Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(Nc1cccnc1Br)c1ccc(F)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cccnc1Br)S(=O)(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
To a solution of N-(2-bromo-pyridin-3-yl)-4-fluoro-benzenesulfonamide (0.3 g, 0.9 mmol) from Step A in DMF (4 ml) was added Cs2CO3 (0.4 g, 1.3 mmol). To the mixture iodomethane (0.128 ml, 2 mmol) was added at room temperature. The mixture was stirred for 5 hours and then was diluted with EtOAc and washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated. The crude was purified through Chromatography. (3-4% EtOAc in dichloromethane). MS 344.9 (M+H)+
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:91]=[CH:90][CH:89]=[CH:88][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][C@H:73]([NH:80][C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:74](OCC#N)=[O:75])=[O:68])=[N+:61]=[N-:62]>C(#N)C>[N:60]([C:63]1[CH:91]=[CH:90][CH:89]=[CH:88][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][C@@H:73]([NH:80][C:81]([O:83][C:84]([CH3:86])([CH3:87])[CH3:85])=[O:82])[C:74]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:75])=[O:68])=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (160 mg, 0.252 mmol) and (S)-cyanomethyl 5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk62) (450 mg, 1.008 mmol) in acetonitrile (1.5 mL) was added to buffer A (33 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk63) (51.3 mg, 20%).
Reaction SMILES: C(Cl)(Cl)=O.C[CH2:6][N:7](CC)CC.[CH3:12][CH2:13][O:14][C:15](C)=[O:16].[C:18]1(C)C=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:12]1([CH:13]2[O:14][C:15](=[O:16])[NH:7][CH2:6]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(C)=O
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1
Agent: O=C(Cl)Cl
Product: O=C1NCC(c2ccccc2)O1
Temperature: 25 °C
Yield: 75 %

Procedure:
Phosgene (6.0 mL of a 1.93 M solution in toluene (PhCH3), 12.0 mmol) was added to a solution of 2-hydroxy-1-phenethylamine (1.18 g, 8.60 mmol) in PhCH3 (100 mL) at 0° C. followed by the dropwise additon of Et3N (1.80 mL, 13.0 mmol). The reaction mixture was warmed to room temperature over 48 h and poured into EtOAc (ca. 200 mL). The layers were separated and the aqueous was extracted with EtOAc (1×50 mL). The combined organics were washed with saturated aqueous NaCl (1×100 mL), dried (Na2SO4) and concentrated under reduced pressure to give 5-phenyl-2-oxazolidinone (1.05 g) as a solid in 75% yield. (1H NMR, 300 MHz) d 7.39 (comp, 5H), 5.69 (br s, 1H), 5.63 (dd, 1H, J=8.4, 8.1 Hz), 3.99 (dd, 1H, J=8.4, 8.1 Hz), 3.55 (dd, 1H, J=8.4, 8.1 Hz). LRMS 181 (M+NH4), 164 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:20]([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1([CH3:31])[O:29][CH2:28][CH:27]([NH2:30])[CH2:26][O:25]1.FC1C=CC(N(CC2SC(C3C=CC(C=O)=CC=3)=CC=2)C(C)C)=CC=1.Cl.N(CC(O)=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:20]([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][NH:30][CH:27]3[CH2:28][O:29][C:24]([CH3:31])([CH3:23])[O:25][CH2:26]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(N)CO1
Reactant: CC(C)N(CCCc1ccc(C=O)cc1)c1ccc(F)cc1
Agent: CC(C)N(Cc1ccc(-c2ccc(C=O)cc2)s1)c1ccc(F)cc1
Agent: CNCC(=O)O
Agent: Cl
Product: CC(C)N(CCCc1ccc(CNC2COC(C)(C)OC2)cc1)c1ccc(F)cc1
Yield: 48 %

Procedure:
When the product of Step C and 2,2-dimethyl-1,3-dioxan-5-amine were substituted for 4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)-thiophen-2-yl)benzaldehyde and sarcosine hydrochloride in Example 22, Step C, the similar process afforded the title compound in 48% yield, as creamy paste. 1H-NMR (CDCl3) 7.24 (d, 2H, J=7.92 Hz), 7.11 (d, 2H, J=7.92 Hz), 6.87 (t, 2H, J=8.9 Hz), 6.69-6.62 (m, 2H), 3.95 (dd, 2H, J=11.7, 3.6 Hz), 3.83-3.69 (m, 4H), 3.06 (t, 2H, J=7.54 Hz), 2.66-2.58 (m, 3H), 1.83-1.76 (m, 3H), 1.41 (s, 3H), 1.4 (s, 3H), 1.08 (d, 2H, J=6.59 Hz).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([N:8]1[CH2:9][CH2:10][N:5]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(c4ccc(OCCN5CCNCC5)cc4)CC3)nn12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
A solution of acetyl chloride (0.029 mL, 0.40 mmol) in DCM (0.5 mL) was added dropwise to 6-[4-[4-(2-piperazin-1-ylethoxy)phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 727) (160 mg, 0.34 mmol) and triethylamine (0.094 mL, 0.67 mmol) in DCM (1 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and the organic layer evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (60.0 mg, 35%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][NH:30][C:31]1[N:36]=[CH:35][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:29][NH:30][C:31]1[N:36]=[CH:35][C:34]([C:17]2[N:18]=[C:19]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]4)[S:28][C:15]=3[N:16]=2)=[CH:33][N:32]=1
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC)nc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CSC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (80 mg) in 1,2-dimethoxyethane (10 mL) was added methyl-(5-tributylstannanyl-pyrimidin-2-yl)-amine (143 mg) (prepared as above) and copper(I)bromide-dimethyl sulfide (74 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (10 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 410. NMR: (CDCl3): 2.65-2.68 (4H, m), 2.82 (3H, s, Me), 3.12 (3H, d, J 5.1, Me), 3.29-3.31 (4H, m), 3.82 (2H, s, CH2), 3.89-3.90 (4H, m), 3.94-3.96 (4H, m), 5.30 (1H, q, J 5.1, NH), 7.14 (1H, s, Ar) and 9.30 (2H, s, Ar)._MS: (ESI+): MH+=505.19
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2cccc(C)c2o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cccc(CBr)c2o1

Procedure:
A solution of 7.38 g of methyl 7-methylbenzofuran-2-carboxylate in 300 ml of carbon tetrachloride is admixed at 70° C. with 6.96 g of N-bromosuccinimide and 1.42 g of dibenzoyl peroxide, heated to reflux with stirring and kept at reflux for 2 hours (succinimide crystallizes out). The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a red-orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.60 (dichloromethane); Rt=17.83 (II).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(O)C>[ClH:1].[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:15])[N:5]=[CH:4][C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:2]2[NH:27][C:26]1[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[CH3:14]
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Cl
Solvent: CCO
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Product: Cl

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate (3.5 g) and 4-methoxyaniline (1.5 g) in ethanol (50 ml) was boiled under reflux for 1.5 hours. The mixture was concentrated to half the volume, cooled and ether added. The solid was collected by filtration to give ethyl 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylate hydrochloride, m.p. 260°-262° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[NH:11][C:10]=2[CH:20]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:17]1([C:15]([NH:14][C:12]2[NH:11][C:10]3[CH:20]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:23]=[CH:22][CH:21]=4)[CH:7]=[CH:8][C:9]=3[N:13]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1H-benzimidazol-2-yl]cyclopropanecarboxamide (159 mg, 516 μmol) and 3-(trifluoromethyl)benzoic acid (191 mg, 1.01 mmol) in pyridine (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (375 mg, 1.96 mmol) and N,N-dimethylpyridine-4-amine (18.5 mg, 151 μmol), and the mixture was stirred at room temperature for 12 hr. Methanol (5 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr and concentrated under reduced pressure. The residue was diluted with methanol (1 mL) and ethyl acetate (30 mL), washed with 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=2/98→80/20), and the obtained crude crystals were recrystallized from acetone and diisopropyl ether to give the title compound (135 mg, 54%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:14]1([C:2]2[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([NH2:9])=[O:8])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 24 h
Yield: 19.9 %

Procedure:
A mixture of 5-chloro-2-nitrobenzamide (2.0 g, 10.0 mmol), morpholine (2.6 mL, 30 mmol), and K2CO3 (4.1 g, 30 mmol) in DMF (20 mL) was stirred at 110° C. for 24 h. The reaction mixture was poured into water (100 mL) and the resulting precipitate was collected by filtration and recrystallized from ethanol to yield the product as a yellow solid (0.5 g, 20%).
Reaction SMILES: N1CCC[CH:2]1C(O)=O.[C:9]([O:13][C:14]([N:16]1[CH2:20][C:19](=[N:21][O:22][CH3:23])[CH2:18][C@H:17]1[C:24]([OH:26])=[O:25])=[O:15])([CH3:12])([CH3:11])[CH3:10].CO.C[Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[CH3:23][O:22][N:21]=[C:19]1[CH2:20][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[C@H:17]([C:24]([O:26][CH3:2])=[O:25])[CH2:18]1
Reactant: O=C(O)C1CCCN1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1

Procedure:
A solution of the oximether- and/or olefin-type 2-pyrrolidinecarboxylic acid intermediate, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (0.648 g, 2.5 mmol), in a 1:1 mixture of methanol and toluene (35 ml) was made. Trimethylsilyl diazomethane (3.8 ml of a 2M solution in hexanes, 7.5 mmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluting with ethyl acetate. Removal of solvent from the filtrate gave the methylester product, e.g. 1-tert-butyl 2-methyl(2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate, as a yellow oil (0.646 g, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[N-:11]=[N+:12]=[N-:13].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:11]=[N+:12]=[N-:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.6 %

