Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=O)=O.[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[N:43]1([CH2:6][CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCn3ccnc3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethyl methanesulfonate (0.3 g), imidazole (0.042 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (0.024 g), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][CH:5]([CH:7]2[O:9][CH2:8]2)[CH2:4][O:3]1.[NH3:11]>>[NH2:11][CH2:8][CH:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]1)[OH:9]
Reactant: N
Reactant: CC1(C)OCC(C2CO2)O1
Product: CC1(C)OCC(C(O)CN)O1

Procedure:
A solution of 73.4 g of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylene oxide in 400 ml of 25% strength ammonia is heated in an autoclave for 4 hours to 130° C. The slightly yellowish solution is concentrated to dryness under vacuum; during this step, the residue crystallizes. 2-Amino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol is re-crystallized from ethanol/ether, mp 94°-96° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Br-].[CH3:21][O:22][C:23]([C:25]1[CH:50]=[CH:49][C:28]([CH2:29][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:27][CH:26]=1)=[O:24]>C1COCC1.C(Cl)Cl.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:29]/[C:28]2[CH:49]=[CH:50][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1
Yield: 41.9 %

Procedure:
4-(Trifluoromethoxy)benzaldehyde (125) (0.928 g, 4.88 mmol), K2CO3 (2.8 g, 20 mmol) and 18-crown-6 (0.04 g, 0.15 mmol) were added to a solution of [4-(methoxycarbonyl)benzyl]triphenylphosphonium bromide (124) (2.00 g, 4.07 mmol) in THF (60 mL) and CH2Cl2 (40 mL). The mixture was refluxed under N2 for 18 h, and then partitioned between EtOAc and water. The organic layer was washed with brine and the solvent was removed. Column chromatography of the residue on silica gel, eluting with 19:1 hexanes:EtOAc, gave a crude product which was recrystallised from hexanes to give methyl 4-{(E)-2-[4-(trifluoromethoxy)phenyl]ethenyl}benzoate (126) (0.549 g, 42%) as white flakes: mp (hexanes) 120-122° C.; NMR (CDCl3) δ 8.03 (d, J=8.4 Hz, 2H), 7.51-7.58 (m, 4H), 7.16-7.24 (m, 3H), 7.09 (d, J=16.3 Hz, 1H), 3.93 (s, 3H). APCI MS m/z 323 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=4[O:39][CH3:40])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 87.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol), K2CO3 (5.2 g, 0.04 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.6 g, 22 mmol), and dimethylformamide (60 ml) was heated at 75° C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent was concentrated to yield initially an oil, which solidified upon standing. The solid was triturated with hexane and collected to afford 7.7 g of the product as a waxy solid. The compound was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with dichloromethane/methanol (5%). Concentration of the appropriate fractions yielded 5.1 g of off-white solid 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone, which when recrystallized from ethyl alcohol yielded 3.2 g (36%) of feathery-white needles, m.p.=88°-90° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:22]([NH:24][C@H:25]([C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([NH:50][C@H:51]([C:53]([NH:55][CH2:56][C:57]([NH:59][C@H:60]([C:71]([N:73]1[CH2:80][CH2:79][CH2:78][C@H:74]1[C:75]([NH2:77])=[O:76])=[O:72])[C@@H:61]([CH3:70])[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:58])=[O:54])[CH3:52])=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:88]([C:110]([O:112][C:113]([CH3:116])([CH3:115])[CH3:114])=[O:111])[C@H:89]([C:100]([N:102]1[CH2:109][CH2:108][CH2:107][C@H:103]1[C:104]([OH:106])=O)=[O:101])[C@@H:90]([CH3:99])[O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1>>[NH:88]([C:110]([O:112][C:113]([CH3:114])([CH3:115])[CH3:116])=[O:111])[C@H:89]([C:100]([N:102]1[CH2:109][CH2:108][CH2:107][C@H:103]1[C:104]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:22]([NH:24][C@H:25]([C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([NH:50][C@H:51]([C:53]([NH:55][CH2:56][C:57]([NH:59][C@H:60]([C:71]([N:73]1[CH2:80][CH2:79][CH2:78][C@H:74]1[C:75]([NH2:77])=[O:76])=[O:72])[C@@H:61]([CH3:70])[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:58])=[O:54])[CH3:52])=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:106])=[O:101])[C@@H:90]([CH3:99])[O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Yield: 84.2 %

