Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:11])(=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH2:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:12][C:13]1[NH:11][C:2](=[O:10])[C:3]2[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:5]=1
Reactant: NC(=O)c1ccccc1N
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: Cc1nc2ccccc2c(=O)[nH]1
Reaction time: 8 h
Yield: 42 %

Procedure:
Anthranilamide hydrochloride was prepared by adding 20 ml of concentrated hydrochloric acid (37% by weight) to a solution of 27.3 g of anthranilamide in 200 ml of methanol. This mixture was cooled in an ice bath to precipitate the hydrochloride which was then collected and dried to obtain a product melting at 234°C with decomposition. A 17.4 g (0.1 mole) portion of the hydrochloride obtained above was refluxed for 3 hours with 100 ml acetic anhydride and allows to stand overnight. The mixture was then cooled in an ice bath and the solids collected by filtration on a Buchner funnel. The filter cake was slurried in 100 ml of water, and warmed to aid solution and then 28% aqueous ammonia was added until the mixture was alkaline. After cooling the 2-methyl-4-(3H)quinazolinone precipitated as a solid, was then collected, washed with a small amount of cold water and dried at 70°C to obtain 6.72 g of the desired product. The 2-methyl-4-(3 H)quinazolinone melted at 236°-8°C and was obtained in a 42% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[CH3:20])[CH2:11][F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:26](OC)([O:29]C)[O:27]C.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([B:26]([OH:29])[OH:27])=[CH:15][C:14]=1[CH3:20])[CH2:11][F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)ccc1[C@@H](CF)COCc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(B(O)O)ccc1[C@@H](CF)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
To a solution of 24B (0.46 g, 1.364 mmol) in THF (7 mL) at −78° C., was added a solution of n-BuLi (2.2 mL, 3.52 mmol) dropwise. The mixture was stirred at −78° C. for 15 min, then was treated with trimethyl borate (0.456 mL, 4.09 mmol). The reaction was stirred at −78° C. for 15 min, then was allowed to warm to rt and stir for 3 h. The reaction mixture was diluted with EtOAc (30 mL), treated with 1N HCl (20 mL). The mixture was stirred at rt for 1 h. The phases were separated, then the aqueous layer was extracted with EtOAc. The combined organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 80% EtOAc/hexanes) to give 24C (0.2 g, 0.662 mmol, 48.5% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.97-8.10 (m, 2H) 7.28-7.44 (m, 6H) 4.82 (d, J=5.56 Hz, 1H) 4.71 (d, J=5.56 Hz, 1H) 4.53-4.59 (m, 2H) 3.56-3.90 (m, 3H) 2.47 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ ppm −223.99 (s, 1F).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:9](#[N:12])[CH2:10]O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([CH:3]([CH2:10][C:9]#[N:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: N#CCO
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C#N)CC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl cyanoacetate (916.0 g, 8.10 mol) in N,N-dimethylformamide (2.5 L) was added slowly glycolonitrile (700.0 g, 6.75 mol) in water (55% solution). To the mixture was added potassium carbonate (932.7 g, 6.75 mol), over 1.5 h, ensuring that the reaction temperature did not rise above 30° C. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was filtered and the filtrate adjusted to pH 3 by addition of acid. The organic phase was separated and partially concentrated in vacuo. To the concentrate was added diethyl ether (1 L) and the solution was washed with water (5×1 L), dried (MgSO4) and concentrated in vacuo to give Preparation 46 (803 g).
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[NH2:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH2:18][CH3:19])[CH2:12][C:11]=2[C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(OCC)(OCC)OCC>[CH2:1]([O:4][CH:5]=[N:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH2:18][CH3:19])[CH2:12][C:11]=2[C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(N)sc2c1CN(CC)CC2
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc2c(c1C(=O)OCC)CN(CC)CC2
Yield: 94 %

Procedure:
0.5 ml of acetic anhydride was added to 3.8 g (14.9 mM [sic]) of 2-amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in 40 ml of triethyl orthoformate and refluxed under nitrogen for 1 h. The solution was decanted off from the insoluble black deposit on the walls of the flask and then completely evaporated in a rotary evaporator at 80° C. 3.5 g (94%) of crude product were isolated as a dark oil which is sufficiently pure for further reaction.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:25][C@@H:26]2[O:31][C@@H:30]([CH2:32]O)[C@H:29](O)[C@@H:28](O)[C@@H:27]2[NH:36]C)[C@@]1(O)C=O.CC(N)C([NH2:52])CCCCCC(O)=O.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N>CC(=O)OCC>[NH2:36][C@H:27]([C:26]([OH:31])=[O:25])[CH2:28][CH2:29][CH2:30][CH2:32][NH2:52]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: CC(N)C(N)CCCCCC(=O)O
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Product: NCCCC[C@H](N)C(=O)O
Temperature: 37 °C
Reaction time: 8 h

