Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.[CH2:31]([O:33][C:34](=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41])[CH3:32]>ClCCl>[CH2:31]([O:33][C:34](=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:41])[N:12]([CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:19][CH:18]=[CH:17][C:16]=2[O:20][CH3:21])[CH2:7][CH2:8]1)[CH:13]([CH3:15])[CH3:14])[CH3:32]
Reactant: COc1cccc(OC)c1CN1CCC(NC(C)C)CC1
Reactant: CCOC(=O)CCCCCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(=O)N(C(C)C)C1CCN(Cc2c(OC)cccc2OC)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
A solution of [1-(2,6-dimethoxybenzyl)piperidin-4-yl]isopropylamine (1.3 g, 4.6 mmol) and N,N-diisopropylethylamine (1.2 mL, 9.9 mmol) in dichloromethane (40 mL) was cooled to 0° C. under nitrogen. 6-Chlorocarbonylhexanoic acid ethyl ester (0.73 mL, 5.0 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 2 h and then at room temperature for an additional 2 h. The reaction mixture was then transferred to a separatory funnel and washed with NaHCO3 (2×) and brine (1×). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title intermediate as a yellow oil (2.2 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[Br:25][C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=5[CH:23]=[CH:24][C:9]3=4)=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3c(c2N1)CCCC3
Yield: 28.5 %

Procedure:
5-(4-Aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (65 mg, 202 mmol) obtained in Example 55, and 3-bromobenzenesulfonyl chloride (78 mg, 0.305 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to obtain the title compound (47 mg, yield 43%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.Cl[C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1>>[CH3:23][O:22][C:16]1[N:17]=[C:18]([O:20][CH3:21])[N:19]=[C:14]([CH:8]2[C:7]3[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[NH:10][C:9]2=[O:12])[N:15]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: COc1cccc2c1NC(=O)C2
Product: COc1nc(OC)nc(C2C(=O)Nc3c(OC)cccc32)n1

Procedure:
7-Methoxy-1,3-dihydro-2H-indol-2-one (1.24 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.84 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 87% area (1.04 g, 43% of theory).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)=[O:2].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCCC.CCOC(C)=O>[C:20]([C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=1)#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Reactant: C#CCCCCC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccc(C=O)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-formyl-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (60 mg, 70%); 1H NMR δ (CDCl3): 10.02 (s, 1H), 7.8 (d, J=8.65 Hz, 2H), 7.53 (d, J=8.62 Hz, 2H), 2.45 (t, J=7.22 Hz, 2H), 1.62 (p, J=7.11 Hz, 2H), 1.48-1.3 (m, 4H), 0.93 (t, J=7.20 Hz, 3H); LCMS m/z: 200
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19]([OH:21])=O)[NH:11][C:12]([O:14]C(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl.[CH2:40]([NH:47][CH2:48]C(OCC)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([N:47]1[CH2:48][C:12](=[O:14])[NH:11][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:19]1=[O:21])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1CN(Cc2ccccc2)C(=O)[C@H](COCc2ccccc2)N1

