Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:14][C:11]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[N+:8]([O-:10])=[O:9])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1[N+](=O)[O-]
Yield: 41.7 %

Procedure:
A solution of 3-[[[3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol), 1-bromo-2-nitrobenzene (52.4 mg, 0.26 mmol), copper(I) trifluoromethanesulfonate benzene complex (3 mg, 2.5 mol %) and cesium carbonate (100 mg, 0.31 mmol) in toluene (1 mL) and ethyl acetate (1 mL) was heated at 95° C. in a sealed vial for 4 d. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 14.1 mg (11%) of the desired 2-nitrophenyl ether product as an orange oil. HRMS calcd. for C24H20F7N2O5: 549.1260 [M+H]+, found: 549.1235. 1H NMR (CDCl3) δ 3.63 (dd, 1H), 3.84 (dd, 1H), 4.35-4.42 (m, 1H), 4.64 (s, 2H), 5.90 (tt, 1H), 6.47-6.67 (m, 3H), 6.98-7.50 (m, 8H), 7.97 (d, 1H)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[O:34][C@H:14]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([OH:13])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45]>C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:8][CH2:9][C@@:10]1([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[O:34][C@H:14]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:12]([O:13][C:44](=[O:45])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=O)c3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 86.9 %

Procedure:
A stirred solution of 3 (128.0 g, 213.3 mmol) in a 4:1 mixture of CH2Cl2 /Et3N (500 mL) was treated with (48.4 g, 40 mL, 344.6 mmol) of BzCl at 23° C. for 8 h. The resultant precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to leave the crude product as a brownish syrup. Purification of the syrup by silica gel column chromatography (hexanes/AcOEt 10:1 then 1:1) gave 130.7 g (87%) of 4 as a white solid. Rf (Hexanes/AcOEt 1:1) 0.82 1H-NMR (CDCl3): 1.40 (s, 9H, C-Me3), 1.60 (s, 3H, 5-Me), 2.37 (ddd, 1H, J=13.8, 9.3, 7.2 Hz, 2'-Hβ), 2.62 (dd, 1H, J=13.8, 4.3 Hz, 2'-Hβ), 4.09 (m, 2H, 5'-H), 4.26 (m, 1H, 4'-H), 4.74 (s, 2H, O--CH2 -Ph), 5.54 (s, 2H, N--CH2 --O), 5.71 (d, 1H, J=7.2 Hz, 3'-H), 6.57 (dd, 1H, J=9.3, 4.3 Hz, 1'-H), 7.24-7.74 (m, 13H, aromatic-H), 8.05-8.15 (m, 3H, 6-H and aromatic-H). 13C-NMR(CDCl3): 12.82 (-, 5-Me), 19.54 (+, C-Me3), 27.16 (C-Me3), 38.28 (+, 2'-C), 64.41 (+, 5'-C), 70.80 (+, O--C-Ph), 72.29 (+, N--C--O), 75.60 (-, 4'-C), 85.28 (-, 1'-C and 3'-C), 110.95 (+, 5-C), 127.72, 128.23, 128.37, 128.50, 128.63 (-, aromatic-C), 129.43 (+, aromatic-C), 129.84, 130.22 (-, aromatic-C), 132.14, 133.07 (+, aromatic-C), 133.60 (-, 6-C), 133.94, 135.32, 135.65 (-, aromatic-C), 138.15 (+, aromatic-C), 151.19 (+, 2-C), 163.50 (+, 4-C), 166.11 (+, benzoyl C=O).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][C@@H:12]([NH:21][CH3:22])[C@H:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]1[N:21]([CH3:22])[C@H:12]([CH3:11])[C@@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5]1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1[C@@H](c2ccccc2)OC(c2ccc(F)cc2Br)N1C
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution 2-bromo-4-fluorobenzaldehyde (15.2 g, 74.9 mmol) in toluene (80 ml) was added (1R,2R)-(−)-pseudoephedrine (13.6 g, 82 mmol) and the resulting mixture was refluxed removing water using a Dean-Stark trap for 16 h. The reaction was halted and cooled down to room temperature. The solution was washed with citric acid solution (1M, 100 ml), saturated sodium bicarbonate solution (50 ml), brine (50 ml) and dried (MgSO4). Then, it was filtered and the solvent was evaporated under vacuum to give title compound as yellow oil. (26.2, yield=97%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH3:13][N:14]([CH3:22])[C:15](=[O:21])[NH:16][C:17](=[NH:20])[S:18][CH3:19]>C(Cl)Cl>[CH3:1][N:2]([CH3:6])[C:3]([N:20]=[C:17]([S:18][CH3:19])[NH:16][C:15]([N:14]([CH3:22])[CH3:13])=[O:21])=[O:4]
Reactant: CSC(=N)NC(=O)N(C)C
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSC(=NC(=O)N(C)C)NC(=O)N(C)C
Temperature: 25 °C

