) and p-chloroaniline (25 g.) was heated on a steam bath for one hour. The reaction mixture was dissolved in chloroform and the solution was washed with 2N hydrochloric acid (2x), water, 2N sodium hydroxide solution (2x) and water (3x). The chloroform solution was stirred with charcoal and anhydrous sodium sulphate, then filtered and evaporated. The residue was purified using prep t.l.c. plates to give ethyl-2-[2-(4-chloroanilino) -5-benzoxazolyl]propionate, mpt 135°-7° C., which was characterised by ir uv and nmr spectroscopy and by micro analysis which gave C 62.45% H 5.11% N 7.97% C18H17ClN3O2 requires C 62.70% H 4.93% N 8.13%
Reaction SMILES: [C:1]([C:3]1[C:4]([C:29](O)=[O:30])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:21][CH2:20][C:19]4[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=4[NH:17][C:16]3=[O:28])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:32]1([C:29]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[CH2:21][CH2:20][C:19]5[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=5[NH:17][C:16]4=[O:28])[CH2:11][CH2:10]3)[CH:5]=2)=[O:30])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)c(C#N)cn3)CC1)C(=O)N2
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ccccc54)c(C#N)cn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.02 g (0.48 mmol) 5′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid, 57 mg (0.48 mmol) 2,3-dihydro-1H-indole and 0.21 mL (1.5 mmol) TEA were placed in 3 mL DMF. 0.17 g (0.52 mmol) TBTU were added. The reaction mixture was stirred overnight at RT and then purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C@@H:16]([NH:27][C:28](=O)OC(C)(C)C)[CH2:17][C:18]2C3C(=CC=CC=3)NC=2)[C:3]=1[C:35]([NH:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1)=[O:36].FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O>C(Cl)Cl>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:13])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C@@H:16]2[CH2:17][CH2:18][CH2:28][NH:27]2)[C:3]=1[C:35]([NH:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nccs1)c1c([C@@H]2CCCN2)nc2c(C(F)(F)F)cccc2c1O
Yield: 150.1 %

Procedure:
Using the procedure of Example 14, 7.8 g of the product of Example 11, 80 ml of methylene chloride, and 40 ml of trifluoroacetic acid were reacted to obtain 8.0 g of 4-hydroxy-2-[(2S) 2-pyrrolidinyl]-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide in the form of its trifluoroacetate melting at 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)N.C(O)(=O)C.N([O-])=O.[Na+].[I-:20].[K+]>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([I:20])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: [I-]
Reactant: COc1cc(N)cc(OC)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(I)cc(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
3,5-Dimethoxyaniline (1.0 g) is suspended in a mixture of hydrochloric acid (3 ml), acetic acid (2 ml) and water (5 ml), and thereto is added dropwise a solution of sodium nitrite (473 mg) in water (5 ml) under ice-cooling over a period of 15 minutes. Ten minutes thereafter, to the mixture is added a solution of potassium iodide (1.62 g) in water (5 ml), and the mixture is warmed to 80° C., and stirred for one hour. The reaction mixture is extracted with diethyl ether, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate), and is recrystallized from ethyl acetate/hexane to give 3,5-dimethoxyiodobenzene (1.05 g), m.p. 73-74° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]2[CH:16]=[CH:15][C:14]([O:17]CC3C=CC(OC)=CC=3)=[CH:13][C:12]2=[O:27])[CH2:10][CH2:9]1>>[CH:8]1([N:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]2=[O:27])[CH2:10][CH2:9]1
Reactant: COc1ccc(COc2ccn(C3CC3)c(=O)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(O)ccn1C1CC1
Temperature: 25 °C

Procedure:
Trifluoroacetic acid (1 mL) was added to a flask charged with a stir bar and 1-cyclopropyl-4-(4-methoxy-benzyloxy)-1H-pyridin-2-one (0.17 g) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 1.5 h and at ambient temperature for another 4.5 h. Then, the solution was concentrated under reduced pressure and the residue was triturated with tert-butyl methyl ether and dried to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)C4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=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.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](C(N)=O)C1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of cis-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (131 mg, 0.367 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (146 mg, 0.441 mmol), Na2CO3 (97.2 mg, 0.917 mmol), Pd(PPh3)4 (25.5 mg, 0.0221 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 18 h. To the cooled reaction solution was added water (15 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (2×15 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz): δ=2.60-2.70 (m, 4H), 2.84-2.90 (m, 1H), 5.14-5.23 (quintet, 1H, J=8.7 Hz), 6.31 (brs, 2H), 6.92 (s, 1H), 7.40 (s, 1H), 7.50-7.62 (m, 3H), 7.78-7.82 (m, 2H), 8.08-8.10 (d, 1H, J=8.4 Hz), 8.15-8.23 (m, 3H), 8.30-8.37 (m, 2H), 8.49-8.51 (d, 1H, J=8.4 Hz). MS (ES+): 435.0 [MH+]. HPLC: tR=2.4 min (polar—5 min).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[CH2:10]=[C:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1>C(Cl)Cl>[CH2:10]=[C:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1
Reactant: C=C1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: ClCCl
Product: C=C1CCC(C=O)CC1
Temperature: 60 °C

Procedure:
To pydridinium dichromate (223 g., 0.59 mole) in 1 liter CH2Cl2, stirring under N2, was added dropwise 4-methylene-1-cyclohexanemethanol (50 g., 0.40 mole) in 75 ml. CH2Cl2 over a few minutes. After stirring for 21 hours at room temperature, the reaction mixture was heated at 60° C. for 24 hours. The reaction mixture was cooled, diluted with 400 ml. ether and decanted from solids. The solids were slurried with 400 ml. of fresh ether and decanted. The combined organic decants were filtered over fluorasil and diatomaceous earth and the filtrate concentrated in vacuo to an oil (41 g.) and distilled to yield title product, 13.6 g., b.p. 82°-90°/15-20 mm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:17])[CH3:16])(=[O:12])=[O:11].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:16])[CH3:17])(=[O:11])=[O:12])(=[O:37])[CH3:36]
Reactant: CC(C)(CCS(=O)(=O)CCOCCOCCO)NC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A solution of benzyl 4-(2-(2-(2-hydroxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (451 mg, 1.08 mmol) in dichloromethane (5 ml) was cooled to 0° C. Pyridine (200 μl, 2.48 mmol), then acetic anhydride (150 μl, 1.59 mmol) were added. The solution was stirred for 3 hours, and another portion of pyridine (200 μl, 2.48 mmol) then acetic anhydride (150 μl, 1.59 mmol) were added. The solution was stirred for an additional 20 hours, concentrated in vacuo, and the residue purified by flash chromatography (20% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (440.2 mg, 0.959 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 6H), 2.04 (s, 3H), 2.15-2.20 (m, 2H), 3.09-3.16 (m, 4H), 3.54-3.61 (m, 6H), 3.85 (t, J=5.6 Hz, 2H), 4.16 (m, 2H), 5.02 (s, 3H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 460 [M+H]+, 482 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:9][C:10](O)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1c(F)cc(F)cc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(F)cc(F)cc1CCO
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a solution of 2-(3,5-difluoro-2-methoxyphenyl)acetic acid (1 g, 4.95 mmol) in THF (20 mL) at 0° C. was added 1M LAH (9.89 mL, 9.89 mmol) in THF and the resulting mixture was heated at 60° C. for 3 h. Mixture was then cooled and quenched with dropwise addition of water (0.5 mL), 1N NaOH (0.5 mL), and then 1 mL H2O. After stirring for 15 min. the mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was dried under high vacuum to afford 2-(3,5-difluoro-2-methoxyphenyl)ethanol (700 mg, 3.72 mmol, 75% yield) as a clear viscous oil. Used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 6.83-6.72 (m, 2H), 3.90 (s, 3H), 3.87 (q, J=5.7 Hz, 2H), 2.92 (t, J=6.5 Hz, 2H), 1.73-1.64 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16](Cl)[C:15]=1[N+:25]([O-:27])=[O:26])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].[NH3:29]>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[N:5]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([NH2:29])[C:15]=1[N+:25]([O-:27])=[O:26])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2-Chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (54 mg, 0.13 mmol) was dissolved in THF (1 ml) and transferred to a 10 ml reactivial. 880 Ammonia (1 ml) was added, the vessel sealed and the mixture stirred vigorously at ambient temperature for 16 h. The solution was concentrated in vacuo to give a crude oil which was purified directly by column chromatography on silica, eluting with 100% EtOAc to give 27 mg of the title compound as a yellow residue.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH2:56][C:57]1[O:61][N:60]=[C:59]([CH:62]([CH3:64])[CH3:63])[CH:58]=1>CN(C=O)C>[CH:62]([C:59]1[CH:58]=[C:57]([CH2:56][NH:55][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[O:61][N:60]=1)([CH3:64])[CH3:63]
Reactant: CC(C)c1cc(CN)on1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2cc(C(C)C)no2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 5-aminomethyl-3-isopropylisoxazole (1 M solution in trifluoroacetic acid, 354 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (112 mg, 81%) which was obtained as a colourless gum. MS: m/e=433.3 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.Cl>CCO>[CH:15]([C:13]1[N:14]=[C:10]([CH2:9][OH:8])[N:11]([CH2:27][C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[C:12]=1[S:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)([CH3:17])[CH3:16]
Reactant: COc1cccc(Sc2c(C(C)C)nc(COCc3ccccc3)n2Cc2ccncc2)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(Sc2c(C(C)C)nc(CO)n2Cc2ccncc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of amine 37 (101 mg, 0.220 mmol) in EtOH (5 mL) was added conc. HCl (5 mL). See Scheme 22 (FIG. 24). After the reaction mixture was warmed to 80° C. and stirred for 16 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc and sat. NaHCO3. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was chromatographed on silica gel (eluting 5-7% MeOH/CH2Cl2) to give [4-isopropyl-5-(3-methoxy-phenylsulfanyl)-1-pyridin-4-ylmethyl-1H-imidazol-2-yl]-methanol 38 (71 mg, 87%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1Br
Yield: 98.3 %

Procedure:
3-Bromo-4-fluorotoluene (9.36 g; 49.5 mmol) was dissolved in carbon tetrachloride (100 ml), and N-bromosuccinimide (8.82 g; 49.6 mmol) and benzoyl peroxide (200 mg) were added thereto. The mixture was heated under reflux for 1 hour, and then cooled. Insoluble matter was filtered off, followed by washing with carbon tetrachloride. The filtrate was concentrated under reduced pressure, and n-hexane (120 ml) was added thereto. The mixture was left to stand, and insoluble matter was filtered off, followed by washing with n-hexane. The filtrate was evaporated, to thereby yield 13.04 g of a mixture of the target-compound, the starting compound, and the dibromo compound (yield based on the weight of the mixture: 98.2%).
Reaction SMILES: [CH:1]1([C:5](=O)[CH2:6][C:7]([O:9]C)=O)[CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH2:16])=[NH:15].C[O-].[Na+]>CO>[C:13]([C:14]1[N:16]=[C:7]([OH:9])[CH:6]=[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[N:15]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: CC(C)(C)C(=N)N
Reactant: COC(=O)CC(=O)C1CCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1nc(O)cc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A mixture of methyl 3-cyclobutyl-3-oxo-propanoate (4.3 g, 27.53 mmol) and 2,2-dimethylpropanamidine (2.3 g, 22.10 mmol) was stirred in dry MeOH (50 mL) and NaOMe (5.0 g, 92 mmol) was added in portions at 10° C. The suspension was stirred at room temperature overnight. The reaction mixture was concentrated to roughly half of the volume and filtered. The filtrate was extracted with water and DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was stirred with acetone and the precipitate collected, dried under vacuum to give the title compound (3.15 g, 15.27 mmol, 66%).
Reaction SMILES: [OH:1]C1C=CC=CC=1C(O)=O.C(OO)(C)(C)C.[CH3:17][CH:18]([C:20](=[CH:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:21]#[N:22])[CH3:19]>C(Cl)Cl.[Se](=O)=O>[OH:1][C:24](=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:23]=[C:20]([CH:18]([CH3:17])[CH3:19])[C:21]#[N:22]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Reactant: O=C(O)c1ccccc1O
Agent: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=C(O)C=C(C#N)C(C)C
Reaction time: 0.5 h
Yield: 317.6 %

Procedure:
To a suspension of selenium dioxide (58 mg) and 2-hydroxybenzoic acid (365 mg) in methylene chloride (10.5 ml) was gradually added an aqueous solution of 80% t-butyl hydroperoxide (11.6 ml) with stirring on a water bath. After 30 minutes, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.56 g, 26.8 mmol)was added to the mixture, which was then allowed to stand at room temperature for 30 hours. Most of the solvent was removed by evaporation in vacuo, and the residue was dissolved in ether. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated. The resultant residue was subjected to silica gel column chromatography to give the aimed 4-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (2.53 g, 31%). The starting material was also recovered (3.10 g, 40%) in the column chromatography. The yield of the aimed product based on the consumed starting material was 52%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[O:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:38])[CH2:30][O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:35]1[CH2:34][CH2:33][CH:32]([O:31][CH2:30][C:29]([N:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)=[O:38])[CH2:37][CH2:36]1)=[O:5]
Reactant: O=C(COC1CCNCC1)N1CCOCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CCOCC1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 1-morpholino-2-(piperidin-4-yloxy)ethanone (76) (0.153 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (0.214 g, 62.8%); 1H NMR (400.132 MHz, CDCl3) δ 1.64-1.53 (1H, m), 1.75-1.67 (2H, m), 1.86-1.75 (1H, m), 1.98-1.93 (1H, m), 3.16-3.07 (1H, m), 3.57-3.39 (3H, m), 3.64-3.58 (2H, m), 3.72-3.66 (5H, m), 4.11-3.99 (1H, m), 4.19 (2H, q), 4.27 (2H, s), 7.02 (1H, t), 7.32-7.26 (2H, m), 7.77-7.69 (3H, m), 8.49-8.44 (1H, m), 10.51 (1H, s); Very broad peaks due to rotamers; m/z (LC-MS, ESI+), RT=1.48 (M+H 509).