Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:10]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])[C:11](=[O:12])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([CH3:20])=[C:13]([N:10]2[C:11](=[O:12])[C:4]3[CH:3]=[C:2]([C:33]4[C:34]([O:36][CH3:37])=[N:35][C:30]([O:29][CH3:28])=[N:31][CH:32]=4)[N:6]([CH2:7][CH3:8])[C:5]=3[CH:9]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:18]=1
Reactant: CCn1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: CCn1c(-c2cnc(OC)nc2OC)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-ethyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate K) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The product was purified by flash chromatography to afford the title compound as a white solid. tR: 5.69 min (HPLC 4); ESI-MS: tR=1.30 min, [M+H]+ 523/525 (LC-MS 1); 1H-NMR (d6-DMSO, 600 MHz, 100° C.): (rotamers) 8.31 (s, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.26 (m, 2H), 7.15-7.23 (m, 2H), 6.37 (s, 1H), 6.29 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.38/3.59 (m, 2H), 2.07 (s, 3H), 0.86 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[N:6]=1.C([O-])([O-])=[O:14].[K+].[K+]>O1CCOCC1.O>[Cl:11][C:9]1[CH:10]=[C:5]2[NH:4][CH2:3][CH2:2][N:6]2[C:7](=[O:14])[N:8]=1
Reactant: Clc1cc(NCCBr)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(Cl)cc2n1CCN2
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of N-(2-bromoethyl)-2,6-dichloropyrimidin-4-amine (10 g, 18 mmol) in 1,4-dioxane (30 mL) and water (30.0 mL) was added K2CO3 (4.85 g, 35.1 mmol). The reaction mixture was stirred at 70° C. for 4 h, and then directly used into next step without further purification.
Reaction SMILES: [C:1]([O:5]CC[N:8]=[C:9]=[O:10])(=[O:4])[CH:2]=[CH2:3].COC1C=CC(O)=CC=1.C(C1C=CC(C)=[C:26]([OH:31])[C:25]=1C(C)(C)C)(C)(C)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:8][C:9]([O:31][CH2:26][CH3:25])=[O:10]
Reactant: Cc1ccc(C(C)(C)C)c(C(C)(C)C)c1O
Reactant: C=CC(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 60 °C

Procedure:
625 g (0.5 mol) of polyester polyol in the form of polycaprolactone diol (Daicel Chemical Industries, PLACCEL212, molecular weight: 1,250) and 142 g (1.0 mol) of 2-acryloyloxyethylisocyanate and 1.0 g each of p-methoxyphenol and di-t-butyl-hydroxytoluene were placed in a reaction vessel equipped with a stirring device, thermometer and condenser. After heating to 60° C. while stirring, heating was discontinued followed by the addition of 0.2 g of dibutyl tin dilaurate. Heating was resumed when the temperature inside the reaction vessel began to drop and stirring was continued at 80° C. The reaction was completed by confirming that the absorption spectrum of the isocyanate group (2,280 cm−1) had disappeared based on the infrared absorption spectrum to obtain a urethane acrylate compound in the form of a viscous liquid. The average molecular weight of the resulting urethane acrylate (UA-1) was 1,600.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:8](Br)[C:9]1C=C[CH:12]=[CH:11][CH:10]=1.C[CH2:17][O:18][C:19](C)=[O:20]>C(Cl)Cl>[CH2:1]([N:3]1[CH2:6][CH2:7][CH2:5][C@H:4]1[C:19]([O:18][CH3:17])=[O:20])[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(C)=O
Reactant: BrCc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
1-praline methyl ester hydrochloride (5.8 g, 35 mmol) was suspended in DCM (40 mL), to it was added triethylamine (12 ml, 84 mmol). After stirring for 10 min, the precipitate formed was filtered off and washed with DCM (5 mL). To the filtrate was added benzyl bromide (5.0 ml, 42 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 25% EtOAc in hexane, to provide (S)-methyl 1-benzylpyrrolidine-2-carboxylate as colorless oil. MS (ESI, pos. ion) m/z: 220.0 (M+1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].Br[CH2:20][CH2:21]Br>O>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:20][CH2:21][NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[F:11])([OH:10])=[O:9]
Reactant: BrCCBr
Reactant: Nc1ccccc1C(=O)O
Reactant: Nc1ccccc1F
Solvent: O
Product: O=C(O)c1ccccc1NCCNc1ccccc1F
Temperature: 100 °C
Reaction time: 10 h
Yield: 9 %

Procedure:
A solution of anthranilic acid (1.0 g, 7.3 mmol) in 1,2-dibromoethane (3 mL, 300 mol %) was heated to 100° C., and then o-fluoroaniline (2 mL, 200 mol %) was added. The reaction mixture was stirred at 100° C. for 10 h, then stirred at rt for 24 h. The reaction mixture was diluted with water and then extracted with EtOAc (3×100 mL). The EtOAc layer was washed with water, dried over MgSO4, filtered, and then concentrated. Purification by LPLC (EtOAc-hexane 1:5, then EtOAc-hexane 1:1) gave 0.17 g (9%) of the title compound which contained an impurity. The title compound was dissolved in small amount of hot EtOAc, hexane was added dropwise, and then the solution was allowed to stand at 0° C. until crystallization commenced, and then it was allowed to stand at rt for 15 h. Filtration and then drying in a vacuum oven several hours at 40°-45° C. gave 70 mg (3.5%) of the title compound: 1H NMR (CDCl3) δ8.00 (d, 1H, J=8, NH), 7.42 (t, 2H, J=6.8), 7.05-6.97 (m, 2H), 6.80-6.65 (m, 4H), 3.55 (d, 2H, J=4.8), 3.51 (d, 2H, J=4); 13C NMR (CDCl3) δ173.37, 151.72 (d, J=238), 151.38, 135.63, 132.83, 124.60 (d, J=3.8), 117.27 (d, J=6.8), 115.30, 114.73, 114.54, 112.32, 111.33, 109.25, 42.75, 42.12; MS (EI, m/z) 274 (M+). HRMS (EI) calcd for C15H15N2O2F 274.1118, found 274.1111.
Reaction SMILES: ClC(O[C:6](Cl)=[O:7])(Cl)Cl.[N:9]1[C:18]2[C:13](=CC=CC=2)[CH:12]=[CH:11]C=1.[F:19][C:20]1[CH:53]=[C:52]([F:54])[C:51]([F:55])=[CH:50][C:21]=1[CH2:22][O:23][CH2:24][C@@H:25]1[CH2:29][C@@H:28]([S:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][NH:26]1.N1CCCC1>C(Cl)Cl>[N:9]1([C:6]([N:26]2[CH2:27][C@H:28]([S:30][C:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:29][C@H:25]2[CH2:24][O:23][CH2:22][C:21]2[CH:50]=[C:51]([F:55])[C:52]([F:54])=[CH:53][C:20]=2[F:19])=[O:7])[CH2:11][CH2:12][CH2:13][CH2:18]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Reactant: c1ccc2ncccc2c1
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(N1CCCC1)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Reaction time: 2 h
Yield: 109 %

Procedure:
A solution of 0.02 ml (0.18 mmol) trichloromethylchloroformate in 3 ml CH2Cl2 was treated at 0° C. with 0.04 ml (0.37 mmol) quinoline and after 15 min with 0.17 g (0.33 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine in 2 ml CH2Cl2. After 2 h, the reaction was evaporated and redissolved in 15 ml CH2Cl2 and treated at 0° C. with 0.14 ml (1.65 mmol) pyrrolidine and stirred for 30 min. The reaction was extracted with aqueous 10% KHSO4/Et2O (3×) and the organic phase was dried over Na2SO4. Evaporation and precipitation from Et2O/pentane gave 121 mg (59%) (2S,4R)-Pyrrolidin-1-yl-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-methanone, MS: 617 (M+H+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:35])[CH:20]([CH:21]=[C:22]([Cl:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:19]1[C:32](Cl)=[O:33].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[F:16][C:15]1[CH:14]=[CH:13][C:10]([CH2:11][O:12][C:32]([CH:19]2[CH:20]([CH:21]=[C:22]([Cl:31])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:18]2([CH3:35])[CH3:17])=[O:33])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: COc1ccc(C(Cl)=CC2C(C(=O)Cl)C2(C)C)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(Cl)=CC2C(C(=O)OCc3ccc(F)c(Oc4ccccc4)c3)C2(C)C)cc1
Reaction time: 3 h
Yield: 84.2 %

Procedure:
4.4 g (0.02 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 7.1 g (0.02 mol) of 2,2-dimethyl-3-(2-chloro-2-(4-methoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., whilst stirring. Stirring was then continued at 25°-35° C. for 3 hours. The reaction mixture was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last solvent residues were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.1 g (84.5% of theory) of 2,2-dimethyl-3-(2-chloro-2-(4-methoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid 4-fluoro-3-phenoxy-benzyl ester were obtained.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.C([O-])(O)=O.[Na+].[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O.CO>[NH:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:7][C:6]=2[N:5]=[CH:4]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: c1nc2c([nH]1)CCNC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A mixture of 2.0 g of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine dihydrochloride, 2.36 g of NaHCO3 and 2.45 g of N-(benzyloxycarbonyloxy)succinimide in 80 ml of dioxane/water mixture (50/50; v/v) is stirred for 16 hours at RT. The reaction mixture is extracted with EtOAc, the organic phase is washed with a saturated solution of NaHCO3, with 0.1M HCl solution, with saturated NaCl solution, it is dried and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/MeOH mixture. 1.9 g of the expected compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH2:15][CH2:16][N:17]=1.C(O)C>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:12]=[C:13]3[N:17]([CH:7]=2)[CH2:16][CH2:15][S:14]3)=[CH:4][CH:3]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: NC1=NCCS1
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2cn3c(n2)SCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 51.6 g (0.3 mol) of 4-fluorophenacylchloride, 33.66 g (0.33 mol) of 2-aminothiazoline and 200 ml of ethanol was heated at reflux for 2 hours. The mixture was cooled to room temperature at which point 300 ml of water was added. After a reflux period of 2 hours, the mixture was concentrated to remove about 190 ml of aqueous alcohol. The pH of the residue was adjusted to about 2 with 10% hydrochloric acid (10 ml). The solid product was separated and dried to give 65.4 g (85%) of 6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 116-118°.
Reaction SMILES: [CH2:1]([C:6]([CH:11]([CH3:13])[CH3:12])([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH:3]([CH3:5])[CH3:4].N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O.O1CCCC1>[C:29]([O:8][CH2:7][C:6]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])([CH:11]([CH3:13])[CH3:12])[CH2:9][O:10][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:32])[CH2:30][CH3:31]
Reactant: CCC(=O)Cl
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CCC(CO)(CO)C(C)C
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)OCC(CCC(C)C)(COC(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
To 7.5 g (0.05 mol) 2-isoamyl-2-isopropyl-1,3-propandiol, which was prepared according to the process described in synthetic example 63, was added 50 ml tetrahydrofuran, then added 4.8 ml (0.06 mol) pyridine with stirring. To the resulting homogenous mixture was slowly added 4.6 ml (0.04 mol) benzoyl chloride. The mixture was stirred at room temperature for 1 hour and heated refluxing for 5 hours. Upon completing the reaction, the reaction mixture was cooled to room temperature. To the mixture was added 30 ml tetrahydrofuran, then added 4.8 ml (0.06 mol) pyridine with stirring. To the resulting homogenous mixture was slowly added 3.5 ml (0.04 mol) propionyl chloride. The mixture was stirred at room temperature for 1 hour, and heated refluxing for 5 hours. Upon completing the reaction, 40 ml water was added to dissolve the resulting salt. The mixture was extracted with ethyl acetate. The organic phase was separated, washed with saturated saline for two times, and dried over anhydrous sodium sulfate. The solvent was removed. Distillation under reduced pressure gave colorless liquid 2-isoamyl-2-isopropyl-1,3-propandiol monobenzoate monopropionate, and the yield was 91%. 1HNMR: δ (ppm) 0.87(d, 6H, CH3 of isoamyl), 0.93(d, 6H, CH3 of isopropyl), 0.99(t, 2H, CH3 of propionyl), 1.06(m, 4H, CH2 of isoamy), 1.11(m, 1H, CH of isoamyl), 1.14(m, 1H, CH of isopropyl), 2.29(m, 2H, CH2O of 1,3-propandiol), 4.28(m, 2H, CH2O of 1,3-propandiol), 4.38 (m, 2H, CH2 of propionyl), 7.41-8.03(m, 5H, ArH)
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=O.[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+].S(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)(=O)C>COCCOCCOC>[CH2:5]([C:4]1[C:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:2]([CH:9]=[CH:8][CH:7]=1)[CH:11]=[O:14])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Product: CCCCC/C=C\C/C=C\CCCCCCCCc1cccc(C=O)c1CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 100 °C
Yield: 98.7 %

Procedure:
3,4-Dihydroxybenzaldehyde (2.76 g, 20.0 mmol) was weighed into a 200 mL round bottomed flask with a stir bar. The flask was charged with diglyme (100 mL), septum sealed and flushed with argon. Cesium carbonate (19.5 g, 60.0 mmol) was added to the solution slowly in portions. Linoleyl mesylate (15.2 g, 44.0 mmol) was added via syringe. The reaction mixture was heated to 100° C. under slight positive pressure of argon. The reaction mixture was cooled to room temperature and filtered. The solids were washed with 1,2-dichloroethane. The combined filtrate and washes were concentrated and then dried under high vacuum at 65° C. to remove residual diglyme. The resultant yellow oil was purified via flash chromatography (5% ethyl acetate in hexanes) to afford 11.9 g (94%) of a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O.N1CCC[CH2:16]1.COC(OC)N(C)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[CH:1]=[CH:16][NH:12]2
Reactant: C1CCNC1
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2[nH]ccc12
Temperature: 60 °C
Yield: 57.2 %

Procedure:
A solution of 2-methyl-1-nitro-3-(trifluoromethyl)benzene (10.00 g, 48.8 mmol), pyrrolidine (4.44 mL, 53.7 mmol) and dimethylformamide dimethylacetal (19.8 mL, 146 mmol) in DMF (100 mL) was heated at 100° C. for 4 h, cooled and concentrated in vacuo. The residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in THF/MeOH (1:1, 200 mL), and transferred to a 3-necked flask equipped with an overhead stirrer, reflux condenser, and dropping addition funnel. Raney-Ni (Raney® 2800 slurry in water, 10 g) was added in one portion and the entire apparatus was thoroughly flushed with N2. The mixture was heated to 60° C., under N2, and a solution of hydrazine monohydrate (8 mL) in THF/MeOH (1:1, 20 mL) was added dropwise over 1 h. The mixture was heated at 60° C. for 1 h, cooled, and filtered through a pad of Celite®. The filtrate was concentrated in vacuo, the residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (10% HCl, H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 5.17 g of the title compound as a light brown liquid: 1H NMR (300 MHz, methanol-d4) δ 7.61 (d, J=8.2 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.19 (partially resolved dd, J≈8.4, 7.5 Hz, 1H), 6.59 (br. s, 1H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][C:11]1([CH3:16])[CH2:15][CH2:14][NH:13][CH2:12]1.CCN(CC)CC>O>[CH3:10][C:11]1([CH3:16])[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:12]1
Reactant: Nc1cccc(F)n1
Reactant: CC1(C)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCN(c2cccc(N)n2)C1
Temperature: 205 °C
Yield: 78.5 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol), 3,3-dimethylpyrrolidine hydrochloride (0.73 g, 5.35 mmol) and Et3N (1.08 g, 10.7 mmol) in water (0.2 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200-300 mesh, ethyl acetate:petroleum ether=1:15) to afford 6-(3,3-dimethylpyrrolidin-1-yl)pyridin-2-amine (0.67 g, 78%) as a yellow oil. LC-MS: [M+1]+=192, tR=1.187 min.
Reaction SMILES: [CH3:1][Li].[NH2:3][C:4]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:5]=1[C:6](N(OC)C)=[O:7]>O1CCCC1.O>[NH2:3][C:4]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:5]=1[C:6](=[O:7])[CH3:1]
Reactant: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(Cl)ccc(Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
At −78° C. a solution of methyl lithium (1.6M in diethyl ether, 25 ml, 40 mmol) was added dropwise to a solution of 2-amino-3,6-dichloro-N-methoxy-N-methyl-benzamide (2.5 g, 10 mmol) in tetrahydrofurane (100 ml). After complete addition, the reaction was warmed to r.t. The dark solution was stirred for 3 hours at room temperature. Under ice cooling 2N aqueous hydrochloride solution (25 ml) was added dropwise and stirred at r.t. for 30 minutes. The reaction was diluted with water, extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica gel, solvent gradient n-heptan/ethyl acetate=3/7) to yield the title compound as an orange oil (0.59 g, 29%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+:30]>[OH-].[NH4+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([NH2:30])=[O:25])=[CH:27][CH:28]=4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Product: NC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Yield: 357.2 %

Procedure:
The product of example 45 (195 mg, 0.500 mmol) in concentrated ammonium hydroxide (5 mL) and ammonium chloride (1.00 mg) was heated in a sealed tube at 100° C. for 4 hours. The resulting precipitate was filtered, dried and purified by chromatography (SiO2, 80% ethyl acetate/hexanes) to provide the title compound (25 mg, 13% yield). 1H NMR (DMSO-d6) δ 13.24 (br s, 1H), 10.42 (s, 1H), 8.53 (s, 1H), 8.12 (s, 1H), 7.97 (m, 6H), 7.74 (d, 1H), 7.55 (m, 2H), 7.37 (t, 2H); ES-MS (m/z) 375 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11][NH:12][C:13](=[O:17])[CH2:14][CH:15]=[CH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[Br:25]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([O:11][N:12]1[CH:15]([CH2:16][Br:25])[CH2:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(=O)NOC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)ON1C(=O)CC1CBr
Reaction time: 0.02 h
Yield: 116.5 %

Procedure:
To a solution of 0.3 g (1.28 mmole) of N-benzyloxycarbonyloxy but-3-eneoic acid amide in 20 ml of acetonitrile was added 0.1857 g (1.36 mmole) of potassium carbonate followed by 2 ml of water. The mixture was stirred vigorously for one minute and a solution of 0.2383 g (1.34 mmole) of N-bromosuccinimide in 5 ml of acetonitrile was added dropwise over 5 minutes with continued vigorous stirring. Stirring was continued for 10 minutes post addition and then the mixture was diluted with 200 ml of ethyl acetate. The solution was washed with water, aqueous 10% sodium bisulfite and brine and was dried over magnesium sulfate. The solvent was evaporated to provide 0.4686 g of the title compound as a pale yellow oil. The product was contaminated with minor amounts of succinimide and N-hydroxy-4-bromomethylazetidinone.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]N)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([BH3-])#[N:21].[Na+]>CO>[C:1]([NH:8][CH2:9][CH2:10][N:21]([CH2:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCCCCC=O
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [Na+]
Solvent: CO
Product: CCCCCCCN(CCCCCCC)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a stirred solution of N—BOC-ethylenediamine (500 mg, 3.12 mmol) in MeOH (15 mL) were added heptanal (802 mg, 7.02 mmol) followed by sodium cyanoborohydride (588 mg, 9.36 mmol) and the reaction was stirred overnight at room temperature. The reaction was concentrated on a rotevaporator and the concentrate was diluted with water (50 mL). The pH was lowered to ˜2 with 6 N HCl and the acidic solution was extracted with ethylacetate (3×100 mL). The layer was washed with 0.1 N NaOH (1×100 mL) and brine (2×100 mL) and the solvent was removed. The product was isolated by column chromatography on silica gel. The solvent was removed from the product fractions and the residue was dried in vacuo at room temperature to yield two major products N—BOC—N′,N′-diheptylethylenediamine (0.51 g, 46%): TLC (silica gel, 1 MeOH:9 CH2Cl2) Rf=0.81; and N—BOC—N′-heptylethylenediamine (0.23 g, 15%): TLC (silicagel 9:1 dichloromethane:methanol) Rf=0.66.