Procedure:
5.4 Parts of dimethylcarbamoyl chloride is combined with 10 parts pyridine and stirred until the temperature returns to 25° C. 8.0 Parts methyl 4,4-dimethylthioallophanimidate (a compound of formula II), in 50 parts methylene chloride is added in one portion. The mixture is refluxed overnight, then cooled to give a white solid. The solid is removed and the organic layer is extracted with 200 parts water at pH 3, dried and evaporated to give 5 parts methyl N-dimethylcarbamoyl-4,4-dimethylthioallophanimidate (a compound of formula I), m.p. 115.5°-117.5° C.
Reaction SMILES: [CH:1]1([N:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[N+:14]([O-])=O)[C:5]2=[O:17])[CH2:3][CH2:2]1.C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]2=[O:17]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(=O)n(C3CC3)ccc12
Temperature: 85 °C

Procedure:
To a suspension of 2-cyclopropyl-5-nitro-2H-isoquinolin-1-one (3.7 g, 0.015 mol) in Ethanol (80 mL, 1 mol) was added ammonium chloride (8 g, 0.2 mol) in Water (80 mL, 4 mol) and the reaction heated at 85° C. and then iron (4 g, 0.06 mol) was added. The reaction started turning dark and became completely brown. The reaction was heated for 1 h. LC/MS showed no starting material left and only one peak which to give the desired MW. The reaction was removed from the oil bath and 150 ml of methylene chloride was added in the flask. The mixture layers were separated and aqueous layer was extracted with CH2Cl2 (100 mL×3). The combined organic layers were washed once with brine. The organic layer was collected, dried over Na2SO4 and reduced in vacuo to produce a yellow-orange solid.
Reaction SMILES: [N:1](CCCCCNCCCCCN=[N+]=[N-])=[N+:2]=[N-:3].[OH:18][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]1[C@@H:33]2[C@@H:28]([NH:29][C:30]([NH:32]2)=[O:31])[CH2:27][S:26]1)=[O:20].C1CN([P+](O[N:51]2[N:59]=[N:58]C3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[N-:1]=[N+:2]=[N-:3].[N-:58]=[N+:59]=[N-:51].[OH:20][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]1[C@@H:33]2[C@@H:28]([NH:29][C:30]([NH:32]2)=[O:31])[CH2:27][S:26]1)=[O:18]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: [N-]=[N+]=NCCCCCNCCCCCN=[N+]=[N-]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=[N-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of di(5-azidopentyl)amine (0.12 g, 0.49 mmol) in anhydrous DMF (5 mL) of were added biotin (0.12 g, 0.41 mmol), PyBOP (0.25 g, 0.49 mmol) and Et3N (0.23 mL, 1.64 mmol). The mixture was stirred for 22 h at room temperature under argon, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CH2Cl2/MeOH=13:1) to give biotin-diazide compound 25 (0.15 g, 79%). C20H35N9O2S; pale yellow oil; 1H NMR (CDCl3, 600 MHz) δ 4.48 (dd, J=7, 5 Hz, 1 H), 4.29 (dd, J=7, 5 Hz, 1 H), 3.28 (t, J=7 Hz, 4 H), 3.25 (t, J=7 Hz, 4 H), 3.20 (t, J=7 Hz, 2 H), 2.89 (dd, J=12, 5 Hz, 1 H), 2.71 (d, J=12 Hz, 1 H), 2.29 (t, J=7 Hz, 2H), 1.84 (br s, 3 H), 1.50-1.67 (m, 8 H), 1.43-1.44 (m, 2 H), 1.32-1.38 (m, 4 H); 13C NMR (CDCl3, 150 MHz) δ 172.4, 163.2, 61.8, 60.1, 55.3, 51.2, 47.0, 46.2, 45.6, 40.5, 32.5, 28.7, 28.6, 28.3, 27.3, 26.4, 25.1, 24.1. ESI-HRMS calcd for C20H36N9O2S: 466.2707, found: m/z 466.2703 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH:19]([CH3:30])[CH2:18]2)=[N:14][CH:15]=1)#[N:9]>C(Cl)Cl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:30][CH:19]1[NH:20][CH2:21][CH2:22][N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:8]#[N:9])=[CH:15][N:14]=2)[CH2:18]1
Reactant: CC1CN(Cc2ccc(C#N)cn2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(Cc2ccc(C#N)cn2)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.8 mL) was added dropwise to the cold solution of tert-butyl 4-((5-cyanopyridin-2-yl)methyl)-2-methylpiperazine-1-carboxylate (200 mg, 0.63 mmol) in CH2Cl2 (3 mL) at 0° C. and the reaction mixture was further stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to afford 6-((3-methylpiperazin-1-yl)methyl)nicotinonitrile TFA salt (180 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C12H16N4: 216.14. found: 217.0 (M+H)+
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:37][CH2:38][CH2:39][CH2:40]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:40][CH2:39][CH2:38][Br:37])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCBr
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(C(=O)OCc2ccccc2)c1
Yield: 79.5 %