Procedure:
By using 3.08 g of Boc-Gln-Thr(Bzl)-Asp(OBzl)-Val-Gly-Ala-Gly-Thr(Bzl)-Pro-NH2 and 1.52 g of Boc-Thr(Bzl)-Pro-OH, and the same procedure as in Reference Example 15 was repeated to obtain 3.21 g (yield: 85.4%) of the above-mentioned objective product.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)[C:2]#[CH:3].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: C#CCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Product: C#CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-{2-[5-Chloro-2-(3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide was prepared from 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide in an analogous manner to Example 322. Product isolated as an orange foam (55 mg, 22%). LCMS (m/e) 497 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.72-7.67 (m, 1H), 7.54-7.48 (m, 2H), 7.38-7.30 (m, 2H), 7.18-7.15 (m, 1H), 7.09-7.04 (m, 1H), 7.03 (s, 1H), 6.6.97-6.91 (m, 1H), 3.45 (s, 2H), 2.93 (s, 3H), 2.91-2.85 (m, 2H), 2.80-2.65 (m, 6H), 2.24 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]3/[C:13](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:14]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=4[O:16][CH2:17][C:11]=3[CH:10]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[N:5]=[C:4]([CH3:32])[N:3]=1.[NH:33]1[CH2:36][CH2:35][CH2:34]1>C(O)C>[N:33]1([C:2]2[C:7]([CH2:8][C:9]3[CH:28]=[CH:27][C:12]4/[C:13](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:14]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=5[O:16][CH2:17][C:11]=4[CH:10]=3)=[C:6]([CH2:29][CH2:30][CH3:31])[N:5]=[C:4]([CH3:32])[N:3]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: CCCc1nc(C)nc(Cl)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Reactant: C1CNC1
Solvent: CCO
Product: CCCc1nc(C)nc(N2CCC2)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 50 °C
Yield: 14.1 %

Procedure:
[step 4] (E)-2-{8-[(4-chloro-2-methyl-6-propylpyrimidin-5-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (140 mg, 3.13 mmol) obtained in step 3 was dissolved in ethanol (3 mL), azetidine (0.148 mL, 2.19 mmol) was added, and the mixture was stirred with heating at 50° C. for 2 hr. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2 v/v) to give the title compound (145 mg, 99%).
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O.[F:40][C:41]1([F:59])[CH2:46][CH2:45][NH:44][CH:43]([CH2:47][N:48]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:42]1>>[NH2:48][CH2:47][CH:43]1[CH2:42][C:41]([F:59])([F:40])[CH2:46][CH2:45][N:44]1[C:31]([C:30]1[CH:34]=[C:26]([CH3:25])[CH:27]=[CH:28][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1CC1CC(F)(F)CCN1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC(F)(F)CC2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and 2-((4,4-difluoropiperidin-2-yl)methyl)isoindoline-1,3-dione. MS (ESI) 336 (M+H).
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][S:19]([O-:22])(=O)=[O:20].[Na+]>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][S:19]([Cl:8])(=[O:22])=[O:20]
Reactant: O=S(=O)([O-])CCc1ccccc1Br
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCc1ccccc1Br
Temperature: 100 °C
Reaction time: 66 h
Yield: 104 %

Procedure:
N,N-Dimethylformamide (4.2 mL) and thionyl chloride (5.1 mL, 69.7 mmol) were sequentially added to a suspension of sodium 2-(2-bromo-phenyl)ethanesulfonate (4.00 g, 13.9 mmol) in toluene. The mixture was stirred at 100° C. for 66 hours and then poured into ice water. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ether. The organic layers were combined and sequentially washed with water and saturated brine, and then dried over sodium sulfate and concentrated under reduced pressure to give 2-(2-bromophenyl)ethanesulfonyl chloride (4.10 g). This was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11]I)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:15][C:13](=[O:16])[CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CI)CCCCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(CSC(C)=O)CCCCC1
Temperature: 10 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
To a cold solution of crude 1261-B (109 mmol) in DMF (90 ml) was added Potassium thioacetate (1.2 equiv, 131 mmol, 15 g) maintaining temperature below 30° C. The reaction was stirred for 18 h then cooled to 10° C. and water (160 mL) was added. Reaction was extracted with EtOAc and washed with NaHCO3 sat., then brine. The dark organic layer was dried over MgSO4, filtered and concentrated down to a dark oil. Purification—HPFC (High Pressure Flash Chromatography) 75+M prepacked silica cartridge (1 to 5% EtOAc), UV collection. After concentration, 20.43 g of product 1261-C was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].II.[C:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:21]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(Cl)c2)C1
Yield: 41.1 %