Procedure:
A mixture of 3,4-dichlorobenzyl chloride (10 g, 0.05 mol), sodium azide (5 g, 0.08 mol) in DMSO (100 mL) was stirred at room temperature overnight. The mixture was poured into water (150 mL). The water layer was extracted with ethyl acetate (100 ml×3). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by distillation to give the title compound as an oil (14 g, quantitative yield). LC/MS: m/z 203 (M+H)+, Rt: 2.26 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:12](Br)[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([O:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Reactant: Oc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(=O)c2c(OCc3ccccc3)nn(C(C)C)c2Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
3-Benzyloxy-5-bromo-1-isopropyl-4-(4-methoxybenzoyl)-1H-pyrazole (43 mg), phenol (14 mg) and potassium carbonate (21 mg) were suspended in N,N-dimethylacetoamide (5 mL) and the mixture was stirred under reflux for 2 hours. The mixture was allowed to cool to room temperature, then 10% citric acid aqueous solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated sodium hydrogen carbonate and brine. After the solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound, (24 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:20])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.CO.C(Cl)(Cl)Cl.[NH3:27]>O1CCOCC1>[NH2:27][C:2]1[C:7]2[C:8](=[O:20])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=C1c2c(Cl)ncnc2OCCN1c1ccc(I)cc1
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Nc1ncnc2c1C(=O)N(c1ccc(I)cc1)CCO2

Procedure:
A solution of 4-chloro-6-(4-iodophenyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (279 mg, 0.70 mmol) in 0.5 N ammonia in p-dioxane was stirred in a sealed tube for 18 hours. Concentration of the reaction mixture, followed by chromatography (10 g silica gel, 0-5% methanol: chloroform) afforded the title compound of Preparation 5 as a white solid, 122 mg. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.80 (d, 2H), 7.60 (br s, 2H), 7.19 (d, 2H), 4.60 (m, 2H), 3.96 (m, 2H). m/z=383.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCCCNc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCC(=O)NCCCCCNc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 1 h

Procedure:
Part B. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylamino)-aminopentane (1.7 g, 0.00531 mol) and triethylamine (0.58 g, 0.0058 mol) in methylene chloride cooled to 0° under a nitrogen atmosphere, heptanoyl chloride (0.788 g, 0.00531 mol) was added slowly. The reaction mixture was stirred for 1 hour at 0°, poured into water and extracted with methylene chloride (2×50 mL). The combined organic extract was washed with water, brine, dried over magnesium sulfate and concentrated to give N-[5-(4,5-diphenyl-1H-imidazol-2-ylamino)pentyl]heptanamide as a viscous oil. The product was purified by flash chromatography on silica gel (250 mL) eluting methylene chloride:methanol (95:5 v:v), to give an amber foam (1.3 g, 0.003 mol). 1H NMR (CDCl3) δ7.43-7.15(m,10H), 6.3(m,1H), 3.24-3.1(m,4H), 2.09(t,2H), 1.6-1.16(m,14H), 0.84(t,3H).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5](=[O:24])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:10]=1)=[O:8])C.[OH-].[Na+]>CO.CC(O)=O.C(Cl)Cl>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH2:15][C:11]1[CH:10]=[C:9]([C:7](=[O:8])[CH2:6][C:5](=[O:24])[C:4]([OH:25])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cc2ccc(F)cc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)C(=O)CC(=O)c1cccc(Cc2ccc(F)cc2F)c1

Procedure:
In a manner similar to example AIV-2-1, 4-[3-(2,4-difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-1 using 1N NaOH to afford L2 as a yellow solid. Rf=0.60 (6:6:94 MeOH/AcOH/CH2Cl2). 1H NMR (400 MHz, CDCl3) δ7.85 (m, 2H), 7.45 (m, 2H), 7.13 (m, 2H), 6.82 (m, 2H), 4.03 (s, 2H). mass spec (FAB, M+1) 319 m/e.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-])=O)[CH:19]=1)[C:7]([CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]1=[O:11])=[O:8])([O-])=O.C(O)C.[H][H]>[Pd].C(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([NH2:20])[CH:19]=1)[C:7]([CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]1=[O:11])=[O:8]
Reactant: [H][H]
Reactant: O=C1NCCCCC1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1cc(N)cc(C(=O)C2CCCCNC2=O)c1

Procedure:
A mixture of 3,5-dinitrobenzoyl caprolactam (2.00 g, 4.07 mmol), 0.08 g of 5 percent palladium on carbon and 30 ml of absolute ethanol is stirred with hydrogen under a pressure of 1 atmosphere at 10° C. When the theoretical quantity of hydrogen (0.024 mol) has been absorbed, the solution is filtered through celite. White crystals form when the filtrate is kept in a freezer, and the final product is obtained by recrystallization from CH2Cl2 to yield 65 percent of white crystals: mp 122°-124° C.