Procedure:
A mixture of 5.0 g (0.01 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester, 10.2 ml (0.1 mol) of 1,3-dibromopropane and 7.0 g (0.05 mol) of potassium carbonate in 75 ml of acetone and 15 ml of DMF was stirred at reflux for 22 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure to an oil. Purification by HPLC using 5% ethyl acetate-hexane gave 4.91 g (79% yield, mp 57°-58°) of 3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [OH:1][C:2]1[C:12]([CH:13]=[O:14])=[CH:11][C:5]2[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Br:15]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:15][C:3]1[C:4]2[O:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]=2[CH:11]=[C:12]([CH:13]=[O:14])[C:2]=1[OH:1]
Reactant: CC1(C)COc2cc(O)c(C=O)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)COc2c1cc(C=O)c(O)c2Br
Yield: 94.2 %

Procedure:
A solution of 5.27 g (27.4 mmol) of 2,3-dihydro-6-hydroxy-3,3-dimethyl-5-benzofurancarboxaldehyde and 5.86 g (32.9 mmol) of N-bromosuccinimide in 135 ml of methylene chloride was stirred at ambient temperature for 3 h. Water (400 ml) was added. The organic phase was dried and evaporated. The residue was chromatographed on silica gel (150 g) using a gradient from 20:80 (v/v) ether:hexane to 40:60 (v/v) ether:hexane eluent. There was obtained 7.0 g (25.8 mmol, 94%) of 7-bromo-2,3-dihydro-6-hydroxy-3,3-dimethyl-5-benzofurancarboxaldehyde. A sample was crystallized from toluene: mp 152°-154° C.
Reaction SMILES: CC#C.C=C=C.[C:7](OC(C)=C)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:30]([OH:49])(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[C:30]([O:49][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: C=C(C)OC(=O)CCCCCCCCCCCCCCCCC
Agent: C#CC
Agent: C=C=C
Product: CCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCC

Procedure:
When the reaction was completed, spent MAPP gas was removed from the product mixture in flash chamber 14. Gases were vented overhead and a liquid seal (not shown) was maintained at the bottom drain 15 to prevent leakage of spent gases into the atmosphere. A sight glass was provided in the barricade to permit remote manual control of the liquid level in chamber 14. Liquid exiting from the flash chamber was at a temperature of about 280° F and contained no apparent dissolved gas. Since isopropenyl stearate reacts slowly with stearic acid to form stearic anhydride the reaction was quenched by rapidly solidifying the product on double drum flaker 16. Drum clearance was 0.044 inches and the drums were cooled by circulating water at a temperature of about 50° F at a rate of about 2.9 gallons per minute. The product, an amorphous solid, was scraped from the drums with doctor blades.
Reaction SMILES: C(O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H:14]2[O:24][Si:25]([C:28](C)(C)C)([CH3:27])[CH3:26])C1)(=O)C.N1C=CC=CC=1.[C:39]([O-:42])(O)=O.[Na+]>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[CH3:26][Si:25]([CH3:28])([CH3:27])[O:24][CH2:14][CH2:39][O:42][Si:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C([O-])O
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)OCCO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a manner similar to that described in Tsunoda T., et al., Tet. Lett., 1980, 21(14), 1357-1358, Hwa et al., J. Org. Chem., 1987, 52(2), 188-191. A solution of 3β-acetoxy-17β-t-butyldimethylsilyloxy-androst-5-en-7-one (40.000 g, 86.821 mmol) from Example 16B or otherwise obtained and 1,2-bis(trimethylsiloxy)ethane (23.00 mL, 93.81 mmole) in CH2Cl2 (300 mL) is prepared at −78° C. Trimethylsilyl trifluoromethanesulfonate (0.20 mL, 1.035 mmol) is added under an inert atmosphere, the reaction is stirred for three hours, pyridine (2.00 mL, 24.73 mmol) is added and the stirred mixture is allowed to warm to room temperature. The organic solution is poured into saturated aqueous NaHCO3 (300 mL) and the resultant biphasic solution is extracted with EtOAc (3×300 mL). The combined organic extracts are washed with brine (200 mL), dried over MgSO4, filtered and evaporated to dryness. The residue is purified by flash chromatography (1:4 EtOAc/hexane) to give 7,7-ethylenedioxy-17β-t-butyldimethylsilylyoxy-androst-5-en-3-ol 3-acetate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([CH2:9][CH3:10])=[CH:6][C:7]=1[Cl:8].[C:12]([O-])(=[O:14])[CH3:13].[Na+]>C(OC(=O)C)(=O)C>[C:12]([NH:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([CH2:9][CH3:10])=[CH:6][C:7]=1[Cl:8])(=[O:14])[CH3:13]
Reactant: CCc1cc(Cl)c(N)c(Cl)n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCc1cc(Cl)c(NC(C)=O)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.8 g (40.8 mmol) of 3-amino-2,4-dichloro-6-ethyl-pyridine are heated under reflux for two hours in a mixture of 40 ml of acetic anhydride and 4 g (49 mmol) of anhydrous sodium acetate. The mixture is subsequently evaporated in vacuo, the residue is partitioned between dilute NH3 solution and CHCl3, and the organic phase is separated off, dried using Na2SO4 and evaporated. The residue (11.2 g) consists of a mixture of mono- and diacetylated amine. It is dissolved in 50 ml of methanol, 10 g of powdered K2CO3 are added and the mixture is stirred for one hour at room temperature. It is subsequently evaporated and partitioned between water and CHCl3, and the organic phase is separated off and washed with 5% strength aqueous NaH2PO4 solution. After drying using Na2SO4, the organic phase is evaporated. The residue is stirred with ether and filtered off with suction. Yield 7.7 g (80.9% of theory) melting point: 142° C.
Reaction SMILES: [CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH3:24])[CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCC1(C(=O)OCC)CCCC1OC(=O)c1cccc(C)c1

Procedure:
6.05 grams (0.025 mol) of ethyl 1-n-hexyl-2-hydroxy-cyclopentane carboxylate obtained in Example 17 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.05 ml (0.0375 mol) of pyridine was slowly added, then 4.99 ml of 3-methyl-benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 10.01 g of brown liquid. MS: m/e 361(M++1), 360(M+′), 315(M+—OCH2CH3), 287(M+—CO2CH2CH3), 276, 241(M+—CH3C6H4CO), 225(M+—CH3C6H4CO2), 195, 151, 140, 119(base), 118, 91, 77.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[C:5]2[C@@H:4]2[CH2:20][CH2:21][N:3]12.[Cl:22][CH2:23][C:24](=N)OCC>CN(C)C=O.C(O)C>[Cl:22][CH2:23][C:24]1[O:17][C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:21][CH2:20][C@H:4]4[C:5]=23)=[N:18][N:19]=1
Reactant: CCOC(=N)CCl
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1c2ccccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Yield: 54.1 %

Procedure:
A solution of 5 g (17.64 mmol) of (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid hydrazide and 3.06 g (19.41 mmol) of ethyl chloroacetimidate in 40 ml of dimethylformamide and 10 ml of ethanol was stirred at 90° for 12 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and water. The aqueous phase was back-washed once with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride/methanol 93:3) yielded 3.26 g (55%) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colourless foam, RF=0.5 (methylene chloride/methanol 10:1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C@@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:60][C@H:58]([C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][CH:54]=2)[CH3:59])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g), (S)-1-(4-chlorophenyl)ethanamine (0.140 mL) and DIPEA (0.524 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.281 g, 70.4%). 1H NMR (400.13 MHz, DMSO-d6) δ 1.37 (3H, d), 1.42-1.45 (2H, m), 1.88-2.01 (2H, m), 2.27 (2H, s), 3.49-3.59 (2H, m), 4.34-4.44 (2H, m), 4.83-4.90 (1H, m), 6.57-6.58 (1H, m), 7.14-7.16 (1H, m), 7.32-7.38 (4H, m), 8.12 (1H, s), 8.30 (1H, d), 11.62 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:34][O:35][C:36](=[O:51])[C@@H:37]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:38][NH2:39].C[Si](C)(C)NC(=O)C>ClCCl.CN(C)C=O>[CH3:34][O:35][C:36](=[O:51])[C@@H:37]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[CH2:38][NH:39][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) and N,N-dimethylformamide (210 μl) in dichloromethane (10 ml) was added dropwise oxalyl chloride (240 μl) at 4° C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (940 mg) and N-(trimethylsilyl)-acetamide (2.85 g) in N,N-dimethylformamide (10 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between a mixture of ethyl-acetate and n-hexane and water. The organic layer was separated, washed in turn with water, aqueous 5% NaHCO3 solution and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (0.89 g) as a foam, which is the same compound obtained in Preparation 15.