Procedure:
Preparation according to Preparation 1. 1-Bromo-3-chloro-4-fluorobenzene (5 g, 23.9 mmol) in dry tetrahydrofuran (100 ml), magnesium turnings (0.57 g, 23.9 mmol) and one crystal of iodine. 1-N-boc-3-pyrrolidone (4.41 g, 23.9 mmol) in dry tetrahydrofuran (50 ml). The crude product was purified by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (3.1 g, 41%). MS m/z (rel. intensity, 70 eV) 214 (16), 157 (21), 143 (19), 129 (11), 57 (bp).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C@@H:16]12[C:25](=[O:26])[O:24][C:22](=[O:23])[C@@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21]2>C(OC(C)C)(C)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:25]([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([OH:24])=[O:23])=[O:26])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(C)OC(C)C
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCC[C@H]1C(=O)O
Yield: 78.3 %

Procedure:
A mixture of 2.3 g (0.01 mole) of 3,5-bistrifluoromethyl aniline and 1.5 g (0.01 mole) of cis-cyclohexane-1,2-dicarboxylic anhydride was stirred in iso-propyl ether at room temperature. The precipitated crystals were filtered off to give 3.0 g of the title compound.
Reaction SMILES: [Si]([N:8]1[C@H:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([C@H:29]([OH:31])[CH3:30])[C:9]1=[O:32])(C(C)(C)C)(C)C.Cl>CO.O.C(OCC)(=O)C>[OH:31][C@@H:29]([C@@H:10]1[C@@H:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[NH:8][C:9]1=[O:32])[CH3:30]
Reactant: C[C@@H](O)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (1.0 mmol) in 20 ml of 9:1 (v/v) methanol-water is cooled to 0° C. Concentrated hydrochloric acid (0.34 ml) is added and the resulting solution is stirred at 0° C. for 15 min., then allowed to warm to room temperature. After 2.5 hrs, at room temperature the reaction mixture is diluted with ethyl acetate (25 ml), washed with water (10 ml) and brine, dried over magnesium sulfate and concentrated in vacuo to yield (3S, 4R)-3-[(R)-1-hydroxyethyl]-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidin-2-one.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7]1.O.[OH-].[Na+].CN([CH:25]=[O:26])C>>[CH:25]([C:8]1[C:9]2[C:14](=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[NH:6][CH:7]=1)=[O:26]
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c(C=O)c[nH]c12

