Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccccn3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.55 g, 1.6 mmol) in acetonitrile (10 mL), was added picolinoyl chloride hydrogen chloride (0.32 g, 1.8 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give pyridine-2-carboxylicacid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as an off-white solid (67 mg, 10% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.85 min (99.4%); mp, 261-263° C.; 1HNMR (DMSO-d6) 2.08-2.27 (m, 1H, CHH), 2.64-2.93 (m, 6H, CHCH2, CH3), 4.91-5.05 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.33-8.69 (m, 7H, Ar), 9.32 (t, J=6 Hz, 1H, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.31, 30.62, 42.12, 56.57, 117.72, 121.86, 125.18, 125.76, 126.60, 134.05, 137.82, 140.30, 148.55, 149.77, 154.87, 161.17, 163.79, 169.47, 172.65. LCMS MH=406; Anal Calcd For C21H19N5O4+0.5H2O: C, 60.86; H, 4.86; N, 16.90. Found: C, 60.72; H, 4.62; N, 16.69.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH:7]=[N:6]1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([NH:14][C:11]2[CH:12]=[C:13]3[C:8]([CH:7]=[N:6][N:5]3[CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])=[CH:9][CH:10]=2)=[O:32])=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CN(C)CCn1ncc2ccc(N)cc21
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)CCn1ncc2ccc(NC(=O)Cc3ccc(OCc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A mixture of 1-(2-dimethylamino-ethyl)-1H-indazol-6-ylamine (484 mg, 2 mmol), 4-benzyloxy-phenylacetic acid (200 mg, 2 mmol), ethyldimethylpropylcarbodiimide hydrochloride (460 mg, 2.4 mmol), N-hydroxybenzotriazole (324 mg, 2.4 mmol), and N-methyl morpholine (513 mg, 4.8 mmol) in DMF (15 mL) was stirred at room temperature for 6 hours and concentrated under reduced pressure The residue was purified by flash chromatography (Silica gel, ethyl acetate/triethylamine, 30/1) to provide the title compound as a pale yellow solid (95%). 1H NMR (300 MHz, DMSO-d6) ppm 2.15 (s, 6H), 2.66 (t, J=6.44, 2H), 3.60 (s, 2H), 4.35 (t, J=6.44, 2H), 5.09 (s, 2H), 6.98 (d, J=8.82, 2H), 7.14 (m, 1H), 7.25–7.45 (m, 6H), 7.65 (m, 1H), 7.94 (m, 1H), 7.94 (s, 1H), 7.95 (s, 1H), 8.12 (s, 1H); MS (DCI/NH3) m/z 429 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cnc2ccc(Br)cc2c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc2ccc(-c3ccc(Cl)cc3)cc2c1
Temperature: 150 °C