Procedure:
First, the pAET7 plasmid described in Example 1 was introduced into a wild-type strain of M. methylotrophus AS1 (NCIMB10515), and a transformant was selected in an SEII agar medium containing 50 mg/L streptomycin. The pMIV-FRTKmFRT-EA plasmid was introduced into the strain by electroporation in accordance with the method described in Example 2, and strains to which the mini-Mu cassette (EA unit) including the lysE24+dapA* genes was transferred to the chromosome were selected in an SEII agar medium containing 50 mg/L streptomycin and 20 mg/L kanamycin. From the strains, 200 strains were selected randomly and inoculated on SEII plates containing 50 mg/L streptomycin and 20 mg/L kanamycin, followed by culturing at 37° C. overnight. Then, bacterial cells present on the medium surface of about 0.3 square centimeters were scraped off and inoculated into an SEII production medium (5 ml) containing 50 mg/l streptomycin and 20 mg/L kanamycin, and the cells were cultured with shaking at 37° C. for 34 hours. After completion of culture, the bacterial cells were removed by centrifugation, and the concentration of L-lysine in each culture supernatant was measured using a Biotech-analyzer AS-210 (manufactured by Sakura Seiki Co., Ltd.) to select the strain having the highest concentration of L-lysine. The strain was designated as V1. Transfer was repeated 12 times in the same way as Example 3 to obtain the V12 strain. The amount of Lys produced by V1 was defined as 100, and the relative value of the amount of Lys produced by the V12 strain was calculated and shown in Table 9.
Reaction SMILES: [K].[O-]CCCC.[Cl:7]/[C:8](=[CH:11]/[N:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:13])/[C:9]#[N:10].C(O)(=O)C>C1(C)C=CC=CC=1>[NH2:10][C:9]1[C:8]([Cl:7])=[CH:11][N:12]([CH3:13])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CN(C)/C=C(/Cl)C#N
Agent: CCCC[O-]
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)c(Cl)cn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Potassium ter.butoxide (0.5 g, 0.0044 mol) is placed in anhydrous toluene (300 ml). At ambient temperature, a solution of (E)-2-chloro-3-[[[(ethoxy)carbonyl]methyl](methyl)amino]-2-propene nitrile (58.0 g, 0.286 mol) (mp. 57° C.) in anhydrous toluene (200 ml) is added dropwise to the resulting suspension and the mixture is stirred for a further 30 minutes. It is then poured into ice water (1 liter), neutralized with acetic acid and then exhaustively extracted with dichloromethane. The combined extracts were dried over sodium sulphate and concentrated in vacuo. The residue remaining is recrystallized from diisopropyl ether/petroleum ether (1:1 v/v) and gives colorless crystals (50.0 g), m.p. 48° C.
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=O)[CH2:2][CH2:3][CH3:4].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]12[CH2:18][CH2:19][C:20](=[O:22])[CH:21]=[C:6]1[C:7]1[C:12](=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:13][CH2:14]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCC(C)=O)CCc2cc(OC)ccc2C1=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C=C1c1ccc(OC)cc1CC2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 2-butyl-6-methoxy-2-(3-oxobutyl)-3,4-dihydro-1(2H)-naphthalenone (91 mg, 0.3 mmol), pyrrolidine (0.025 mL, 0.3 mol), acetic acid (0.017 mL, 0.3 mmol), and toluene (0.5 mL) was stirred and heated in an oil bath at 100° C. for 3 hours. After standing at room temperature overnight, the mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with 5% NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 5% EtOAc in CH2Cl2. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 10a-butyl-7-methoxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone as a clear oil.
Reaction SMILES: C(OC1C=CC(C=O)=CC=1)(C)C.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.COC(=O)[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1>>[N:23]1[CH:22]=[CH:27][CH:26]=[C:25]([O:28][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:24]=1
Reactant: BrC1=NOCC1
Reactant: COC(=O)c1ccc(O)cn1
Agent: CC(C)Oc1ccc(C=O)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-140a and I-140b were prepared in 4 steps from 4-iso-propoxybenzaldehyde using Method 8 followed by cycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using Method 5 followed by hydrolysis using the analogous conditions as in Example 94 These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=343.5 m/z. Activity: A
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[NH:20][CH:19]=1)=O.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:16][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=4)[NH:20][CH:19]=3)[C:35]([C:31]3[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: Cn1ccnc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: N#Cc1ccc2[nH]cc(C=O)c2c1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(C#N)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 3-formyl-1H-indole-5-carbonitrile, followed by 1-methyl-1H-imidazole-2-carbaldehyde. Mass: 457.14 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].CO>CN(C=O)C>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
83.6 g (0.5 mol) of carbazole are dissolved in 250 ml of dry DMF. This solution is added dropwise at 0° C. to a suspension of 12.0 g (0.4 mol) of sodium hydride in 500 ml of DMF. An 80% oil suspension of NaH is used. After stirring for a further 2 hours at 0° C., 38 ml (0.45 mol) of allyl bromide are added dropwise. After the end of the addition, the mixture is warmed to room temperature within one hour, with stirring. To decompose residual NaH, 100 ml of methanol are also added. The solvent mixture is then removed in vacuo in a rotary evaporator and the residue is extracted with 400 ml of petroleum ether (40°-60° C.). Finally, the petroleum ether extract is filtered and evaporated in a rotary evaporator. The remaining brownish oil is distilled in a high vacuum. This gives 65.1 g of a pale yellow, microcrystalline solid. Melting point: 52°-54° C., boiling point: 112° C./13 Pa. Yield 78.5% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](N(OC)C)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Mg]Cl)[CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17](=[O:18])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Mg]Cl
Reactant: CON(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by treating 3-(4-benzyloxy-phenyl)-N-methoxy-N-methyl-propionamide prepared in Example T (8.5 g, 28 mmol) with n-butyl magnesium chloride (21.4 mL, 2.0M, 42.8 mmol) in 100 mL of THF. The reaction mixture was stirred at room temperature for 1 hour and refluxed for 3 hours. The reaction mixture was cooled to 0° C., quenched with 1N HCl, and extracted with EtOAc. After evaporation of the solvents, the crude product was purified by flash silica gel column chromatography, eluting with EtOAc:hexane (5:95, then switching to 3:7). 1H NMR (CDCl3) δ 0.86 (t, 3 H), 1.27 (m, 2 H), 1.34 (m, 2 H), 2.33 (t, 2 H), 2.64 (t, 2 H), 2.78 (t, 2 H), 5.0 (s, 2 H), 6.85 (d, 2 H), 7.06 (d, 2 H), 7.25 (t, 1 H), 7.31-7.42 (m, 4 H).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1CCCCC1.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:23][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(NCCO)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCNCC1
Product: O=S(=O)(NCCCl)c1ccccc1

