Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([CH2:11][CH2:12][C:13]#[N:14])[CH2:8][CH:7]2[CH2:9][CH2:10][CH:4]1[CH:5]=[CH:6]2)#[N:2]>CO.[Pd]>[C:1]([C:3]1([CH2:11][CH2:12][C:13]#[N:14])[CH2:8][CH:7]2[CH2:9][CH2:10][CH:4]1[CH2:5][CH2:6]2)#[N:2]
Reactant: N#CCCC1(C#N)CC2C=CC1CC2
Agent: [Pd]
Solvent: CO
Product: N#CCCC1(C#N)CC2CCC1CC2

Procedure:
An amount of 128.7 g (0.69 mole) of 2-cyano-bicyclo[2.2.2]oct-5-ene-2-propionitrile is dissolved in 1.3 liters of the purest methanol; an addition is then made of 3 g of palladium charcoal (5% Pd) and hydrogenation performed at 15°-25° under normal pressure to effect a hydrogen absorption of 90% of theory. After removal by filtration of the catalyst, the solvent is evaporated off and the residue fractionated to obtain 2-cyano-bicyclo[2.2.2]octane-2-propionitrile, B.P. 114°-116°/0.01 Torr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C(O)(=O)C>C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:2]([F:1])[CH:7]=1
Reactant: CN(C)C(=O)CCCc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)C(=O)CCCc1ccc(N)cc1F
Temperature: 21 °C
Yield: 89.2 %

Procedure:
A solution of compound 4-(2-Fluoro-4-nitrophenyl)-N,N-dimethylbutanamide (77) (15 mg, 0.06 mmol), Fe (20 mg, 0.37 mmol) and acetic acid (1 mL) in ethyl acetate (3 mL) was heated under reflux for 2 h. The reaction mixture was allowed to cool to 21° C. and then filtered. The organic layer was concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give desired 4-(4-Amino-2-fluorophenyl)-N,N-dimethylbutanamide (76) (12 mg, 87%): 1H NMR δ 6.95 (dd, 1H, J=8.3, 8.2 Hz), 6.40 (dd, 1H, J=8.3, 2.2 Hz), 6.35 (dd, 1H, J=11.6, 2.2 Hz), 3.66 (br s, 2H), 2.95 (s, 3H), 2.93 (s, 3H), 2.58 (t, 2H, J=7.4 Hz) 2.30 (t, 2H, J=7.6 Hz) 1.85-1.95 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:20]1[CH2:21][CH2:22][N:17]([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:9]2[C:4]([NH2:1])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ncccc1Oc1cccc(N2CCOCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ncccc1Oc1cccc(N2CCOCC2)c1
Yield: 96.7 %

Procedure:
In a 125 mL round-bottom flask, 4-(3-(2-nitropyridin-3-yloxy)phenyl)morpholine (0.92 g, 3.05 mmol) was dissolved in 30 mL of ethanol and 200 mg of 10% Pd/C (Degussa type, 50% wet) added. The resulting mixture was agitated overnight under the atmospheric pressure of hydrogen. The mixture was filtered and the solvent was evaporated to give the title compound (0.80 g, 97%) as thick oil.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(C(C)c5ccccn5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 16 h
Yield: 49 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.12 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.42 mmol, 0.42 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.14 mmol, 18 mg). After 16 h, concentration in vacuo and preparation by preparative tlc (EtOAc—CH2Cl2-MeOH, 50:50:2) gave the product (29 mg, 48%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.38 (d, J=6.8 Hz, 3H, CHCH3), 2.60 (s, br, 2H, piperazine NCH2), 2.70 (br s, 2H, piperazine NCH2), 3.64 (s, br, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.9 Hz, 2H, methoxyphenyl), 7.25-7.28 (m, 1H, pyridine H-5), 7.50 (d, J=7.9 Hz, 1H, pyridine H-3), 7.79 (td, J=7.7, 1.5 Hz, 1H, pyridine H-4), 8.12 (d, J=8.9 Hz, 2H, methoxyphenyl), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.53 (d, J=4.2 Hz, 1H, pyridine H-6), 13.37 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][CH2:28][C@H:27]1[OH:31]>>[Br:1][C:2]1[C:3]([N:29]2[CH2:30][C@@H:26]([O:25][CH3:24])[C@H:27]([OH:31])[CH2:28]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CO[C@@H]1CNC[C@H]1O
Agent: Cl
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C[C@H]1O

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and Trans-4-methoxy-3-pyrrolidinol hydrochloride to afford a white amorphous solid. UPLC-MS (condition 1) tR=2.65 min, m/z=475.9-477.9 [M+H]+, m/z=474.0-475.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.31 (s, 3H) 3.58 (d, J=11.49 Hz, 1H) 3.66 (d, J=12.23 Hz, 1H) 3.72-3.77 (m, 1H) 3.92 (dd, J=11.86, 4.28 Hz, 1H) 3.97 (dd, J=12.10, 4.28 Hz, 1H) 4.22 (br. s, 1H) 5.30 (d, J=3.18 Hz, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.85 (d, J=9.29 Hz, 2H) 8.36 (d, J=2.20 Hz, 1H) 8.68 (d, J=2.20 Hz, 1H) 10.25 (s, 1H).
Reaction SMILES: BrC1C=CC(C2OC3C4C(C=CC=3C=2)=CC=CC=4)=CC=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]3[C:34]4[C:39]([CH:40]=[CH:41][C:31]=3[CH:30]=2)=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]3[CH:34]=[CH:35][C:36]4[C:41]([C:31]=3[CH:30]=2)=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc(-c2cc3ccc4ccccc4c3o2)cc1
Agent: Brc1ccc(-c2cc3ccc4ccccc4c3o2)cc1
Product: N#Cc1ccc(-c2cc3c(ccc4ccccc43)o2)cc1

Procedure:
Similarly, 2-(p-bromophenyl)naptho[1,2-b]furan (Example 3b) can be converted to 2-(p-cyanophenyl)naphtho[1,2-b]furan [I; R is p-CN, R' is H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[C:8]([NH:10][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1cc(N)nn1Cc1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(NCc2ccc(F)cc2)nn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
In a round bottom flask, 5-amino-2-(4-methoxy-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester (109, 1.4 g, 5.4 mmol) was combined with 4-fluoro-benzaldehyde (110, 0.565 mL, 5.36 mmol), trifluoroacetic acid (2.06 mL, 26.8 mmol), triethylsilane (4.28 mL, 26.8 mmol) and 50 mL of acetonitrile. The reaction was stirred at room temperature for 15 minutes, then concentrated under vacuum, combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The residue was recrystallized from a mixture of ethyl acetate and hexane to provide the desired compound (111, 1.6 g). 1H NMR was consistent with the compound structure.
Reaction SMILES: [C:1]1([CH3:13])[C:2]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([CH3:29])[C:21]=1[S:22]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:24])=[O:23])[NH2:18]>C(Cl)Cl>[CH3:29][C:20]1[CH:19]=[C:17]([NH:18][C:11]([NH:10][S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:13])(=[O:9])=[O:8])=[O:12])[CH:16]=[C:15]([CH3:14])[C:21]=1[S:22]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:24])=[O:23]
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)Nc1cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 0.77 ml (5.09 mmol) of o-toluenesulphonyl isocyanate in 7.7 ml of anhydrous methylene chloride is added dropwise to a suspension, maintained under a nitrogen atmosphere, of 1.3 g (5.32 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 25.6 ml of anhydrous methylene chloride. The temperature of the reaction medium rises spontaneously by 7° C. A precipitate forms in the solution initially obtained. Stirring is continued for 1 hour at room temperature and the solid is then isolated by filtration and washed with hexane to give 1.9 g (yield=86%) of 1-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-3-[(2-methylphenyl)sulphonyl]urea.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:15](OC)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.CO>C1COCC1>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([CH:15]=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(C[C@@H](C=O)NC(=O)OCc2ccccc2)ccc1O
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of Z-Tyr(3-tBu)-OMe (3.30 g, 8.57 mmol) in THF (200 ml), diisobutyl aluminum hydride (1.0 M toluene solution) (42.9 ml, 42.9 mmol) was added dropwise at −78° C. over 15 min. After stirring for 1 hour, the mixture was mixed with methanol and a saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2), giving the titled compound (2.18 g, 72%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][C:12](=[N:16]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C1CCCC(COCc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NC1CCCC(COCc2ccccc2)C1
Yield: 86.9 %

Procedure:
To a solution of the compound (12) (0.75 g; 3.2 mmol) in diethyl ether (30 ml), lithium aluminum hydride (0.75 g; 20 mmol) is added, and the resultant mixture is refluxed for 3 hours. After cooling, wet ether is dropwise added to the reaction mixture, and the organic layer is collected by decantation and dried, followed by concentration under reduced pressure to give 3-benzyloxymethylcyclohexylamine (13) (0.61 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11](B(O)O)=[CH:12][CH:13]=[CH:14][CH:15]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:10]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cc(Cl)ccn1
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccccc2-c2ccccc2)ccn1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A nitrogen flushed mixture of 4-chloro-2-methoxypyridine (3.0 g, 21.03 mmol), 2-biphenylboronic acid 5.0 g, 25.23 mmol), Pd2(dba)3 (381 mg, 0.414 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (681 mg, 1.66 mmol), toluene (250 mL) and a slurry of K3PO4.H2O (14.57 g, 63.09 mmol) in water (25 mL) were refluxed for 18 h. After the mixture cooled to room temperature the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by flash chromatography on silica (hexane:ethyl acetate) and recrystallized from ethyl acetate to give 4-(biphenyl-2-yl)-2-methoxypyridine (4.2 g, 76.5%).
Reaction SMILES: [C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:31](=O)(O)[O-].[Na+]>>[C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:8])[CH3:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Agent: Cl
Agent: [Na+]
Product: CC(C)(Nc1nc(N)c2ncn([C@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1

Procedure:
Treat the secondary amine (3) (0.46 g, 1.05 mmol) with 1M hydrochloric acid (40 ml) and heat the reaction to 45° C. for 15 minutes. Cool the reaction and pour into saturated sodium bicarbonate (300 ml). Extract the reaction with chloroform (3×150 ml). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter, and concentrate under vacuum to provide the title compound (0.40 g) as the free base. Treat this with ethereal hydrogen chloride, filter, and dry the solid under high vacuum over phosphorous pentoxide. Recrystallize from 10% methanol/diethyl ether to provide, after drying under high vacuum over phosphorous pentoxide, the hydrochloride salt of the Formula I (184 mg), m.p. 155° C. dec.; [α]D20 =+9.75° (c=1.01, H2O).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1S([N:16]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)[CH2:17][C:18]1[N:19]=[N:20][N:21]([CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:22]=1)(=O)=O)([O-])=O>C(N)CC>[CH3:26][Si:24]([CH2:23][N:21]1[CH:22]=[C:18]([CH2:17][NH:16][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)[N:19]=[N:20]1)([CH3:25])[CH3:27]
Reactant: COC(=O)c1ccc(CN(Cc2cn(C[Si](C)(C)C)nn2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Solvent: CCCN
Product: COC(=O)c1ccc(CNCc2cn(C[Si](C)(C)C)nn2)cc1
Reaction time: 8 h

Procedure:
Crude methyl 4-{[[(2,4-dinitrophenyl)sulfonyl]({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate (732 mg, 1.30 mmol) was dissolved in propylamine (2.25 mL) and stirred overnight. The reaction was concentrated and purified via MPLC, 1-8% MeOH in DCM to afford the requisite product as a clear, colorless oil. MS: cal'd 333 (MH+), exp 333 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1.Cl>C(O)C.[OH-].[Na+]>[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26])([OH:21])=[O:20]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCCCCCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
In a mixture of 50 ml of ethanol and 25 ml of 1N aqueous sodium hydroxide solution, 18-aminooctadecanoic acid (400 mg, 1.33 mmoles) was dissolved at 40° C. To the obtained solution, being maintained at 40° C., was gradually added maleic anhydride (1.97 g, 20.0 mmoles) over a period of 2 hours. The reaction mixture was stirred for 30 minutes, then acidified with hydrochloric acid under ice-cooled condition and subjected to centrifugation. The precipitate was collected by filtration, sufficiently washed with water and then dried under reduced pressure, to give N-(17-carboxyheptadecyl)maleamic acid (436 mg, 88%) having the following properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:11]=[N:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:18]3)[CH:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:28])([F:27])[F:29])[CH2:11][NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2ccc(C(N)=O)nc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2ccc(C(N)=O)nc12)C(F)(F)F
Reaction time: 16 h

Procedure:
703 mg (1.47 mmol) of 8-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]quinoline-2-carboxylic acid amide in 10 ml of methanol and 5.0 ml of tetrahydrofuran are mixed with 449 mg (11.8 mmol) of sodium borohydride. After 16 hours, the solvent is concentrated by evaporation, the residue is taken up in water and ethyl acetate, extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0-50%) as well as dichloromethane-methanol (0-7%), 358 mg (51% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([SH:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([S:23][CH:21]([CH3:22])[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)S
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 32 %

Procedure:
A suspension of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (300 mg), isopropylthiol (0.121 mL) and potassium carbonate (451 mg) in DMF (5 mL) was stirred with heating at 100° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 3→40% ethyl acetate/hexane), and further by preparative HPLC to give the title compound (111 mg, 32%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][NH:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][OH:22])[CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[O:3]1.[CH2:24]([C:26]1[S:30][CH:29]=[C:28]([C:31](O)=[O:32])[CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[S:30][CH:29]=[C:28]([C:31]([N:6]2[CH2:5][C:4]3([CH2:12][CH2:11][N:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][OH:22])[CH:15]=4)[CH2:9][CH2:8]3)[O:3][C:2]([CH3:23])([CH3:1])[CH2:7]2)=[O:32])[CH:27]=1)[CH3:25]
Reactant: CC1(C)CNCC2(CCN(Cc3cccc(CCO)c3)CC2)O1
Reactant: CCc1cc(C(=O)O)cs1
Product: CCc1cc(C(=O)N2CC(C)(C)OC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1

Procedure:
The subtitled compound was prepared using a similar method to that described in Example 271 step (f) using 2-(3-((2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenyl)ethanol (0.2 g) (Example 271, step e) and 5-ethylthiophene-3-carboxylic acid. Yield 0.22 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: Cc1ccc(NC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 85 °C

Procedure:
Under N2-atmosphere, a suspension of N-(4-methyl-3-trifluoromethyl-phenyl)2,2,2-trifluoro-acetamide (Stage 128.4; 5.21 g, 19.2 mmol), N-bromosuccinimide (15 g, 84 mmol) and azo-iso-butyronitrile (740 mg, 4.5 mmol) in 430 ml of CCl4 is heated to 85° C. for 15 h. The hot mixture is filtered, the solid washed with CCl4 and discarded. The filtrate is concentrated, the residue re-dissolved in CH2Cl2 (0.7 L) and washed twice with 0.5 M solution of Na2S2O3 and brine. The inorganic phases are extracted with 2 portions of CH2Cl2, the organic phases dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/CH2Cl2 1:1) yields the title compound: 1H-NMR (DMSO-d6): 11.59 (s, HN), 8.06 (d, 1H), 7.97 (dd, 1H), 7.76 (d, 1H), 4.77 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(#N)C>[N:26]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCCN2CCCCC2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, piperidine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=98%, [M+H]+=343.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)oc(CO)c1OCc1ccccc1
Agent: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Product: O=Cc1oc(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c1OCc1ccccc1
Yield: 82.3 %

Procedure:
N-(5-Benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-3-chloro-benzenesulfonamide (11-05) (2.3 g, 82.36%) was synthesized as a white solid from N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-chloro-benzenesulfonamide (10-05) (2.8 g, 6.44 mmol) following the procedure described for N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (11-01).