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step A, except using O-benzyl Boc-L-serine (10 g, 33.8 mmol), dicyclohexylcarbodiimide in methylene chloride (0.5M) (68 mL, 34.0 mmol) and ethyl N-benzylglycinate (6.34 mL, 34.0 mmol). After deprotection with hydrogen chloride in dichloromethane (200 mL), neutralization, and recrystallization of the crude product from ethyl acetate, the title compound was obtained as a white solid (10.3 g). NMR (300 MHz, CDCl3) δ 7.58 (10H, m), 6.41 (1H, br s), 4.74 (1H, d, J=15 Hz), 4.53 (2H, AB q, J=12 Hz, Δν=20 Hz), 4.45 (1H, d, J=15 Hz), 4.22 (1H, m), 3.92 (1H, d, J=17 Hz), 3.88 (1H, dd, J=8, 10 Hz), 3.81 (1H, dd, J=6, 10 Hz), 3.75 (1H, d, J=17 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]2[CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[N+:20]([O-])([OH:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:18])[N:15]=[C:14]2[CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(C)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a stirred solution of 8-methyl-6-(2,4-dimethylimidazol-1-yl)-2-(1H)-quinolone (0.5 g) in concentrated sulphuric acid (4 cm3) at 0° was added concentrated nitric acid (1 cm3). The mixture was stirred for 1 hour, poured carefully onto ice (100 g), and the solution basified to pH8 with solid sodium carbonate. The resulting suspension was extracted with dichloromethane (3×100 cm3) and the combined organic phases were dried (MgSO4), filtered, and evaporated to yield a foam which was triturated with ethyl acetate/ether or afford 8-methyl-6-(2,4-dimethyl-5-nitro-imidazol-1-yl)-2-(1H)-m.p. 244°-247°, (0.52 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:13][C:14]1[C:15]([NH:26][NH2:27])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]#[N:25])=[CH:19][CH:18]=2.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[C:15]([NH:26][NH:27][C:10](=[O:11])[CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]#[N:25])=[CH:19][CH:18]=2
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Reactant: N#Cc1ccc2nc(NN)c(Cl)nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(=O)NNc1nc2ccc(C#N)cc2nc1Cl)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (2.15 g, 10 mmol) in 20 ml of dry tetrahydrofuran was added to a solution of 3-chloro-6-cyano-2-hydrazinoquinoxaline (2.0 g, 9 mmol) and dry triethylamine (1.4 ml, 10 mmol) in 100 ml of dry tetrahydrofuran. The mixture was stirred at room temperature overnight, and filtered. The filtrate was evaporated, and the title compound was isolated as a semisolid residue, which was used in the next step without further purification; 1H-NMR (DMSO-d6): δ 1.26 (t, 6H), 3.09 (d, 2H), 4.10 (quint, 4H), 7.71 (d, 1H), 7.97 (dd, 1H), 8.39 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:30])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])(=[O:22])=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.[Li+].[OH-]>C1COCC1.O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([NH:19][CH2:18][CH2:17][C:16]([C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[C:14]=1[CH3:15])=[CH2:30])(=[O:21])=[O:22]
Reactant: C=C(CCNS(=O)(=O)c1ccccc1Cl)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CCNS(=O)(=O)c1ccccc1Cl)c1c(C)c(CC(=O)O)cc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a solution of {4-[3-(2-Chloro-benzenesulfonylamino)-1-methylene-propyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (140 mg, 0.294 mmol) in THF (6 mL) was added a solution of LiOH (141 mg, 5.88 mmol) in water (1.5 mL). The resulting mixture was warmed with a heat gun to produce a clear solution, which was stirred for 15 hours at room temperature. At this time, LCMS analysis indicated the complete conversion of starting material. The THF was evaporated and the aqueous layer was diluted with water and slowly neutralized with 1.0 N HCl to obtain a white precipitate which was collected by filtration and washed with water and hexanes. After air drying, 125 mg of {4-[3-(2-chloro-benzenesulfonylamino)-1-methylene-propyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid was isolated as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (bs, 1H), 7.96 (t, J=5.6 Hz, 1H), 7.87-7.93 (m, 2H), 7.73 (s, 1H), 7.59-7.62 (m, 2H), 7.45-7.51 (m, 1H), 7.29-7.38 (m, 2H), 5.50 (dd, J=3.3, 1.2 Hz, 1H), 4.93 (d, J=1.0 Hz, 1.2H), 3.72-3.80 (m, 2H), 3.00-3.12 (m, 2H), 2.30-2.39 (m, 2H), 2.17 (s, 3H). MS cald. for C23H22ClFNO4S [(M+H)+] 462.1, obsd. 462.0.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH:6]=[CH:5][N:4]=1>CO.CCOC(C)=O>[NH2:17][C:12]1[CH:11]=[C:10]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: CNc1nccc(Oc2ccc(O)c([N+](=O)[O-])c2)n1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1nccc(Oc2ccc(O)c(N)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(2-Methylamino-pyrimidin-4-yloxy)-2-nitro-phenol (Step D, 0.163 g, 0.620 mmol) was dissolved in 7 mL MeOH and 15 mL EtOAc. To the argon-degassed solution was added 10% by weight Pd/C (0.08 g). The reaction was stirred vigorously at RT under 1 atm H2 gas for 18 h. The reaction was filtered through a Celite® plug and concentrated to dryness to yield the title compound. MS (MH+)=233.1; MW Calc'd 232.24 for C11H12N4O2.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[N:24]([CH:30]2[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]2=[O:37])[CH2:23]3)=[O:17])=[CH:11][C:10]=1[CH3:38])(C(C)(C)C)(C)C.Cl>C(Cl)Cl.CCOCC>[O:37]=[C:31]1[CH:30]([N:24]2[CH2:23][C:22]3[C:26](=[CH:27][CH:28]=[C:20]([CH2:19][NH:18][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH3:38])[CH:11]=4)=[O:17])[CH:21]=3)[C:25]2=[O:29])[CH2:35][CH2:34][C:33](=[O:36])[NH:32]1
Reactant: Cc1cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.2 %

Procedure:
To a solution of the product from Step 3 (0.5 g, 0.9 mmol) in methylene chloride (20 mL) was added 2N HCl in ether (2 mL). The mixture stirred for 16 h at ambient temperature. The precipitated product was isolted by filtration, and was rinsed with methylene chloride (20 mL) and dried under vacuum, providing 0.4 g of 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-hydroxy-3-methylphenyl)urea as an off-white solid, in quantitaive yield; HPLC:Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 1.88 min (96.94%); mp 210-212° C.; 1H NMR (DMSO-d6) δ 1.94-2.18 (m, 4H), 2.30-2.51 (m, 1H), 2.58-2.72 (m, 1H), 2.87-3.06 (m, 1H), 4.25-4.56 (m, 4H), 5.15 (dd, J=5.0, 13.3 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 7.02 (dd, J=2.5, 8.6 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.54 (s, 1 H), 7.73 (d, J=7.7 Hz, 1H), 8.32 (br. s., 1H), 11.02 (s, 1H); 13C NMR (DMSO-d6) δ 16.15, 22.51, 31.20, 42.77, 47.12, 51.56, 114.47, 117.11, 121.32, 121.83, 122.88, 123.61, 126.86, 130.22, 131.72, 142.35, 145.17, 150.10, 155.58, 170.99, 172.85; LCMS MH=423; Anal. Calcd for C22H22N4O5+0.25 CH2Cl2: C, 60.23; H, 5.11; N, 12.63; Found: C, 60.14; H, 5.43; N, 12.54.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[S:6][CH:7]=1.Cl.C[O:24][C:25](=[O:31])[C@H:26]([CH:28]([CH3:30])[CH3:29])[NH2:27]>>[CH3:29][CH:28]([CH3:30])[C@H:26]([NH:27][C:16](=[O:18])[C@H:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([C:2]([F:1])([F:21])[F:20])[N:4]=2)=[CH:14][CH:13]=1)[CH3:19])[C:25]([OH:31])=[O:24]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: C[C@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)C(=O)O
Yield: 40.4 %

Procedure:
Following the same procedure described for 16 and starting from (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (3) (0.18 g, 0.57 mmol) and L-valine methyl ester hydrochloride (0.095 g, 0.57 mmol), after workup compound 17 (0.093 g, 0.23 mmol) was isolated as a white solid (69%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].[CH2:20]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CN(C)C=O>O>[CH2:39]([N:38]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 87.2 %

Procedure:
A mixture of 1-chloro-2,4-dinitrobenzene (Aldrich, 2.02 g, 10 mmol), sodium carbonate (1.27 g, 12 mmol), dioctadecylamine (Pfaltz & Bauer, 6.26 g, 12 mmol) and dry dimethylformamide (10 mL) was heated to 80°-90° C. under a nitrogen atmosphere for 1 h. The cooled mixture was diluted with water and extracted with ether. The extracts were washed with water and dried over magnesium sulfate. The solvent was removed and the solid recrystallized to give N,N-dioctadecyl-2,4-dinitrobenzenamine (6.0 g, 87%): mp 55.5°-57.5° C.
Reaction SMILES: [F:1][C:2]([F:22])([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][CH2:19][CH2:20][CH3:21])[C:3]([CH3:5])=[CH2:4].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:4][C:3]([C:2]([F:22])([F:1])[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][CH2:19][CH2:20][CH3:21])=[CH2:5]
Reactant: C=C(C)C(F)(F)CCCCCCCCCCCCCCCC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)C(F)(F)CCCCCCCCCCCCCCCC

Procedure:
A slurry of 140 mg of 3,3-difluoro-2-methyl-1-nonadecene in 2 ml of carbon tetrachloride containing 43 mg of N-bromosuccinimide and a catalytic amount of azobisisobutryonitrile is stirred at ambient temperature for 30 minutes. The mixture is filtered through a short pad of silica gel which is repeatedly washed with hexane. The combined filtrates are evaporated and the residue is purified on silica gel using hexanes to give 38 mg of the desired product as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(OCC)(=O)C>CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][O:12][C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:6][CH:5]=1
Reactant: CCCCC(CO)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCC(COc1ncccn1)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a flask was charged 0.15 g (0.0034 mole) of 60% sodium hydride, washed with 2×30 mL hexane, in 20 mL of tetrahydrofuran. While stirring at room temperature, 1.0 g (0.0034 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexan-1-ol was added. The slurry was stirred at room temperature and 0.39 g of 2-chloropyrimidine (0.0034 mole) was added. The reaction was stirred overnight after which TLC using ethyl acetate indicated the reaction was complete. The product was isolated from ether after quenching and washing with water. After drying and removal of the solvent, 1.30 g (100% yield) of an oil resulted.
Reaction SMILES: Br[CH:2]1[C:6]2[C:7]([Cl:14])=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(N(CC)CC)C.CS(C)=[O:26]>F[B-](F)(F)F.[Ag+]>[Cl:14][C:7]1[C:6]2[C:2](=[O:26])[C:3]([CH3:16])([CH3:15])[O:4][C:5]=2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: CC1(C)Oc2c([N+](=O)[O-])ccc(Cl)c2C1Br
Reactant: CS(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CC1(C)Oc2c([N+](=O)[O-])ccc(Cl)c2C1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 15.0 g (0.0489 mole) of 3-bromo-4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran in 100 mL of dimethyl sulfoxide was added slowly to a mixture of 9.73 g (0.050 mole) of silver tetrafluoroborate in 100 mL of dimethyl sulfoxide. Upon completion of addition, 5.0 g (0.050 mole) of triethylamine was added to the reaction mixture, and stirring was continued for approximately 16 hours at ambient temperature. At the conclusion of this period the reaction mixture was heated at 60° C. for one hour and then cooled to ambient temperature. The mixture was filtered, and the filtrate was poured into 200 mL of water. This mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving a residue. This residue was passed through a column of silica gel, yielding 5.35 g of 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-one as a solid residue, m.p. 167°-168° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[N:29]1([C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (50.64 g, 220.9 mmol) in anhydrous tetrahydrofuran (552 mL) at 2° C. was added 1,1′-carbonyldiimidazole (77.59 g, 460 mmol). The mixture was stirred at room temperature for 2 h, cooled to 10° C. and then pyrrolidine (74 mL, 890 mmol) was added slowly. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and water (200 mL) was added to the residue. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with aqueous hydrochloric acid (200 mL×4, 1N) and with a saturated aqueous solution of sodium bicarbonate (200 mL×2). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate as a white solid (58.82 g). The compound was used for the next step without further purification. 1H NMR (400 MHz, CD3OD) δ 1.39-1.54 (m, 10H) 1.59-1.65 (m, 1H) 1.67 (d, 1H) 1.69-1.77 (m, 1H) 1.80-2.05 (m, 5H) 2.58 (tt, 1H) 2.77 (br s, 1H) 3.33-3.46 (m, 2H) 3.51-3.66 (m, 2H) 3.98-4.12 (m, 2H); MS (AP+) (M+H) 283.3.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:6]=2[C:5]=1[C:14]([O:16]C)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=1>>[CH3:18][C:19]1[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH2:26][N:27]2[C:14](=[O:16])[C:5]3[C:6]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:23]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCCC2
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCCCC4)cn1

Procedure:
The compound was synthesized starting from methyl 5,6,7,8-tetrahydro-2-isothiocyanato-4H-cyclohepta[b]thiophene-3-carboxylate (0.111 g. 0.42 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.058 g, 0.42 mmol) as described above.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>[Pd]>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CNC(=O)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Product: CNC(=O)Cn1ccnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 355, 2-[2-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-imidazol-1-yl]-N-methyl-acetamide and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki palladium conditions to give 405 MS: (ESI+)=497.2. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.93 (s, OH), 7.38 (d, J=0.8 Hz, 1H), 7.32 (dd, J=8.3, 1.8 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.05 (d, J=0.8 Hz, 0H), 5.23 (s, 1H), 4.72 (s, 1H), 4.34 (t, J=5.0 Hz, 1H), 4.04 (s, 1H), 2.66 (t, J=4.4 Hz, 2H), 1.08 (s, 6H)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[I:33]I.O>CC#N>[F:1][C:2]1[CH:9]=[C:8]([I:33])[C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: II
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COc1cc(C=O)c(F)cc1I
Temperature: 80 °C
Yield: 82 %

Procedure:
A solution of 2-fluoro-5-methoxybenzaldehyde (Oakwood, 6.000 g, 38.9 mmol) and Selectfluor (13.79 g, 38.9 mmol) in 40 mL MeCN was treated with iodine (10.87 g, 42.8 mmol) and was heated to 80° C. for one hour. LC/MS showed mostly product, so the reaction mixture was poured into water and was extracted with DCM. The organic were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-20% EtOAc/heptane) gave 2-fluoro-4-iodo-5-methoxybenzaldehyde (8.92 g, 31.9 mmol, 82% yield) as a 3:1 mixture with starting material. (M+H)+=281.0.