Procedure:
40.2 g. of N-(β-hydroxyethyl)-benzene sulfonamide was slurried in 100 ml. of carbon tetrachloride containing 5 drops of piperidine. Then, 47.6 g. of sulfonyl chloride was added over 10 minutes, keeping the temperature at 20°-25° C. during the addition. The reaction was completed by heating on a steam bath for one hour. The mixture was concentrated on the steam bath, dissolved in benzene and washed twice with dilute aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the benzene evaporated on the steam bath with air. The product was crystallized from benzene cyclohexane to yield 28.0 g. of product, m.p. 58°-62° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]1([C:25](=[O:26])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])[CH2:24][CH2:23][CH2:22]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC(=O)c2ccc(Br)cc2)CCC1
Reaction time: 18 h

Procedure:
2-Amino-1-(4-bromo-phenyl)-ethanone HCl (5.8 g, 23 mmol) in DMF (75 mL) was treated with 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid (5.0 g, 23 mmol), HATU (9.7 g, 25 mmol), and DIPEA (12.9 mL, 34 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (25 mL), and washed with saturated NaHCO3 (3 10 mL), H2O (10 mL), and brine (10 mL). The solution was dried over MgSO4 to afford crude {1-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclobutyl}-carbamic acid tert-butyl ester, which was used without further purification. This material (6.54 g, 16 mmol) in xylenes (40 mL) was treated with ammonium acetate (6.1 g, 80 mmol). The reaction was stirred at 130° C. in a sealed tube for 18 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO3 (50 mL). The solution was dried over MgSO4 to afford crude {1-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 393 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].C([C:14]1[C:15]2[C:23]([C:24]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH2:34])[CH:27]=3)=[O:25])=[CH:22][NH:21][C:16]=2[N:17]=[C:18]([NH2:20])[N:19]=1)(C)C.N1C=C[CH:38]=[CH:37][CH:36]=1>>[NH2:19][C:14]1[C:15]2[C:23]([C:24]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH:34][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[O:10])[CH:27]=3)=[O:25])=[CH:22][N:21]([CH:37]([CH3:38])[CH3:36])[C:16]=2[N:17]=[CH:18][N:20]=1
Reactant: COc1cc(C(=O)c2c[nH]c3nc(N)nc(C(C)C)c23)cc(N)n1
Reactant: O=C=Nc1ccccc1F
Reactant: c1ccncc1
Product: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(NC(=O)Nc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
1-Fluoro-2-isocyanato-benzene (0.04 mL, 0.37 mmol) was added to a solution of (4-isopropyl-Amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-6-methoxy-pyridin-4-yl)-methanone (0.10 g, 0.31 mmol) in pyridine (2 mL) and stirred in a sealed tube for 2 h at room temperature. The reaction mixture was quenched with water (100 mL) and extracted with hot EtOAc/MeOH (95:5, 3×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (ethyl acetate/MeOH 99:1) afforded the title compound as a yellow solid (132 mg, 93%). MS: 464.2 (MH+); HPLC Rf: 1.7 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([C:21]([OH:23])=O)[CH2:20][CH:11]3[CH2:12][N:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][CH:10]3[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CC(C)=O.O>[CH:1]1([CH2:7][C:8]2([C:21]([N:37]=[N+:38]=[N-:39])=[O:23])[CH2:20][CH:11]3[CH2:12][N:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:14][CH:10]3[CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)N1CC2CC(CC3CCCCC3)(C(=O)O)CC2C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)N1CC2CC(CC3CCCCC3)(C(=O)N=[N+]=[N-])CC2C1
Yield: 97.6 %

Procedure:
Upon cooling by an ice-water bath, 5-cyclohexylmethyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 15c (0.75 g, 2.33 mmol) was dissolved in 20 mL of acetone with stirring followed by dropwise addition of triethylamine (0.36 mL, 2.56 mmol) and a solution of 2 mL of ethyl chloroformate (0.25 mL, 2.56 mmol) in acetone. The reaction mixture was stirred for 15 minutes and a solution of 2 mL of sodium azide (0.303 g, 4.66 mmol) in water was added. The reaction mixture was reacted for another 30 minutes at 0° C.˜5° C. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated to remove acetone and diluted with 10 mL of water. The mixture was extracted with ethyl acetate (10 mL×5). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-cyclohexylmethyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carbonyl azide 15d (0.79 g) as a yellow oil which was directly used in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>CC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 84.9 %

Procedure:
To a mixture of 4-nitrobenzene (3.0 g, 14.8 mmol) and 3-methylphenylboronic acid (2.06 g, 15.1 mmol) in 35 mL of acetone and 40 mL of water was added K2CO3.1.5H2O (5.93 g, 37.5 mmol) and Pd(OAc)2 (101 mg, 0.50 mmol). The deep black mixture was refluxed for 6 hr and then cooled. The mixture was extracted with ether and the organic layer was passed through a layer of celite. The pale yellow solution was dried over Na2SO4 and evaporated to dryness. The residue was recrystallized from hot methanol to give pale yellow crystals (2.68 g, 85%). m.p.59-60° C.1H NMR (CDCl3) δ 8.26 (d, 8.7 Hz, 2H), 7.70 (d, 8.7 Hz, 2H), 7.41 (m, 3H), 7.26 (d, 7.1 Hz, 1H), 2.43 (s, 1H). 13C NMR (CDCl3) δ 147.6, 146.8, 138.8, 138.6, 129.6, 128.9, 128.0, 127.6, 124.4, 123.9, 21.4. LRMS (EI) for C13H11NO2 213 (M+, intensity 100); HRMS (EI) calcd 213.0789, obsd 213.0778.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH2:16](N)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24]1(C)C=CC=CC=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH:24][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: NCc1ccccc1
Reactant: CN(C)CCCOc1ccccc1C=O
Product: CN(C)CCCOc1ccccc1C=CCc1ccccc1

Procedure:
A solution of 20.0 g of 2-(3-dimethylaminopropoxy)-benzaldehyde and 10.3 g of benzylamine in 100 ml of toluene is heated at reflux for 1 hour in a procedure described for Example 1. The yield of product is 22.1 g, boiling point 175°-178° C/0.05 mm of Hg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.C[N+]1([O-])CC[O:15]CC1.S(S([O-])=O)([O-])=O.[OH2:25]>CC(C)=O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[N:3]=[C:4]([C:8]([OH:15])([CH3:10])[CH2:9][OH:25])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)c1cccc(Br)n1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Solvent: CC(C)=O
Product: CC(O)(CO)c1cccc(Br)n1
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-6-isopropenylpyridine (0.510 g, 2.57 mmol) in acetone (1 mL) and water (2 mL) was added N-methylmorpholine N-oxide (0.317 g, 2.70 mmol) followed by osmium tetroxide (0.257 mL, 0.013 mmol). After 16 hours, dithionite (0.05 g) and water (1.5 mL) were added. After an additional 15 minutes, the reaction mixture was filtered though a pad of Celite. The filter was rinsed with acetone (3×1.5 mL), and the filtrate was concentrated under vacuo to remove the acetone. The remaining liquid was diluted with 9:1 chloroform:isopropanol (4 mL) and aqueous hydrogen chloride (2 M) was added until the aqueous layer was acidic. The layers were separated, and the acidic (pH=1) aqueous layer was extracted with 9:1 chloroform:isopropanol (2×4 mL). The combined organic layers were washed with 3:1 water:brine (2.5 mL), saturated aqueous sodium bicarbonate (4 mL), and brine (4 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound.