Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:27]=[C:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:27])[CH2:33]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (111 mg, 0.3 mmol) in CH2Cl2 (2 mL) were added 2-oxopiperazine (33 mg, 0.33 mmol), diisopropylethylamine (DIPEA) (80 μL, 0.45 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (130 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 2 h then diluted with CH2Cl2. The organic phase was washed with aqueous water, dried over MgSO4, filtered and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane, then 0 to 100% ethyl acetate/acetone) followed by preparative HPLC yielding Compound 69 as a brown solid (69.7 mg).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[C:22]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: COC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Yield: 80 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [3-(trifluoromethoxy)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.O[CH2:12][NH:13]C(=O)C(F)(F)F>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:13][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: c1ccc2cnccc2c1
Reactant: O=C(NCO)C(F)(F)F
Product: CNc1cccc2cnccc12

Procedure:
Isoquinoline is reacted with N-(hydroxymethyl)trifluoroacetamide in acid followed by reduction to afford isoquinolin-5-yl-methylamine. Carbamylation using aminotetralin as described above, produces aminotetralin-derived ureas in which L=CH2 (methylene) (Scheme 7).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)[CH3:6].[OH:28][CH2:29][C:30]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>ClCCl.C1CCCCC1>[Cl:24][C:9]1[CH:8]=[C:7]([CH:5]([O:28][CH2:29][C:30]2([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (600 mg, 1.27 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.41 g, 1.40 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 8 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (40 μL, 0.26 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate, and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), 1M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (18% ethyl acetate/hexanes) gave 380 mg (50%) as a yellow film. 1H-NMR (CDCl3, 300 MHz) δ 7.96 (s, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.28-7.35 (m, 4H), 7.17-7.23 (m, 1H), 6.86 (m, 1H), 5.62 (s, 2H), 4.93 (q, J=6.2 Hz, 1H), 3.72 (m, 2H), 3.55-3.60 (m, 2H), 3.38 (d, J=9.2 Hz, 1H), 3.34 (d, J=8.8 Hz, 1H), 2.97-3.08 (m, 2H), 2.10-2.21 (m, 2H), 1.91-1.97 (m, 2H), 1.42 (d, J=6.2 Hz, 3H), 1.41 (s, 9H), 0.82-0.87 (m, 2H), 0.08 (s, 9H). Mass spec.: 600.22 (MH)+.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].CO.[CH3:11][O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=[C:22]([CH2:25]OC)[C:23]#[N:24])=[C:15]([CH3:28])[CH:14]=1>C[O-].[Na+].CS(C)=O>[CH3:11][O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21][C:22]2[C:23]([NH2:24])=[N:7][C:6]([NH2:8])=[N:5][CH:25]=2)=[C:15]([CH3:28])[CH:14]=1
Reactant: COCC(C#N)=Cc1cc(OC)c(OC)cc1C
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(C)c(Cc2cnc(N)nc2N)cc1OC
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
In step 2, 3-(4,5-dimethoxy-2-methyl-phenyl)-2-methoxymethyl-acrylonitrile and sodium methoxide were dissolved in dry DMSO and stirred for 3.5 hours at 85° C. under nitrogen. Guanidine carbonate was then added to the stirring solution, after which the temperature was raised to 125° C. for three hours, during which methanol removed via a Dean-Stark trap. The solution was cooled to room temperature, diluted with water, and the crude filtrate was recrystallized in DMF to yield 5-(4,5-dimethoxy-2-methyl-benzyl)-pyrimidine-2,4-diamine as a white solid. Mp: 232° C. Mass Spec (M+H): 275.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:34])[CH:40]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: Oc1cccc(Cl)c1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccc(Cl)c2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (315 mg) was reacted with 3-chlorophenol (113.2 μl) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (214.48 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([NH:28][C:25]2[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cn1ccc(N)n1
Reactant: CC(C)CO/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CO/N=C(/C(=O)Nc1ccn(C)n1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid (104 mg, 0.31 mmol), 1-methyl-1H-pyrazol-3-ylamine (30 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.94 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (119 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isobutoxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (122 mg, 95%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H21ClN4O4S [M+] 412.10, found 413 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=6.7 Hz, 6 H, 2×CH3), 2.05 (m, 1 H, CH), 3.29 (s, 3 H, SO2CH3), 3.84 (s, 3 H, NCH3), 4.06 (d, J=6.8 Hz, 2 H, OCH2), 6.68 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.69 (d, Jm=1.5 Hz, 1 H, Ar), 8.19 (d, Jo=8.2 Hz, 1 H, Ar), 9.13 (brs, 1 H, NH).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][CH2:7][NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: OCCNN=Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(CCO)N=Cc1ccccc1

Procedure:
0.78 g (10-2 moles) of acetyl chloride is added dropwise to a solution containing 10-2 moles of benzaldehyde (2-hydroxyethyl)hydrazone and 0.79 g (10-2 moles) of anhydrous pyridine in 20 ml of anhydrous ethyl acetate, with stirring in the cold.
Reaction SMILES: C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1CCN2C(=NCCC2)CC1.[CH2:35]([O:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][CH:47]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44]>CN(C)C=O>[CH2:35]([O:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:54][CH2:53]2)=[CH:48][CH:47]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44]
Reactant: C=CCCCCCCCCOc1ccc(N2CCNCC2)cc1
Reactant: CCCCCCCCBr
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C=CCCCCCCCCOc1ccc(N2CCN(CCCCCCCC)CC2)cc1
Temperature: 0 °C

Procedure:
A total of 0.2 g of a polymerization inhibitor (phenothiazine) was dissolved in N,N-dimethylformamide. To the resulting solution were added and dissolved 0.62 g (0.0032 mol) of octyl bromide, 2.5 g (0.016 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and 1 g (0.0032 mol) of the above-prepared 1-[4-(9-decenyloxy)phenyl]piperazine, followed by a reaction at 60° C. in an atmosphere of nitrogen gas for 48 hours with stirring. After completion of the reaction, the solution was poured into ice water, extracted with two portions of 300 mL of diethyl ether, washed with 300 mL of distilled water and dehydrated over anhydrous sodium sulfate overnight. After filtration, the solution was diluted with hexane and separated into soluble matters and insoluble matter. The hexane-soluble matter was then recrystallized from ether and hexane (1:3) and thereby yielded the target compound, 1-[4-(9-decenyloxy)phenyl]-4-octylpiperazine.
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][C:4](=[N:8][OH:9])[C:5](=[O:7])[CH3:6].[C:11](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:11][O:9][N:8]=[C:4]([CH2:3][C:2]([CH3:1])=[CH2:10])[C:5](=[O:7])[CH3:6]
Reactant: C=C(C)CC(=NO)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: C=C(C)CC(=NOC)C(C)=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
141 g of 5-methylhex-5-ene-2,3-dione 3-oxime from Example 1 were dissolved in 750 ml of acetone and admixed with 165.6 g of potassium carbonate. 145 g of dimethyl sulfate in 100 ml of acetone were then added dropwise, and the mixture was stirred at 23° C. for 4 hours. The solvent was subsequently removed under reduced pressure, the residue was taken up with methyl tert-butyl ether/water and the aqueous phase was extracted repeatedly with methyl tert-butyl ether. The combined organic phases were washed with 15% strength ammonia solution and water and dried over sodium sulfate, and the solvent was removed under reduced pressure. This gave 141 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[C:1](=[N:15][OH:16])([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1cccc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 120 h
Yield: 65 %

Procedure:
In a 50 ml round-bottom flask, a mixture of acetonaphthone, hydroxylamine hydrochloride in pyridine was stirred, at room temperature under nitrogen blanket, for five days. The reaction mixture was then concentrated under vacuum to remove most of pyridine. The oil was then dissolved in dichloromethane. The product precipitated on standing. The product was obtained as a white solid in 65% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.3 g (1.6 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (route 15, step a) in 3 mL DCM at 0° C. were added 0.33 mL (2.4 mmol) triethylamine and 0.19 mL (2.4 mmol) methanesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for 3 hours. 10 mL DCM was added and the mixture was washed with H2O (3×15 mL). The organic phase was dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3 to 6:4).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:20][C@@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22]([OH:24])=[O:23])[C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Rh]>[CH:2]1([CH2:1][C@@H:8]([CH2:20][C@H:21]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:22]([OH:24])=[O:23])[C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O)C(=O)O
Agent: [Rh]
Solvent: O
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@@H](CC1CCCCC1)C[C@H](CC1CCCCC1)C(=O)O)C(=O)O
Reaction time: 36 h

Procedure:
A suspension of 0.5 g of N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-(L)-leucine and 0.5 g of 5% Rh/C in 10 ml of ethanol and 10 ml of water is hydrogenated for 36 hours at 3 atmospheres pressure (50 psi). The mixture is filtered through celite and concentrated. The colorless oil is treated with 1.0N sodium hydroxide in methanol and concentrated to yield N-[(S,S)-2,4-di-(cyclohexylmethyl)-4-carboxybutyryl]-(L)-leucine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 4-fluoro-3-nitro aniline (1.00 g, 6.41 mmol) in anhydrous CH2Cl2 (25 ml) was added pyridine (1.52 g, 19.23 mmol) and the solution was cooled to 0° C. under argon. Benzoyl chloride (0.90 g, 6.41 mmol) was added slowly and the solution was then allowed to slowly warm to room temperature and stir for 24 h. The solution was poured into 1NHCl and the organic layer was separated. The aqueous layer was extracted 3× with ethyl acetate (50 ml). The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (4:1) to give N-(4-fluoro-3-nitro-phenyl)-benzamide. (1.60 g, 96%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:22]=O)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5](OC)=[O:6].[NH2:24][C@@H:25]1[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[C:4]2[C:3]=1[CH2:22][N:24]([C@@H:25]1[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]1)[C:5]2=[O:6]
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(Cl)c1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc3c(c(Cl)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.4 %

Procedure:
To a solution of methyl 3-chloro-2-formyl-5-(4-methoxybenzyl)-4-methylbenzoate (0.10 g) in THF (2.00 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.04 g) and anhydrous magnesium sulfate (0.07 g), and the mixture was stirred at room temperature for 6 hr. The insoluble substance was removed by filtration, the filtrate was concentrated, and the residue was diluted with methanol (2.00 mL)-THF (2.00 mL). Sodium triacetoxyborohydride (0.19 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.05 g).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[NH:4][C:5]1[CH:10]=[C:9]([CH2:11][NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)[CH:8]=[CH:7][N:6]=1.[CH3:24][O:25][C:26]([C:28]1[N:29]([CH3:38])[N:30]=[C:31]2[C:36]=1[CH:35]=[CH:34][C:33]([NH2:37])=[CH:32]2)=[O:27].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[N:29]([CH3:38])[N:30]=[C:31]2[C:36]=1[CH:35]=[CH:34][C:33]([NH:37][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[NH:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][C:3]([N:2]([CH3:1])[CH3:23])=[O:22])[CH:10]=1)=[CH:32]2)=[O:27]
Reactant: CN(C)C(=O)Nc1cc(CNc2ccccc2C(=O)O)ccn1
Reactant: COC(=O)c1c2ccc(N)cc2nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1c2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N(C)C)c3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoic acid (112 mg, 0.35 mmol), 6-amino-2-methyl-2H-indazole-3-carboxylic acid methyl ester (62 mg, 0.3 mmol), N-methylmorpholine (0.09 mL, 0.82 mmol) and HATU (152 mg, 0.4 mmol) were suspended in dry DMF (3 mL) and stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane. The organic phase was washed consecutively with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 9:1) to give 6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylic acid methyl ester (53 mg, 35%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.30 (1H, s), 8.79 (1H, s), 8.30 (1H, m), 8.15 (1H, d), 7.92-7.99 (2H, m), 7.82 (1H, s), 7.75 (1H, dd), 7.62 (1H, dd), 7.25-7.29 (1H, m), 6.93-6.96 (1H, m), 6.68 (1H, t), 6.55 (1H, d), 4.45 (2H, d), 4.41 (3H, s), 3.99 (3H, s), 2.92 (6H, s); m/z (ES+) 502 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16].C(Cl)Cl.[C:22]([C@@H:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:24]([C:22]#[N:23])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:26]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Yield: 76.3 %

Procedure:
6.2 g of dicyclohexycarbodiimide were added to a solution of 9.5 g of the product of Step C, 30 ml of methylene chloride and 3 ml of pyridine and the reaction mixture was stirred for half and hour. 6.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added thereto and the mixture was stirred for an hour and half and filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried, and evaporated to dryness. The 15.3 g of oil residue were chromatographed over silica gel and eluted with a 97-3 mixture of benzene-ethyl acetate to obtain 12 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonylethynyl)-cyclopropane-carboxylate melting at 101° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]2[CH:13]3[O:14][CH:12]3[C:11]([CH3:16])([CH3:15])[O:10][C:9]=2[CH:17]=1)(=[O:3])[CH3:2].[NH3:21]>C(O)C>[C:1]([NH:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]2[C@@H:13]([NH2:21])[C@H:12]([OH:14])[C:11]([CH3:16])([CH3:15])[O:10][C:9]=2[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C1OC1C(C)(C)O2
Reactant: N
Solvent: CCO
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](N)[C@H](O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
7-Acetamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran (0.76 g,) was dissolved in dry ethanol and saturated with dry ammonia, and stirred at room temperature for 21 hr. Evaporation gave a crude mixture which was purified on the chromatotron (using pentane-ethyl acetate in a gradient elution), to give the title compound (280 mg).