Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)#[N:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[CH:45][C:40]([C:38]#[N:39])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 4-cyanophenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl) benzene as colorless powder. APCI-Mass m/Z 657/659 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (128 mg) was suspended in ethanol (2 ml) and added thereto was a concentrated hydrochloric acid aqueous solution (1 ml). The mixture was heated reflux for 8.5 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene (39 mg) as pale yellow foam. APCI-Mass m/Z 536/538 (M+NH4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)=[CH:3][CH:2]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1
Reactant: CN(C)CCCCl
Reactant: Oc1ccc(Nc2nccc(-c3ccncc3)n2)cc1
Product: CN(C)CCCOc1ccc(Nc2nccc(-c3ccncc3)n2)cc1

Procedure:
A 2.78 g portion of 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol and 2.35 g of 3-dimethylaminopropyl chloride were reacted as described in Example 255, giving 850 mg of the desired product, mp 123°-124.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:14][CH:13]3[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)(O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1.[ClH:27].CCOC(C)=O>CCOC(C)=O>[Cl:27][C:15]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:14]2
Reactant: Cl
Reactant: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(OC)c2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CC3CCC(C2)C3(Cl)c2cccc(OC)c2)cc1

Procedure:
3-(4-Methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octan-8-ol (1.48 g, 4.19 mmol) was dissolved in EtOAc (20 mL), charged with 2.5N HCl/EtOAc (6 mL), and azeotroped with MeOH (2×50 mL) to yield the HCl salt. This salt was slurried in CH2Cl2 (20 mL) and pyridine (0.34 mL, 4.19 mmol) then treated with thionyl chloride (0.92 mL, 12.6 mmol) dropwise, causing the dispersion to dissolve. The reaction was judged complete by TLC after 2 h, at which time it was carefully added to 1N NaOH (50 mL) at 0° C., bringing the final pH to 9. The product was extracted with CH2Cl2 (3×20 mL), washed with saturated aqueous NaCl solution (1×50 mL), filtered through a cotton plug and concentrated to brown oil. Flash chromatography provided a white solid (1.31 g, 84%). (TLC 40% EtOAc/hexanes Rf 0.75); 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 3H), 7.04 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.84 (d, J=8.7 Hz, 2H), 6.79 (dd, J=7.9, 2.1 Hz, 1H), 3.78 (s, 6H), 3.53 (br s, 2H), 2.95 (d, J=10.3 Hz, 2H), 2.67 (br s, 2H), 2.65 (m, 2H), 1.79 (d, J=1.0 Hz, 2H), 1.45 (m, 2H); LCMS m/z 372.2 (M+1)+; mp 99–102° C.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.C(N(CC)C(C)C)(C)C.[CH2:27]([N:29]1[C:33]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[N:32][C:31]([NH2:42])=[N:30]1)[CH3:28]>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:42][C:31]2[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[N:29]([CH2:27][CH3:28])[N:30]=2)=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CC(C)(C(=O)O)S(=O)(=O)CC1CC1
Reactant: CCn1nc(N)nc1-c1ccc(OC)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1nc(NC(=O)C(C)(C)S(=O)(=O)CC2CC2)nc1-c1ccc(OC)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
Activation of 0.43 g (2.09 mmol) of 2-cyclopropylmethanesulfonyl-2-methyl-propionic acid as the corresponding acid chloride is achieved by treatment with thionyl chloride (3 mL) at 50° C. for 3 h. The reaction is cooled to room temperature and excess thionyl chloride is removed under reduced pressure. The crude acid chloride is dissolved in THF (5 mL) and N,N-diisopropylethylamine (0.39 mL, 2.25 mmol) solution is added followed by 0.30 g (1.38 mmol) of 1-ethyl-5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-ylamine. After complete addition the reaction is heated to 70° C. for 18 h. The reaction is cooled to room temperature and the reaction mixture is diluted with DCM (20 mL) and washed with saturated aqueous NaHCO3 solution (20 mL). The combined organic layers are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is slurried in DCM/ether (1/1, 10 mL) to yield 0.52 g of 2-cyclopropylmethanesulfonyl-N-[1-ethyl-5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-yl]-2-methyl-propionamide. Yield: 92%; ES-MS: m/z 407 [M+H].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:16][C@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][NH:14]3)[C:9]([CH3:18])([CH3:17])[C:8]=2[CH:19]=1.O.O.O.[C:23]([O-])(=[O:25])[CH3:24].[Na+].C(OC(=O)C)(=O)C>>[C:23]([N:14]1[C@@H:15]2[C@@H:10]([C:9]([CH3:17])([CH3:18])[C:8]3[CH:19]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=3[CH2:16]2)[CH2:11][CH2:12][CH2:13]1)(=[O:25])[CH3:24]
Reactant: COc1ccc2c(c1)C(C)(C)[C@H]1CCCN[C@H]1C2
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)[C@H]1CCCN(C(C)=O)[C@H]1C2

Procedure:
A mixture of 0.56 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline hydrochloride, 0.27 g. of sodium acetate trihydrate, and 7 ml. of acetic anhydride was stirred and heated on a steam bath for three hours. The reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was partitioned between water and diethyl ether. The ether layer was washed with 1N-hydrochloric acid and with saturated aqueous sodium bicarbonate solution. After drying the ethereal solution, filtering, and removing the solvent by evaporation under reduced pressure, there was obtained 0.52 g. of a syrup which crystallized from hexane to yield cis-1-acetyl-1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline, m.p. 81°-85° C.; ir (CHCl3), 1630 cm.-1 (C=O); nmr (CDCl3), 80 (s,3), 78 (s,3).
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH3:10].OS(O)(=O)=O.[N+:19]([O-])([O-:21])=[O:20].[K+]>>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:19]([O-:21])=[O:20])[C:6]([Br:9])=[CH:5][C:4]=1[CH3:10]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(Br)cc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
4-Bromo-2-methylphenyl methyl carbonate (4.0 g, 16.32 mmol) was added portion-wise to H2SO4 (12.0 mL) to generate a homogeneous solution. This solution was then cooled to 0° C. internal temperature and KNO3 (2.0 g, 19.6 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured over ice. The aqueous layer was extracted with dichloromethane, washed with saturated NaHCO3 and water, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (0-5% ethyl acetate/hexanes) provided 4-bromo-2-methyl-5-nitrophenyl methyl carbonate (3.4 g, 71% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.95 (s, 1H), 3.88 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [CH:1]#[N:2].[CH:3]([O:6][C:7]([C:9]1[CH:10]2[CH:12]([CH2:13][N:14]=1)[CH2:11]2)=[O:8])([CH3:5])[CH3:4]>C(OCC)C.C(Cl)(Cl)Cl>[C:1]([C:9]1([C:7]([O:6][CH:3]([CH3:5])[CH3:4])=[O:8])[NH:14][CH2:13][CH:12]2[CH:10]1[CH2:11]2)#[N:2]
Reactant: CC(C)OC(=O)C1=NCC2CC12
Reactant: C#N
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)OC(=O)C1(C#N)NCC2CC21
Temperature: 25 °C

Procedure:
30 ml of liquid hydrogen cyanide was rapidly added drop-by-drop to a stirred and ice-cooled solution of 2 g of 2-isopropoxycarbonyl-3-azabicyclo[3.1.0]hex-2-ene in 50 ml of dry diethyl ether. The solution was stirred at 0° to 5° C. for 7 hours and then allowed to warm up to room temperature. The diethyl ether and residual hydrogen cyanide were blown off with nitrogen. The residue was taken up in diethyl ether, dried over sodium sulphate and evaporated down. An orange liquid was obtained; it was dissolved in chloroform and passed over an alumina column, eluting with chloroform. After the first 100 ml was collected, the next 300 ml was collected and evaporated down, to give 1 as a straw-colured liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C@H:23]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24](C)C)[C@@H:10]([OH:21])CC(=C)C(NCCCC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:57][C@H:58]([CH2:62][O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH:59](C)C)[C@H:45]([OH:56])CC(=C)C(NCCCC)=O)=[O:42])([CH3:39])([CH3:38])[CH3:37].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:36][O:40][C:10](=[O:21])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:22][C@@H:23]([CH3:24])[CH2:27][O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1.[CH2:64]([O:63][CH2:62][C@H:58]([CH3:59])[CH2:57][C@H:44]([NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH:45]=[O:56])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: C=C(C[C@@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Reactant: C=C(C[C@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C[C@@H](C)COCc1ccccc1)NC(=O)OC(C)(C)C
Product: C[C@@H](COCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C

Procedure:
(2S,3S,5R)-2-[6-Benzyloxy-3-(tert-butoxycarbonyl)amino-2-hydroxy-5-methylhexyl]-N-(butyl)acrylamide (A) and (2R,3S,5R)-2-[6-benzyloxy-3-(tert-butoxycarbonyl)amino-2-hydroxy-5-methylhexyl]-N-(butyl)acrylamide (B): In a manner analogous to that described in Example 1h), there is obtained first, by reduction of (2S,4R)-5-benzyloxy-2-(tert-butoxycarbonyl)amino-4-methylpentanoic acid methyl ester (9.51 g) in the presence of a 1.2M diisobutylaluminium hydride solution in toluene, (2S,4R)-5-benzyloxy-2-(tert-butoxycarbonyl)amino-4-methyl-pentanal (8.2 g of crude product) in the form of a pale-yellow oil. The crude aldehyde is reacted in a manner analogous to that described in Example 1g) without being purified further. The crude product (17.1 g) so obtained comprises an approximately 1:1.45 mixture of the two diastereoisomers A and B. Purification by column chromatography with separation of the two stereoisomers on silica gel (0.6 kg, eluant gradient from C to E) yields title compound A (2.05 g) in the form of a waxy solid, Rf (E)=0.43, MS(FAB) m/e 463 (M+ +1), and title compound B (3.01 g) in the form of a light-yellow oil, Rf (E)=0.35, MS(FAB) m/e 463 (M+ +1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH3:12]
Reactant: CC1=NCCc2c(Br)cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2c(Br)cccc21

Procedure:
In close analogy to the procedure described above, 5-bromo-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C1(=O)[O:20][CH:19]=[CH:18][O:17]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@@H:12]3[CH:19]([OH:20])[CH:18]([OH:17])[C@@H:5]([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=c1occo1
Reactant: Clc1ccc2cc3ccccc3cc2c1
Product: OC1C(O)[C@H]2c3ccccc3[C@@H]1c1ccc(Cl)cc12

Procedure:
A solution of 15.0 g. of 2-chloroanthracene in 60.8 g. of vinylene carbonate is refluxed for 20 hours and then vacuum distilled. The residue is recrystallized from methylene chloride-methanol giving cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate as gray crystals, m.p. 200°-230° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:20]=[C:21]=S)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]1[NH:2][C:3]2[CH:7]=[C:6]([Cl:8])[S:5][C:4]=2[S:9](=[O:10])(=[O:11])[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: S=C=NCc1ccccc1
Agent: Cl
Product: O=S1(=O)N=C(NCc2ccccc2)Nc2cc(Cl)sc21

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and benzyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 223°-226° C.; 1H-NMR (DMSO-d6): δ 4.42 (d, 2H), 7.05 (s, 1H), 7.30 (m, 5H), 7.78 (br t, 1H), 11.22 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:17])[CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1cc(O)cc(C)c1CN1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a stirred solution 3-methoxy-5-methyl-4-piperidin-1-ylmethylphenol (563 mg, 2.4 mmol) and pyridine (0.77 mL, 10.0 mmol) in DCM (20 mL) at 0° C. was added trifluoromethanesulfonyl chloride (0.81 mL, 4.8 mmol). After the addition was complete the reaction was allowed to warm to ambient temperature. The mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil that was purified by flash chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a red oil (698 mg, 58%). 1H NMR (CDCl3, 300 MHz): 6.82 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.28 (s, 2H), 3.96 (s, 3H), 3.67-3.35 (m, 1H), 2.99-2.66 (m, 1H), 2.47 (s, 3H), 2.21-1.75 (m, 4H), 1.73-1.35 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24]Cl)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:26][S:27]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][N:31]=1)(=[O:29])=[O:28].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]([CH2:24][N:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:30]([S:27]([CH3:26])(=[O:28])=[O:29])=[N:31]3)=[N:16][C:17]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(CCl)nc3cc(Cl)ccc32)CC1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNCC2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-13 by using 4-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-methanesulfonyl-1H-indazole instead of 3-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[N:12]2)=[N:6][CH:7]=1>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH:15]=1
Reactant: O=[N+]([O-])c1cnn(CCNc2ccc(F)cn2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnn(CCNc2ccc(F)cn2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-fluoro-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-amine (100 mg, 0.34 mmol) in EtOAc (0.4 mL, degassed) and EtOH (1.2 mL, degassed), PtO2 (12 mg, 0.05 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 6 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as a red oil, which was used in the next step without further purification. LC-MS conditions A: tR=0.18 min, [M+H]+=222.34.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:16])=[CH2:15].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C.C(OCC)(=O)C.CCCCCC>C1C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH2:13]1
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OCC2(C)C
Temperature: 120 °C
Yield: 36.2 %

Procedure:
A mixture of methyl 4-bromo-3-(2-methylallyloxy)benzoate (0.500 g, 1.754 mmol), tributyltin hydride (0.708 mL, 2.63 mmol), and AIBN (0.035 g, 0.210 mmol) in benzene (20 mL) was heated in a pressure tube at 120° C. for 22 h. The volatiles were removed under vacuum. The residue was diluted with ethyl acetate (100 mL) and shaken with 10% KF solution. The resulting precipitate was removed by suction filtration through CELITE®. The organic layer of the filtrate was separated, washed with saturated NaHCO3 solution and brine, and dried over anhydrous MgSO4. The desired product, methyl 3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (0.131 g, 0.635 mmol, 36.2% yield) was isolated as a colorless oil with ISCO (40 g silica gel, 1-10% ethyl acetate/hexane).
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:23]([NH:25][N:26]1[C:30](=[O:31])[C:29](=[O:32])[N:28]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:27]1=[O:40])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[CH2:33]([N:28]1[C:29](=[O:32])[C:30](=[O:31])[N:26]([NH:25][C:23](=[O:24])[C@@H:22]([C@@H:12]([C:10](=[O:11])[NH:9][OH:8])[CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:41][CH:42]([CH3:43])[CH3:44])[C:27]1=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 34 %

Procedure:
A solution of 0.076 g of (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-4-methylvaleramide in 5 ml of methanol was hydrogenated in the presence of 0.025 g of 5% palladium-on-carbon for 6 hours. The catalyst was removed by filtration and the mixture evaporated. The residue was redissolved in 5 ml of methanol and hydrogenated in the presence of 0.020 g of 10% palladium-on-carbon for 3 hours. The catalyst was removed by filtration and the solvent was evaporated and the residue was then triturated with hexane and then with diethyl ether to give 0.022 g of N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].[N+:13]([O-])([OH:15])=[O:14].OS(O)(=O)=O>C(O)(=O)C>[C:11]([CH2:10][C:3]1[C:4]([CH3:9])=[C:5]([N+:13]([O-:15])=[O:14])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])#[N:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(C)c([N+](=O)[O-])c(C)c1CC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,4,6-trimethylphenylacetonitrile (4.5 g) in acetic acid (40 mL) at RT was added dropwise 70% HNO3 (20 mL) and conc. H2SO4 (5 mL). The brown reaction mixture was stirred for 1 h, poured into ice-water (500 mL). The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4 and concentrated to give 3-cyanomethyl-1-nitro-2,4,6-trimethylbenzene as an oil (5.8 g, quantitative yleld).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[C:11]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:21].C(N(C(C)C)CC)(C)C.Cl.[F:32][C:33]([F:45])([F:44])[CH:34]([C:40]([F:43])([F:42])[F:41])[O:35][CH:36]1[CH2:39][NH:38][CH2:37]1>ClCCl>[CH3:5][C:6]1[C:11]([B:12]2[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:10][CH:9]=[CH:8][C:7]=1[NH:21][C:1]([N:38]1[CH2:39][CH:36]([O:35][CH:34]([C:33]([F:32])([F:44])[F:45])[C:40]([F:43])([F:41])[F:42])[CH2:37]1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)C(OC1CNC1)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(NC(=O)N2CC(OC(C(F)(F)F)C(F)(F)F)C2)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Phosgene (20% in toluene, 0.26 mL, 0.49 mmol) was added to a solution of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.096 g, 0.411 mmol) and diisopropylethylamine (0.29 mL, 1.7 mmol) in 4 mL of dichloromethane at 0-5° C. The reaction mixture was then stirred at RT for 30 min., then transferred via Pasteur pipette to a flask containing 3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-azetidine hydrochloride prepared as in the above example (0.41 mmol). A total of 6 mL of additional dichloromethane was used in rinsing. The very pale yellow solution was stirred for 18.5 h. 10 g of silica gel was added, and the mixture was concentrated to a white powder. Column chromatography (0->50% EtOAc/hexanes) afforded 0.117 g (59%) of 3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-azetidine-1-carboxylic acid [2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide as a colorless oil.