Procedure:
To a 2-5 mL microwave vial fitted with a stirbar was added methyl 6-bromoquinoline-3-carboxylate (Int-1, 0.15 g, 0.564 mmol), 4-chlorophenylboronic acid (0.114 g, 0.733 mmol), sodium carbonate (0.179 g, 1.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0651 g, 0.056 mmol). The vial was capped and 1,4-dioxane (1.6 mL) and water (0.47 mL) were added by syringe. The mixture was purged with argon for 5 min. The contents of the vial were heated in a microwave at 150° C. for 30 min. The reaction mixture was cooled to room temperature and the vial was opened. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with water. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was used as obtained in the following step. LC-MS: (FA) ES+ 298.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+:9]([O-])([OH:11])=[O:10]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:9]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1cccs1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
2-Thiophenecarboxylic acid (6.4 g, 50 mM) was suspended in acetic anhydride (15 ml) and fuming nitric acid (16 ml) in glacial acetic acid (25 ml) added slowly over 1 hour with stirring, while keeping the temperature of the reaction mixture below 30° C. The reaction mixture was stirred at ambient temperature for 2 hours. The product was purified by subjecting to chromatography (470 ml) on HP20SS resin using methanol/(water+1% acetic acid): as eluant. The pure title compound was obtained together with a mixture of 4- and 5-nitrothiophene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23]Br)=[CH:18][CH:17]=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][CH3:14].C1N2CN3CN(C2)C[N:27]1C3.C(Cl)(Cl)[Cl:37]>>[ClH:37].[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][NH2:27])=[CH:18][CH:17]=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][CH3:14]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClC(Cl)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)CBr)cc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)CN)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
88 g of p-tetradecyloxy-ω-bromoacetophenone are dissolved in 320 ml of anhydrous chloroform. 30.4 g of urotropine are added at room temperature. The solution heats up spontaneously. It is then stirred for 2 hours at room temperature. The chloroform is evaporated off and the solid residue is triturated with acetone. The crystalline precipitate is suction filtered and washed several times with acetone. The crude product is then introduced into a solution of 140 ml of concentrated hydrochloric acid in 1000 ml of ethanol and stirred for 24 hours at room temperature. The product is suction filtered and washed with a mixture of ethanol and concentrated hydrochloric acid (7:1). 80 g =95% of p-tetradecyloxy-ω-aminoacetophenone-hydrochloride melting at 190° to 195° C. are obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)#[N:22]
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C#N)ccc2NC1C(F)(F)F
Temperature: 80 °C
Yield: 48 %

Procedure:
N,N-Dimethylformamide (5 mL) was degassed with nitrogen for thirty minutes in a three neck round bottom flask equipped with a condenser, temperature monitoring, nitrogen purge and heating mantle. Ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) were added to the N,N-dimethylformamide and stirred vigorously for ten minutes. Tetrakis(triphenyl-phosphine)palladium(0) (0.068 g, 0.53 mmol) was added and the contents gently warmed to 80° C. for 2 hours under a nitrogen atmosphere. Ethyl acetate (20 mL) was added, followed by extraction with aqueous 2 N ammonium hydroxide (2×10 mL), water (2×10 mL), saturated ammonium chloride (2×10 mL), dried over sodium sulfate and solvent removed in vacuo to yield a yellow solid. The product was purified by flash chromatography (silica gel, ethyl acetate-hexanes, 3:1) to yield, upon concentration of the appropriate fractions, ethyl 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (188 mg, 48%): mp 211–212° C. 1H NMR (CDCl3/300 MHz) 7.68 (s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J=8.3 Hz), 5.22 (m, 1H), 4.98 (br s, 1H), 1.30 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). EIHRMS m/z 314.1147 (M+NH4+, Calc'd 314.1116). Anal. Calc'd for C14H11F3N2O2: C, 56.76; H. 3.74; N, 9.46. Found: C, 56.44; H, 4.03; N, 9.29.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1F)[N:10]=[CH:9][N:8]=[C:7]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)([O-:3])=[O:2].[N:24]1([CH2:30][CH2:31][CH2:32][OH:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CC(C)([O-])C.[K+].Cl>CS(C)=O.O>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][C:13]([O:33][CH2:32][CH2:31][CH2:30][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: OCCCN1CCOCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
6-nitro-4-(3-chloro-4-fluorophenylamino)-7-fluoro-quinazoline (1 eq.) and morpholine-propanol (1.5 eq.) were dissolved in DMSO (10 ml), the solution was stirred for 5 mins with a water bath. A solution of potassium tert-butoxide (3.0 eq.) in DMSO (5 ml) was added slowly to the solution mentioned-above in drops, the mixture was stirred at room temperature for further 30 mins. After the reaction finished, the mixture was diluted with 100 ml water and pH was adjusted to neutral with concentrated hydrochloric acid, then stirred for 30 mins, large amount of yellow solid was precipitated, then filtering, the filter cake was washed with water twice and dried to give yellow solid of N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine (yield 90%).
Reaction SMILES: [Br:1][CH:2]([CH3:15])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:7]=2[CH:6]=1)=O.[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].C(O)(=O)C>C(O)C>[BrH:1].[F:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]3[N:18]4[CH2:19][CH2:20][N:16]=[C:17]4[S:21][C:2]=3[CH3:15])[S:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CC(Br)C(=O)c1cc2c(F)cccc2s1
Reactant: S=C1NCCN1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: CC1=C(c2cc3c(F)cccc3s2)N2CCN=C2S1
Temperature: 20 °C
Yield: 94.7 %

Procedure:
A mixture of 2-bromo-1-(4-fluorobenzo[b]thiophen-2-yl)propan-1-one (0.67 g), 2-imidazolidinethione (0.24 g), acetic acid (10 ml) and ethanol (5 ml) was heated under reflux for 2 hours then cooled to 20° C. The mixture was concentrated in vacuo and the resulting solid was collected by filtration, washed with ethanol (5 ml) and dried in vacuo at 60° C. for 2 hours to give 3-(4-fluorobenzo[b]thiophen-2-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.82 g) as beige solid, m.p. 224-226° C.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C@H:46]2[CH2:51][CH2:50][C@H:49]([C@H:52]3[CH2:57][CH2:56][C@H:55]([CH:58]=O)[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)=[CH:40][CH:39]=1)#[N:37]>C(OCC)(=O)C>[F:2][CH2:3][CH2:4][CH:5]=[CH:58][C@H:55]1[CH2:56][CH2:57][C@H:52]([C@H:49]2[CH2:50][CH2:51][C@H:46]([CH2:45][CH2:44][C:41]3[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[CH:39][CH:40]=3)[CH2:47][CH2:48]2)[CH2:53][CH2:54]1
Reactant: N#Cc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](C=CCCF)CC3)CC2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (15.1 g, 37.4 millimols) with THF (70 ml) was cooled down to -20° C., followed by adding t-BuOK (4.2 g, 37.4 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (100 ml) solution of trans-4-(trans-4-(2-(4-cyanophenyl)ethyl)cyclohexyl)cyclohexanecarbaldehyde (11.0 g, 34.0 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2, except that the quantity of ethyl acetate was made 500 ml, to obtain raw 4-(2-(trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)ethyl)benzonitrile (11.3 g).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr.O.[OH-].[NH4+]>C(O)(=O)C>[CH2:11]([NH:10][C:8]1[S:9][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C(NCc1ccccc1)Nc1ccccc1
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(CNc2nc3ccccc3s2)cc1

Procedure:
To a stirred solution of 12.1 g (0.05 mol) of N-phenyl-N'-benzylthiourea in 150 ml of glacial acetic acid was added dropwise 8.0 g (0.05 mol) of bromine in 60 mL of glacial acetic acid. The reaction was poured into 10 volumes of water and made basic with concentrated ammonium hydroxide. A solid precipitated from the aqueous solution and was filtered. The solid could be recrystallized from an appropriate solvent to yield N-benzyl-2-benzothiazolamine.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH:10]([OH:14])[C:11]([OH:13])=[O:12].[CH3:19]O>>[F:6][C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH:10]([OH:14])[C:11]([O:13][CH3:19])=[O:12]
Reactant: CO
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1cc(F)cc(F)c1

Procedure:
2 ml of sulfuric acid at 95% by mass are added to 2 g of 3,5-difluoromandelic acid in solution in 25 ml of methanol, and the mixture is kept under reflux for 6 hours. The medium is concentrated, the residue is taken up in ethyl acetate and washed with a sodium hydroxide solution (0.1 N). The organic phase is dried over anhydrous sodium sulfate and 2 g of oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:31])[N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:18][C:17]=2[CH:32]([CH3:34])[CH3:33])[N:14]=[C:13]([C:35]([NH:37][C:38]2([C:48]([OH:50])=[O:49])[CH:45]3[CH2:46][CH:41]4[CH2:42][CH:43]([CH2:47][CH:39]2[CH2:40]4)[CH2:44]3)=[O:36])[CH:12]=1.C[O-].[Na+:53].CCOCC>CO.C(Cl)Cl>[Na+:53].[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:31])[N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:18][C:17]=2[CH:32]([CH3:34])[CH3:33])[N:14]=[C:13]([C:35]([NH:37][C:38]2([C:48]([O-:50])=[O:49])[CH:39]3[CH2:40][CH:41]4[CH2:42][CH:43]([CH2:44][CH:45]2[CH2:46]4)[CH2:47]3)=[O:36])[CH:12]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)[O-])C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Temperature: 5 °C
Yield: 70.6 %

Procedure:
0.206 g of the compound obtained in EXAMPLE 1' and 0.026 g of sodium methylate are dissolved in 1 ml of MeOH and a few drops of DCM, and this solution is then poured into 50 ml of ether cooled to 5° C. The gelatinous precipitate formed is drained and dried over P2O5 and under vacuum. 0.15 g of the expected product is obtained, m.p.=191° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9]Br.[C-:11]#[N:12].[K+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Cc1cccc(CBr)c1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CC#N)c1Br
Temperature: 90 °C
Reaction time: 8 h
Yield: 66811.3 %

Procedure:
2-bromo-1-(bromomethyl)-3-methylbenzene (15 g, 0.057 mmol) and potassium cyanide (9.6 g, 0. 148 mol) were added to dimethylformamide (75 ml) and stirred at 90° C. overnight. The solvent was evaporated under reduced pressure and the residue partitioned between water (150 ml) and methylene chloride. The aqueous layer was extracted twice with methylene chloride, the organic extracts was separated, washed twice with water and was evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using heptane:methylene chloride (3:7) as eluent gave 8.0 g (67%) of the title compound.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[CH2:21]([NH:24][CH:25]1[CH2:33][CH2:32][C:28]2[N:29]=[CH:30][S:31][C:27]=2[CH2:26]1)[CH2:22][CH3:23]>>[CH2:21]([N:24]([CH:25]1[CH2:33][CH2:32][C:28]2[N:29]=[CH:30][S:31][C:27]=2[CH2:26]1)[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH2:22][CH3:23]
Reactant: O=CCCCNC(=O)N1CC=C(c2ccccc2)CC1
Reactant: CCCNC1CCc2ncsc2C1
Product: CCCN(CCCCNC(=O)N1CC=C(c2ccccc2)CC1)C1CCc2ncsc2C1
Yield: 45 %

Procedure:
Compound 62 is prepared from 62C and 1C as described for 1. The salt of maleic acid is crystallized from acetonitrile/diethylether.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[OH-].[Pd+2].[OH-]>[F:13][C:8]1[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Fc1ncccc1C1=CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ncccc1C1CCOCC1

Procedure:
To a rbf was added 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine (2.1320 g, 11.90 mmol) and palladium hydroxide (0.835 g, 1.190 mmol) in EtOAc (39.7 mL). The rbf was flushed with argon and then placed under vacuum three times. A hydrogen balloon was then attached to the reaction. Upon completion, the reaction was filtered through celite and concentrated. MS (ESI, pos. ion) m/z: 182.1.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]4[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:17]5[CH2:18][CH2:9][CH:10]([OH:27])[CH2:11][CH2:16]5)=[CH:14][CH:15]=4)[C:10](=[O:27])[C:9]=3[CH:8]=2)=[O:5])[CH2:31][CH2:30]1
Reactant: OC1CCNCC1
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Product: O=C(CCN1CCC(O)CC1)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCC(O)CC4)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (1.0 g, 2.5 mmol) was treated with 4-hydroxypiperidine (5 mL) according to the general aminolysis procedure to give the desired product JM-ACO-08 (776 mg, 58%) as a pale yellow/green solid.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[Cl:9]N1C(=O)CCC1=O>C1C=CC=CC=1>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][Cl:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Product: Cc1ccc(SCl)cc1
Yield: 88.2 %

