Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:29][CH3:30])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC(S(O[CH2:49][C@H:50]2[CH2:54][O:53][C:52]([CH3:56])([CH3:55])[O:51]2)(=O)=O)=CC=1.O>CN(C=O)C>[CH:1]1([C:4]2[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([O:28][CH2:49][C@H:50]6[CH2:54][O:53][C:52]([CH3:56])([CH3:55])[O:51]6)[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:29][CH3:30])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: COc1cc(C2CN(C(=O)c3cc(O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2CN(C(=O)c3cc(OC[C@H]4COC(C)(C)O4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 47.4 %

Procedure:
To a suspension of {3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]-azetidin-1-yl}-(4-hydroxypyridin-2-yl)-methanone (0.45 g) prepared in a manner similar to Example (6) using 4-hydroxypyridine-2-calboxylic acid and K2CO3 (0.21 g) in DMF (8.0 mL) was added (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl toluene-4-sulfonate (0.33 g). The reaction mixture was stirred at 100° C. for 13 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=1/2) to give the title compound (0.27 g, 49%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5].[C:34]([NH:41][CH2:42][C:43](O)=[O:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[NH:41][CH2:42][C:43]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][C:11]3[N:12]=[CH:13][C:8]4[CH:7]=[C:6]([C:4](=[O:5])[N:3]([CH3:33])[CH3:2])[N:27]([CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[C:9]=4[N:10]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)=[O:44])([CH3:40])([CH3:38])[CH3:39]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CNC(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1

Procedure:
By repeating procedures described in Example 88, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide hydrochloride (150 mg, 0.318 mmol), N—BOC-glycine (56 mg, 0.318 mmol) gave a crude product which is purified by SiO2 chromatography, eluting with 0-7% methanol/dichloromethane to give (2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester which is used directly in the next step.
Reaction SMILES: C[N:2]1C(N)=NC(=O)C1.N.O=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13]>>[NH2:2][C@H:11]([C:12]([OH:14])=[O:13])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CN1CC(=O)N=C1N
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: N
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Creatinine is catalytically hydrolyzed to ammonia by the enzymatic activity of an unknown creatinine iminohydrolase enzyme sample, and the resultant ammonia reacts with the reagent α-ketoglutaric acid in the presence of GDH as catalyst to produce glutamic acid. The latter reaction catalyzed by GDH concomitantly converts NADPH to NADP, the disappearance of the NADPH absorption peak at 340 nm providing the spectroscopically detectable means for monitoring the assay. That is, the NADPH disappearance rate measures the rate of glutamic acid production which, in turn, measures the rate of ammonia production. The reaction mixture employed in the GDH assay method contained, in a total volume of one milliliter of 0.1 M N,N-bis(2-hydroxyethyl)-glycine-KOH buffer solution having a pH of 7.5: 0.4 mg (ethylenedinitrilo) tetraacetic acid, disodium salt (Na2EDTA), 1.6 mg α-ketoglutaric acid, 0.24 mg NADPH, 15 units GDH (ammonia free), and 4.52 mg creatinine. One unit of L-glutamic dehydrogenase is defined as that amount of enzyme which catalyzes the reduction of 1 micromole of α-ketoglutarate to glutamate per minute at pH 7.6 and 37° C. Reaction was initiated in the above-noted reaction mixture by addition of a small sample (about 2-10 milliunits) of the desired creatinine iminohydrolase enzyme preparation after equilibration of the reaction mixture at 37° C. Creatinine iminohydrolase activity was calculated by measuring the rate of NADPH disappearance at 340 nm (the molar extinction coefficient of NADPH at 340 nm being 6.22×103) in a Beckman Model 25 spectophotometer. One unit of enzyme activity was defined as that amount of enzyme necessary to catalyze the conversion of 1 micromole of creatinine to 1 micromole of ammonia per minute under the above-noted GDH assay reaction conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
2-Chloro-4-nitrobenzoic acid (50 g, 248 mmol) was subjected to methylation using methanol (500 mL) and H2SO4 (98%, 15 mL) according to the procedure described in the example 66 to obtain the title compound(83)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CBr
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 8 h
Yield: 98.2 %

Procedure:
2,6-Dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-phenol (1.0 g, 1.78 mmol), methyl bromoacetate (0.35 mL, 3.70 mmol), potassium carbonate (0.50 g, 3.62 mmol) and N,N-dimethylformamide (5 mL) were combined and stirred at ambient temperatures overnight. The reaction mixture was added to water and filtered. The solid was washed with water and dried in vacuo to provide the title compound as a white solid (1.11 g, 98%): mp 183-184° C.: NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.84 (ddd, J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.62 (s, 2 H), 7.57 (ddd, J=8, 1, 1 Hz, 1 H), 7.51 (ddd, J=8, 7, 1 Hz, 1 H), 7.42 (ddd, J=8, 7, 1 Hz, 1 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.72 (ddd, J=8, 1, 1 Hz, 1 H), 4.88 (s, 2 H), 3.94 (s, 3 H); MS (EI): [M+], 3 bromine isotope pattern, 632 (30%), 634 (90%) 636 (100%) 638 (35%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.17, H, 2.19, N, 0.09.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)O)c3)c3ccc(Cl)cc32)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)NS(C)(=O)=O)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in the synthesis of Example 117 using the following starting materials: {3-[6-Chloro-1-(1-propyl-1H-pyrazol-4-yl)-2-methyl-1H-indol-3-ylsulfanyl]-phenyl}-acetic acid and methanesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][C:5]2=O.O.[NH2:14][NH2:15]>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:15][NH:14][C:5]2=[O:6]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc2c(=O)[nH][nH]c(=O)c2c1
Yield: 71.9 %

Procedure:
A mixture of 5-methyl-isobenzofuran-1,3-dione (6.0 g, 34.1 mmol) and hydrazine hydrate (2.48 mL, 51.1 mmol) in isopropanol (120 mL) was heated at reflux for 4 h. The mixture was allowed to cool and the precipitate was filtered and washed with water (50 mL). The filter cake was dried to afford the title compound (4.32 g, 72%) as a white solid. m/z (M+1)=177.18
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH:5][CH2:4][CH2:3][Cl:2])(=[O:21])=[O:22])[CH:19]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Br)cc1S(=O)(=O)NCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 13.4 g (0.115 mol) of 2-chloroethylamine hydrochloride in 150 ml of CH2Cl2 there are added 34 ml (0.241 mol) of triethylamine and then, dropwise, 30 g (0.105 mol) of the product obtained in Step A above dissolved in 200 ml of CH2Cl2. The solution is stirred for 2 hours at ambient temperature and is then washed with 1N HCl solution, water and brine. The organic phase is dried over MgSO4 and evaporated. The solid is re-suspended in ethyl ether and filtered off to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:13][C:14]([F:27])([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[CH:15]([F:17])[F:16].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:13][C:14]([F:27])([O:18][C:19]1[CH:20]=[C:21]([CH2:22][NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:24]=[CH:25][CH:26]=1)[CH:15]([F:16])[F:17]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Ethyl 3-aminobenzoate (6.75 mL, 0.045 mol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (10 g, 45 mmol) were dissolved in 100 mL of dichloroethane and acetic acid (2.7 mL, 47 mmol), then solid NaBH(OAc)3 (14.3 g, 67 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and evaporated to give 16.7 g (98%) of the desired ethyl 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzoate product as a yellow oil. 1H NMR (CDCl3) δ 1.3 (t, 3H), 4.3 (q, 2H), 4.5 (s, 2H), 6.5 (tt, 1H), 6.9 (d, 1H), 7.1-7.4 (m, 7H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[C:16]=2[OH:20])[C:11]1=[O:22]>C(O)C>[C:1]1(=[N:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[C:16]=3[OH:20])[C:11]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Agent: Br
Solvent: CCO
Product: O=C1c2ccc(O)c(O)c2CCC1N=C1CCCCC1

Procedure:
In a mixture of 50 volume parts of cyclohexanone and 200 volume parts of ethanol is dissolved 0.151 part of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide to produce 2-cyclohexylideneamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[NH:15]2)=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(=[O:35])[NH:33][C:32](=[O:34])[CH:31]=[CH:30]1>>[CH2:1]([O:8][C:9]1[C:10]([O:27][CH3:28])=[CH:11][C:12]2[C:13]3[CH:30]4[C:29](=[O:35])[NH:33][C:32](=[O:34])[CH:31]4[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH2:18][C:14]=3[NH:15][C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2cc(C=Cc3ccccc3Cl)[nH]c2cc1OCc1ccccc1
Reactant: O=C1C=CC(=O)N1
Product: COc1cc2c3c([nH]c2cc1OCc1ccccc1)CC(c1ccccc1Cl)C1C(=O)NC(=O)C31
Yield: 87 %

Procedure:
Reaction of the diene (155) prepared as described in example 255 with maleimide using the procedure described in example 69 gave the adduct (161) as a tan powder (87%), which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26](CC[Si](C)(C)C)[C:25](=[O:36])[CH2:24]1)C1C=CC=CC=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([S:43]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]2[CH2:16][CH2:15][C:13]2[CH:12]=[CH:11][C:10]([N:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:36])[CH2:24]3)=[C:9]([OH:8])[CH:14]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C1CN(c2ccc(CCC3CCCCN3S(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-[2-benzyloxy-4-(E)-2-piperidin-2-yl-vinyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 92, step A) and benzenesulfonyl chloride analogous to Example 193: LC retention time=1.28 min (Method A); (M−1)−=478.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=O>CCOCC>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:5]([CH2:3][OH:2])[CH2:6]1
Reactant: COC(=O)C1CNc2ccccc2C1
Solvent: CCOCC
Product: OCC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the 1,2,3,4-Tetrahydro-quinoline-3-carboxylic acid methyl ester (93 mg, 0.49 mmol) in 1.5 mL of Et2O at 0° C. under nitrogen was added LiAIH4 (1M in Et2O) dropwise with vigorous gas evolution and a white precipitate formation. After 30 min., the reaction was carefully quenched with 15% NaOH (3 mL) and 3 mL of Et2O was added and the mixture stirred rapidly at RT for 15 min. The layers were separated and the aqueous layer extracted (1×10 mL) with Et2O. The organics were combined, dried (MgSO4), filtered and concentrated to the alcohol (64 mg, 80%). 1H-NMR (400 MHz, CDCl3) δ 6.97 (m, 2H), 6.62 (dd, 1H), 6.47 (d, 1H), 3.66 (m, 1H), 3.58 (m, 1H), 3.40 (m, 1H), 3.08 (m, 1H), 2.82 (m, 1H), 2.53 (m, 1H), 2.18 (m, 1H).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]4[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:23]([O:25][C@@H:26]5[CH2:30][O:29][C@@H:28]6[C@H:31]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:32][O:33][C@H:27]56)=[N:24][C:19]4=[CH:18][C:17]=3[Cl:50])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Si:35]([O:34][C@H:31]1[C@H:28]2[O:29][CH2:30][C@@H:26]([O:25][C:23]3[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:20]4=[N:21][C:16]([C:13]5[CH:14]=[CH:15][C:10]([C@@H:7]6[CH2:8][CH2:9][C@H:4]([NH2:1])[CH2:5][CH2:6]6)=[CH:11][CH:12]=5)=[C:17]([Cl:50])[CH:18]=[C:19]4[N:24]=3)[C@H:27]2[O:33][CH2:32]1)([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N=[N+]=[N-])CC4)cc3)nc2n1COCC[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 40 °C
Reaction time: 12 h

Procedure:
5-(4-((cis)-4-Azidocyclohexyl)phenyl)-2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (210 mg) is dissolved in tetrahydrofurane (1 mL) treated with triphenylphosphine (90 mg) and stirred for 4 hours at room temperature and for 12 hours at 40° C. Water (220 μL) is added and the mixture is stirred for further 12 hours at 80° C. Then the mixture is partitioned between hydrochloric acid (1 M) and diethylether. The organic phase is washed with aqueous NaOH solution (1 M), dried (MgSO4) and concentrated. The residue is chromatographed over aluminium oxide (ethyl acetate/methanol 100:0→0:100) to give the title compound. LC (method 4): tR=0.61 min; Mass spectrum (ESI+): m/z=715 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:44]1([CH2:50][C:51]([NH:53][NH2:54])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:44]1([CH2:50][C:51]([NH:53][NH:54][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 8, 50 mg, 0.25 mmol) in DMF (10 mL) was added DIPEA (89 μL, 0.51 mmol), HOBt (34 mg, 0.25 mmol), EDCI (63 mg, 0.33 mmol) and phenylacetic acid hydrazide (38 mg, 0.25 mmol) and the mixture was stirred at rt for 72 h. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×30 mL). The combined organics were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound. m/z (ES+)=329 [M+H]+; RT=3.07 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:32]#[N:33].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[CH2:10][CH2:11][C:32]#[N:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCC#N)c1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1.88 g (4.16 mmol) Toluene-4-sulfonic acid 3-tert-butoxycarbonylamino-3-(3-nitro-phenyl)-propyl ester were dissolved in 5 ml DMF and 306 mg (6.24 mmol) sodium cyanide were added. The mixture was stirred for 5 h at 60° C. The reaction mixture was poured into 50 ml water, the precipitate was filtered, washed with water and dried in vacuo. The crude product was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[C:5](C1CC(=O)N(O)C1=O)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>C(Cl)(Cl)Cl.O>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCN
Reactant: O=C(OCc1ccccc1)C1CC(=O)N(O)C1=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: NCCNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-aminoethylamine LVIII (150 mL; 2.25 mol) in chloroform (1.5 L), cooled to 0° C. was added a solution of carbobenzoxy N-hydroxysuccinimide (112.14 g; 0.45 mol) in water (0.5 L) with vigorously stirring for one hour. The solid was filtered and the solution was washed with brine (3×), once with water and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure and the residue was purified on a silica gel column (100:1→30:1 DCM:MeOH) to yield benzyl 2-aminoethylcarbamate LIX as a colorless viscous oil (350 g; 1.80 mol; 80% yield). 1H NMR (CDCl3) 2.79-2.83 (m, 2H), 3.21-3.28 (m, 2H), 5.10 (s, 2H), 5.19 (brs, 1H), 7.29-7.34 (m, 1H), 7.35-7.38 (m, 4H); ESIMS found for C10H14N2O2 m/z 195.2 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[O:6]([CH2:5][CH:4]([OH:13])[CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=2)[CH2:24][CH2:25]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: O=[N+]([O-])c1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
Following the procedure of Example 25, the title compound is prepared from 4-chloro-1-phenoxy-2-butanol and 1-(4-nitrophenyl)piperazine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:12]([OH:14])=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>C1C=CC=CC=1>[S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)([OH:33])(=[O:32])=[O:31].[CH2:15]([O:13][C:12](=[O:14])[C@@H:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: N[C@H](CCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Yield: 83.7 %

Procedure:
A solution of D-Homophenylalanine hydrochloride (1.7 g, 7.93 mmol), benzyl alcohol (7.2 mL, 64.0 mmol) and p-toluenesulfonic acid monohydrate (1.8 g, 9.5 mmol) in benzene (30 mL) was heated at reflux in Dean Stark apparatus during 5 hrs, after which time additional benzene (100 mL) was distilled from reaction mixture. The residue was triturated with diethyl ether, the solid was filtered and dried to give title product (2.93 g).
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([CH2:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)=[C:4]([O:21][CH3:22])[CH:3]=1.O.NN>CCO>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([CH2:6][NH2:7])=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)c(Cl)cc1CN
Yield: 77.6 %

Procedure:
To a solution of 2-(4,5-dichloro-2-methoxybenzyl)isoindoline-1,3-dione (1.8 g, 5 mmol) in EtOH (5 mL), hydrazine hydrate (1.34 g, 27 mmol) was added and the resulting mixture was stirred at reflux for 1 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=20:1) to afford the desired product (0.8 g, 78% yield).