Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=O)=[C:4]([Cl:13])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:13][C:4]1[CH:3]=[C:2]([NH2:1])[CH:12]=[CH:11][C:5]=1[CH2:6][N:8]([CH3:9])[CH3:10]
Reactant: CN(C)C(=O)c1ccc(N)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(N)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Using the procedure of Example 1, Compound 13a2 was used in place of Compound 1j3 and carried forward to prepare 4-amino-2-chloro-N,N-dimethyl-benzamide Compound 13a3. 1M LAH (3.53 mL, 3.53 mmol) was added dropwise to a solution of Compound 13a3 (700 mg, 3.53 mmol) in THF (10 mL). After 10 minutes, the reaction was cooled to 0° C. and quenched with water. The mixture was extracted from ethyl ether with 1N HCl. The aqueous layer was adjusted to pH 10 with NaOH and the product was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give 3-chloro-4-dimethylaminomethyl-phenylamine Compound 13a (150 mg) as a viscous brown oil. MS 185 (MH+).
Reaction SMILES: O=C(NN[C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])CCC1C=CC=CN=1.[F:31][C:32]([F:45])([CH:37]([OH:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[C:33]([NH:35][NH2:36])=[O:34].ClC1C=CC2OC3C=CC=CC=3CN(C(Cl)=O)C=2C=1.Cl>C(O)(=O)C>[F:45][C:32]([F:31])([CH:37]([OH:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[C:33]([NH:35][NH:36][C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])=[O:34]
Reactant: NNC(=O)C(F)(F)C(O)c1ccncc1
Reactant: O=C(CCc1ccccn1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Agent: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CC(=O)O
Product: O=C(NNC(=O)C(F)(F)C(O)c1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
The free base of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)carboxylic acid, 2-[2,2-difluoro-3-hydroxy-1-oxo-3-(4-pyridinyl)propyl]hydrazide (51) was prepared in the same manner as 8-chlorodibenz[b,f][1,41oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(2-pyridinyl)propyl]hydrazide (6), as described above in Example 6, on a 1.75 mmol scale from α,α-difluoro-β-hydroxy-3-(4-pyridinyl)-propanoic acid, hydrazide (50), prepared in the manner described above in Example 50, and 8-chlorodibenz[b,f]8 1,4]-oxazepine-10(11H)-carbonyl chloride (2), prepared in the manner described above in Example 2, for a yield of 0.098 g (12%) of product. The free base was taken up in acetic acid 1.5 mL) and 1M HCl (1.5 mL). The material was lyophilized to yield 0.049 mg of the hydrochloride salt. Analysis calculated for C22H17N4O4F2Cl.HCl.0.25 H2O (M.W. 514.83): C, 51.23; H, 3.62; N, 10.86. Found: C, 50.85; H, 3.67; N, 10.94.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([C:20]=1[N+:21]([O-])=O)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:16]=1[N+:24]([O-])=O)[CH:11]=2)[CH3:2].[H][H]>[Pd].C(OC(=O)C)(=O)C>[CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([C:20]=1[NH:21][C:5](=[O:6])[CH3:4])=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:16]=1[NH:24][C:15](=[O:27])[CH3:14])[CH:11]=2)[CH3:2]
Reactant: [H][H]
Reactant: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c([N+](=O)[O-])c3nc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(NC(C)=O)c3nc2c1NC(C)=O

Procedure:
3,6-bis(2-diethylaminoethoxy)-4,5-dinitroacridine is reduced with hydrogen and palladium catalyst in acetic anhydride as the solvent in the reduction, giving the desired product.
Reaction SMILES: [C:1]([O:5][P:6]([C:13]([F:38])([F:37])[C:14]1[CH:36]=[CH:35][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH:20]C(OCC2C=CC=CC=2)=O)=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.CO>CO.[Pd]>[C:9]([O:8][P:6]([C:13]([F:38])([F:37])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH2:20])=[CH:35][CH:36]=1)([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Yield: 60 %

Procedure:
A solution of benzyloxycarbonyl-protected 11 (45 mg, 0.081 mmol) in MeOH (0.8 mL) is stirred at ambient temperature under 1 atm of H2 over 10% Pd C (9 mg). After 2.5 hours the reaction mixture is filtered through silica gel and taken to dryness in vacuo to yield crude 12 quantitatively. Pure 12 (60% yield) can be obtained by silica gel chromatography [CHCl3 :MeOH(20:1)].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C1(C)C=CC=CC=1.O>[C:29]1([CH2:28][N:25]2[CH2:26][CH2:27][CH:22]([NH:21][CH2:17][C:16]3[CH:19]=[CH:20][C:13]([O:12][CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=[CH:2][CH:3]=4)=[CH:14][CH:15]=3)[CH2:23][CH2:24]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=Cc1ccc(OCc2ccnc3ccccc23)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(NCc3ccc(OCc4ccnc5ccccc45)cc3)CC2)cc1
Yield: 90 %

Procedure:
A mixture of 4-(4-quinolinylmethoxy)benzaldehyde (2.63 g, 10 mmol), 4-amino-1-benzylpiperidine (2.5 g, 13.1 mmol), and 4-toluenesulfonic acid (0.38 g, 2 mmol) was refluxed in toluene (500 mL) for 15 hours with azeotropic removal of water. The solvent was removed in vacuo, and the residue redissolved in MeOH. The stirred solution was treated with solid sodium borohydride (1 g, 26.5 mmol) at room temperature for 1 hour. The solvent was removed in vacuo, the residue redissolved in methylene chloride, and extracted with 1N NaOH (aq) (2×100 mL), and water(2×100 mL). The dried (MgSO4) organic phase was evaporated in vacuo and treated with etheral-hydrogen chloride(g) in methanol to afford the title compound (4.6 g, 9.0 mmol, 90% yield) as the dihydrochloride salt. The dihydrochloride salt was converted to the free base with 1N NaOH (aq) and extracted with methylene chloride. The organic phase was washed with water (2×75 mL), dried (MgSO4), evaporated in vacuo, and the residue crystallized from ether-hexane to afford, after drying in vacuo (6 hours at 45° C.) overnight, the free base of the title compound, m.p. 72°-75° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([Br:25])=[C:7]([CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:8]([CH2:15][CH3:16])=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.CO[C:28](OC)([CH3:30])[CH3:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[C:8]([CH2:15][CH3:16])=[C:7]([CH2:17][CH2:18][O:19][CH2:20][CH:21]2[CH2:22][O:23][C:28]([CH3:30])([CH3:29])[O:24]2)[C:6]=1[Br:25]
Reactant: COC(C)(C)OC
Reactant: CCc1c(OCOC)cc(OCOC)c(Br)c1CCOCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OCOC)cc(OCOC)c(Br)c1CCOCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 93 %

Procedure:
3-(2-Allyloxyethyl)-1,5-bis(methoxymethoxy)-2-bromo-4-ethylbenzene (5.0 g, 13 mmol) obtained in Example 33, Step 2 was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and water (10 mL). To the solution were added 4-methylmorpholine N-oxide (1.9 g, 16 mmol) and a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol (1.0 mL) at room temperature with stirring, and the mixture was stirred overnight. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was further stirred for 2 hours and then extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-{2-[3,5-bis(methoxymethoxy)-2-bromo-6-ethylphenyl]ethoxy}propane-1,2-diol. The obtained 3-{2-[3,5-bis(methoxymethoxy)-2-bromo-6-ethylphenyl]ethoxy}propane-1,2-diol was dissolved in N,N-dimethylformamide (50 mL), and 2,2-dimethoxypropane (6.4 mL, 52 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) were added thereto at room temperature with stirring, followed by stirring for 30 minutes. After neutralization with a saturated aqueous solution of sodium hydrogencarbonate, the reaction mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/4) to obtain 1,5-bis(methoxymethoxy)-3-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-2-bromo-4-ethylbenzene (5.6 g, 93%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]=[O:18]>O1CCOCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:17]([NH:16][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CCOC(=O)CCN=C=O
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
Prepared by reacting 4-amino-4'-cyano-biphenyl with ethyl 3-isocyanato-propionate in dioxane at 50° C.
Reaction SMILES: C([O:4][C:5](=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[CH3:9])C#N)(=O)C.[OH-:20].[Na+:21]>O>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:8]([CH3:9])[C:5]([O-:4])=[O:20])=[CH:11][CH:12]=1)[CH:17]([CH3:19])[CH3:18].[Na+:21]
Reactant: CC(=O)OC(C#N)=C(C)c1ccc(CC(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Temperature: 25 °C

Procedure:
55.41 g. portion of the crude enol-acetate solution from part A, representing 49.3 mmoles of 2-acetoxy-3-(4'-isobutylphenyl)-3-methylacrylonitrile (V) was placed in a 250 ml. one-necked flask and stirred magnetically while 10 ml. of water and 16.0 g. (200 meq.) of 50 percent sodium hydroxide solution were added. The mixture was stirred at 70° C. for 7 hours and cooled to 25° C. to effect hydrolysis of the enol-acetate and to form the sodium salt (VI). The ph of the mixture was adjusted to 11 with 12 percent sulfuric acid (3.5 ml.). Sodium hypochlorite solution (15 percent W/V, 30 meq.; 24.8 ml.) was added over 30 minutes with ice water cooling of the flask. Methylene chloride (10 ml.) and 0.8g. of a filter aid (Celite) were added and the mixture was slowly cooled to 0° C. After 3 hours the solids were filtered (3 minutes on a coarse frit) and washed with cold brine (8 ml. of saturated sodium chloride solution plus 3 ml. of ice) and with 10 ml. of cold methylene chloride. The cake was dried to give 9.68 g. A 1 gram sample was removed for cyanide assay; it showed 40 parts per million sodium cyanide. The remaining salt, 8.68 g. was slurried with water. The slurry gave a negative picric paper test, and then 56 ml. of Skellysolve B (SSB) and 8 ml. of 12 N sulfuric acid were added, with warming to 40° C. The mixture was filtered and phases were separated. The upper phase was washed with 20 ml. of warm water. The combined aqueous phase were back washed in sequence with a 20 ml. portion of SSB. The two SSB phases were then stirred with a mixture of sodium sulfate and decolorizing charcoal (0.5 g.), filtered through a filter aid and concentrated to about 15 ml. volume. The resulting acid solution was seeded with crystals of 2-(4'-isobutylphenyl)propionic acid and held at 0° C. for 2 hours. The resulting precipitate of 2-(4'-isobutylphenyl)propionic acid (1) was filtered, washed with two 3 ml. portions of cold SSB and dried overnight at 50° C. The yield of 2-(4'-isobutylphenyl)propionic acid, based upon the glycidonitrile starting material, with correction for removed analysis samples of the sodium salt was 8.00 g. (78.8 percent). A thin layer chromatogram analysis showed no impurity. The mother liquor still contained 0.120 g. of the acid (I).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1.C(NC(C)C)(C)C.O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: COc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccc(C#Cc2cccc(OC)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a mixed solution of 3-ethynylanisole (347.0 mg, 2.63 mmol), 3-iodoanisole (670.0 mg, 2.86 mmol, 1.1 eq), (PPh3)2PdCl2 (37.2 mg, 0.0530 mmol, 0.02 eq), CuI (5.1 mg, 0.0268 mmol, 0.01 eq) in THF (5 ml), diisopropylamine (0.57 g, 5.63 mmol, 2.1 eq) was added at 0° C., and stirred at room temperature for 1 h. 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. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/15) to give bis(3-methoxyphenyl)ethyne (594.4 mg, 95.0%).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:14]3[N:15]=[C:16]([NH2:24])[N:17]=[C:18]([C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)[C:13]=3[N:12]=[N:11]2)[CH:6]=[CH:5][CH:4]=1.[C-:25]#[N:26].[Na+].O>CN(C=O)C>[C:25]([CH2:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:14]3[N:15]=[C:16]([NH2:24])[N:17]=[C:18]([C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)[C:13]=3[N:12]=[N:11]2)[CH:6]=[CH:5][CH:4]=1)#[N:26]
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CBr)n3)c2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)n1
Yield: 29.1 %

Procedure:
A solution of 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.517 mmol) and sodium cyanide (51 mg, 1.03 mmol) in DMF (5 mL) was stirred at 60° C. for 16 h, poured into water (40 mL), extracted with EtOAc (3×8 mL), the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2;isohexane:EtOAc (1:1)] to give title compound (50 mg, 26%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([S:25][CH2:26][CH3:27])=[CH:4][CH2:3]1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([S:25][CH2:26][CH3:27])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(SCC)=CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCSC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 50 °C

Procedure:
To a solution of 150 mg (0.38 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151) in 4 ml of ethanol was added 1 ml of KOH (2N aqueous solution). The solution was heated to 50° C. for two hours, cooled to room temperature, concentrated in vacuo, diluted with dichloromethane (5 ml) and acidified with 10% aqueous HCl at 0° C. The layers were separated and the aqueous layer was extracted with dichloromethane (2×). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from acetonitrile gave the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[CH:3]=1.[CH3:10][NH:11][CH3:12]>>[CH3:10][N:11]([CH3:12])[C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: CNC
Reactant: Cc1cc(Cl)cc(N)n1
Product: Cc1cc(N(C)C)cc(N)n1
Temperature: 130 °C

Procedure:
To 6-amino-4-chloro-2-picoline (500 mg, 3.51 mmol) in a vial under nitrogen was added dimethylamine (40% in water, 17.5 ml, 35.0 mmol). The reaction mixture was sealed and heated at 130° C. in a microwave for 2.5 hours. The reaction mixture was cooled, concentrated under reduced pressure, and purified by silica gel chromatography (2-10% methanol/DCM with 1% ammonium hydroxide, linear gradient) to give N4,N4,6-trimethylpyridine-2,4-diamine. MS ESI calc'd. for C8H14N3 [M+H]+ 152. found 152. 1H NMR (500 MHz, DMSO-d6) δ 6.15 (s, 2H), 6.02 (s, 1H), 5.54 (s, 1H), 2.90 (s, 6H), 2.18 (s, 3H).
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[S:19][CH3:20])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:21]O>C(O)(=O)C>[N:1]1([C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[S:19]([CH3:20])=[O:21])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: COc1cc(NC(=O)N2CCCC2)c(SC)cc1OC
Solvent: CC(=O)O
Product: COc1cc(NC(=O)N2CCCC2)c(S(C)=O)cc1OC

Procedure:
A reaction mixture containing 52 g. of N-pyrrolidinylcarbonyl-2-methylthio-4,5-dimethoxyaniline 19.8 ml. of 31 percent aqueous hydrogen peroxide and 1 l. of glacial acetic acid was stirred for about 20 hours at ambient temperature. The reaction mixture was then concentrated under reduced pressure to a residual wax. The residue was dissolved in 1 l. of methylene chloride and the methylene chloride layer washed twice with water and then dried. Removal of the methylene chloride in vacuo yielded a residue comprising N-pyrrolidinylcarbonyl-2-methylsulfinyl-4,5-dimethoxyaniline which, after recrystallization from a benzene-hexane solvent mixture, yielded material melting at 124°-7° C. (80 percent yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([CH:35]5[CH2:37][CH2:36]5)=[O:34])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1)C1CC1

Procedure:
Example 112 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.03–7.87 (br, 1H), 7.56–7.02 (m, 8H), 6.91–6.65 (br, 1H), 3.30–3.05 (m, 4H), 2.62–2.38 (m, 3H), 2.38–2.21 (m, 2H), 1.98–1.51 (m, 15H), 1.14–1.01 (m, 2H), 0.93–0.70 (m, 2H); ESMS m/e: 508.2 (M+H)+.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:2]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of (bromomethylene)dibenzene (115 mg, 1.0 mmol) and piperidin-4-ylmethanol (247 mg, 1.0 mmol) in DMF (5 mL) was added potassium carbonate (276 mg, 2.0 mmol), and the reaction mixture was stirred at 100° C. for 16 h. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography (eluting with petroleum ether/ethyl acetate=3/1) to give (1-benzhydrylpiperidin-4-yl)methanol (280 mg, 99% yield) as white solid. LCMS (ESI) m/z: 281.9 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6].I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CS(C)=O>[CH2:3]([C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC(CCCC)(C(=O)OCC)C(=O)OCC
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A mixture of sodium hydride (50% w/w suspension in mineral oil, 2.40 g, 50.0 mmol) in dimethylsulfoxide (50 mL) was cooled to 5° C., and a solution of diethyl butylmalonate (10.0 mL, 45.5 mmol) in dimethylsulfoxide (10 mL) was added dropwise with vigorous stirring. After 4 hours, the solution was treated with iodooctane (8.20 mL, 44.3 mmol), and the solution was stirred an additional 12 hours. It was poured into water (400 mL), and extracted with ethyl acetate (2×500 mL). The extracts were washed in sequence with water (3×400 mL), then saturated brine (400 mL). The extracts were then combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting oil was separated by flash chromatography (3:97 ethyl acetate-hexane) to afford the product, diethyl butyl-octylmalonate, as an oil (13.7 g, 41.7 mmol, 94%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].F[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:1]([O:9][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[C:20]([F:21])([F:22])[F:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(C)=O)cc1C(F)(F)F

Procedure:
1-octanol (2 mL), 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (2.62 g), potassium tert-butoxide (14 mL, 1.0M) and tetrahydrofuran (30 mL) were heated at 65° C. for 3 hrs to produce the title product as a brownish oil (4.00 g). The product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) as white solid in 60% (1.20 g). TLC (1:5 EtOAc:Hex), Rf=0.4; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J=2.0 Hz), 8.10 (dd, 1H, J=8.8 Hz, J=2.3 Hz), 7.02 (d, 1H, J=8.8 Hz), 4.12 (t, 2H, J=6.4 Hz), 2.58 (m, 3H), 1.80-1.89 (m, 2H), 1.42-1.54 (m, 2H), 1.22-1.40 (m, 8H), 0.89 (t, 3H, J=6.7 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][NH2:30]>>[O:25]=[S:17]1(=[O:26])[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH2:20][N:14]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][CH2:27][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=3)[N:5]=2)[CH2:15][CH2:16]1
Reactant: NCCCN
Reactant: C#Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: C#Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro-6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 421, 1H NMR (400 MHz, CD3OD) δ ppm 8.25 (s, 1 H), 8.01-7.99 (d, J=7.6 Hz, 1 H), 7.94-7.92 (d, J=7.2 Hz, 1 H), 7.87-7.85 (d, J=8.8 Hz, 1 H), 7.82-7.79 (m, 1 H), 7.65-7.61 (m, 1 H), 7.50-7.47 (m, 1 H), 7.32 (s, 1 H), 5.30 (s, 2 H), 3.65-3.60 (m, 6 H), 2.70 (s, 3 H), 2.14-2.11 (t, J=5.2 Hz, 2 H).