Procedure:
By the method of Example 7, 6.2 g. of p-toluenethiol (6.2 g., 50 mmoles) was reacted with N-chlorosuccinimide (6.67 g., 50 mmoles) in 100 ml. of benzene to yield p-toluenesulfenyl chloride (7.0 g.) as an oil.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[C:8]=1OS(C(F)(F)F)(=O)=O.[I-:25].[Na+]>O>[Br:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[C:8]=1[I:25]
Reactant: O=[N+]([O-])c1cc(Br)c(OS(=O)(=O)C(F)(F)F)c(Br)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c(I)c(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Dimethylformamide (4 L) and trifluoromethane sulfonic acid 2,6-dibromo-4-nitrophenyl ester (1135 g, 2.65 moles) were charged into a 22 L jacketed vessel equipped with a mechanical stirrer, a condenser, and a nitrogen purge. Sodium iodide (1595 g, 10.64 moles) was added to the reaction mixture in portions while maintaining the reaction temperature below 25° C. The reaction mixture was then heated to 100° C. and monitored for completion by HPLC. Upon completion, the reaction mixture was cooled to 0° C. Water (4 L) was added while maintaining the temperature below 14° C. The reaction mixture was stirred for 30 min, then filtered and washed with water (1.5 L). The resultant solid product was dried overnight by evaporation under air flow at room temperature to yield 1,3-dibromo-2-iodo-5-nitrobenzene (892.7 g, 82.9%). The product may optionally be purified further by recrystallization from ethanol.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([Mg]Br)C.[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19]C(=O)OC(C)(C)C)=O.C[Li]>C1COCC1.CCOCC>[CH3:7][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)Oc1ccccc1C=O
Reactant: C#C[Si](C)(C)C
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C#C[Si](C)(C)C)c1ccccc1O
Reaction time: 2 h

Procedure:
A solution of 18.5 grams (188 mmol, 2.2 eq) of trimethylsilylacetylene in 90 mL of dry THF was stirred under argon in a dry 500 mL round bottom flask at room temperature. To this solution was then slowly added 171 mL (171 mmol of a 1.0 M solution in THF, 2.0 eq) of ethyl magnesium bromide. The colorless solution was stirred for 2 hours. In a separate dry 1 L round bottom flask; 19.0 grams (85.5 mmol, 1.0 eq) of aldehyde 4 was dissolved in 270 mL of dry THF under argon. This solution was then cooled to −78° C. in an acetone/dry ice bath at which time 56.0 mL (89.7 mmol of a 1.6 M solution in Et2O, 1.05 eq) of methyl lithium was added with a syringe pump (2.5 mL/minute) and stirred at −78° C. for 25 minutes. The dry ice bath was then removed and the solution was stirred for 10 minutes at room temperature. The initial Grignard solution from the first flask was then added via cannula to the room temperature 1 L flask and the combined solutions were stirred for 2 hours under argon at room temperature. The solution was then diluted with Et2O and washed sequentially with 1.0 M HCl, saturated NaHCO3, brine and dried over MgSO4. The resulting colorless oil could be purified via silica gel chromatography (hexanes/EtOAc) or used directly in the subsequent step, Rf 0.29 (7:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.16 (m, 2H), 6.89 (m, 2H), 6.18 (s, 1H), 3.89 (q, J=7.1 Hz, 1H), 1.51 (d, J=7.3 Hz, 3H), 0.20 (s, 9H). 13C-NMR (500 MHz, CDCl3): 154.02, 128.56, 128.41, 128.26, 121.15, 117.19, 108.45, 88.53, 29.24, 22.58, 0.16. IR (cm−1): 3447 (b), 2959 (w), 2163 (w), 1591 (w), 1453 (m), 1249 (s), 843 (s), 754 (s). HRMS (EI) calcd. for C13H18OSi: 218.1127. found: 218.1129.