Procedure:
2.9 ml of phosphorus oxychloride are added slowly to 7 ml of N,N-dimethylformamide in a nitrogen atmosphere (formylation solution). 5 g (0.029 mol) of methyl indole-7-carboxylate are dissolved in 7 ml of DMF and added slowly to the formylation solution, during which the temperature does not rise above 30 degrees. The mixture is then warmed at 100° for one hour. After cooling, the mixture is poured into water and neutralised using sodium hydroxide solution, and the deposited crystals are filtered off with suction. m.p. 154°. Yield 5.3 g (89.9% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14]C[CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC)[N:3]=1.CC(C)([O-])C.[K+].[OH:30][CH2:31][C:32]1[CH:36]=[CH:35][S:34][CH:33]=1>ClCCl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:30][CH2:31][C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)[N:3]=1
Reactant: OCc1ccsc1
Reactant: CSc1nc(N)c(C#N)c(-c2ccc3c(c2)OCCO3)c1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1c(N)nc(OCc2ccsc2)c(C#N)c1-c1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of 2-amino-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(methylsulfanyl)-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry, Vol. 33, No. 7, 1997, pages 1014-1017 or Vol. 34, No. 4, 1998, pages 557-563] are, together with 181 mg (1.6 mmol) of potassium tert-butoxide and 184 mg (1.6 mmol) of 3-hydroxymethylthiophene, stirred at 50° C. for 4 h. After cooling, the reaction mixture is diluted with dichloromethane and washed with water. The organic phase is dried with sodium sulfate and concentrated under reduced pressure. The residue is crystallized from diethyl ether.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([NH:14]C(OC(C)(C)C)=O)[CH2:11][CH2:10][C@@H:9]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[NH2:14][C@H:12]1[CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:9]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CN1Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)C[C@H]1CC[C@@H](N)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of ethyl {cis-1-benzyl-5-[(tert-butoxycarbonyl)amino]piperidin-2-yl}acetate (2.0 g, 5.31 mmol, step 6 of Example 1) and 10% hydrochloric acid in methanol was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane/methanol (10/1, 10 mL). The solution was filtered through amine-silica gel washing with dichloromethane/methanol (10/1, 200 mL). The filtrate was concentrated under reduced pressure to give 1.65 g (quant.) of the title compound as a brown amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[Cl:28][C:29]1[C:30]([CH2:35][NH2:36])=[N:31][CH:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:28][C:29]1[C:30]([CH2:35][NH:36][C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])=[N:31][CH:32]=[CH:33][N:34]=1
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Reactant: NCc1nccnc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A THF (370 mL) solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (15.14 g, 81.30 mmol) and CDI (13.18 g, 81.30 mmol) was placed under a nitrogen atmosphere and stirred at 60° C. for 4 h. The reaction mixture was cooled to r.t., then, (3-chloropyrazin-2-yl)methylamine bis-hydrochloride salt (16.00 g, 73.91 mmol) and DIPEA (31.52 g, 244.00 mmol, 42.5 mL) was added. After stirring at 60° C. for 20 h, the reaction was concentrated in vacuo. The crude reaction mixture was purified by a silica gel glass column chromatography (eluted with 3:2 DCM/EtOAc) to obtain the pure desired product as a slightly yellowish creamy white powder; 1H NMR (CDCl3, 400 MHz) δ 1.43-1.65 (m, 4H), 2.01-2.14 (m, 4H), 2.25 (tt, J=12.0, 3.6 Hz, 1H), 2.34 (tt, J=11.6, 3.2 Hz, 1H), 3.68 (s, 3H), 4.70 (d, J=4.4 Hz, 2H), 6.81 (s, br, —NH), 8.32-8.36 (m, 1H), 8.46 (d, J=2.4 Hz, 1H); MS (ES+): m/z 312.17/314.12 (84/32) [MH+]; HPLC: tR=2.44 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)/C=C/N(C)C)cc1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: COc1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 3.84 (3H, s), 6.46 (1H, d, J=5.6 Hz), 6.88 (2H, dd, J=6.8, 2.0 Hz), 7.20 (2H, dd, J=6.4, 2.0 Hz), 7.37 (1H, dd, J=5.2, 1.6 Hz), 7.75 (1H, d, J=1.6 Hz), 7.91 (1H, s), 8.44 (1H, dd, J=4.8, 0.8 Hz).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7]CO[CH2:4][C@@H:3]1[N:8]1[CH2:16][C:15]2[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]([CH2:21][C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:11][C:10]=2[C:9]1=[O:30].N[C@@H]1[C@@H](O)CC[O:34][CH2:33]1>>[CH3:29][O:28][C:25]1[N:24]=[CH:23][C:22]([CH2:21][C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]3[CH2:16][N:8]([C@@H:3]4[C@@H:2]([OH:1])[CH2:7][O:34][CH2:33][CH2:4]4)[C:9](=[O:30])[C:10]=3[CH:11]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2COCC[C@@H]2O)C3=O)cn1
Reactant: N[C@H]1COCC[C@@H]1O
Product: COc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCOC[C@@H]2O)C3=O)cn1

Procedure:
1,5-Anhydro-2,3-dideoxy-3-{5-[(6-methoxypyridin-3-yl)methyl]-3-oxo-1,3-dihydro-2H-benzo[e]isoindol-2-yl}-L-threo-pentitol was prepared employing the procedures described for the construction of 2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-[(6-methoxypyridin-3-yl)methyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one in Example 11, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol.