Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=C(C=CC=1)CN(C1C=CC(C#N)=CC=1)N1C=NN=C1)C1C=CC=CC=1.[H-].[Na+].[C:32]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][N:41]2[CH:45]=[N:44][N:43]=[CH:42]2)=[CH:36][CH:35]=1)#[N:33].[C:46]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[Cl:63])[CH2:58]Br)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.CCOC(C)=O>[C:46]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[Cl:63])[CH2:58][N:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][CH:38]=1)[N:41]1[CH:42]=[N:43][N:44]=[CH:45]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: O=C(Oc1cc(CBr)ccc1Cl)c1ccccc1
Agent: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Yield: 82.5 %

Procedure:
The title compound was prepared by adapting the method for 4-[(3-benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole using NaH (60% dispersion in oil, 0.20 g, 5.0 mmol), 4-[(4-cyanophenyl)amino]-4H-[1,2,4]triazole (0.926 g, 5.0 mmol) and 3-benzoyloxy-4-chlorobenzyl bromide (1.63 g, 5.0 mmol) in anhydrous DMF (20 mL) to give 4-[(3-benzoyloxy-4-chlorobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole as a white solid (1.773 g, 82%) after chromatography [SiO2, EtOAc (100%)]; δH (400 MHz, CDCl3) 4.93 (s, 2H), 6.66 (AA′BB′, 2H), 7.06 (dd, J=8.2, 2.0, 1H), 7.27 (d, J=2.0, 1H), 7.45 (d, J=8.2, 1H), 7.47-7.58 (m, 4H), 7.60-7.69 (m, 1H), 8.16-8.21 (m, 2H), 8.24 (s, 2H); LRMS (FAB+) m/z (rel. intensity) 430.1 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[CH2:18][C:12]3(N3CCCC3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>O.S(=O)(=O)(O)O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[CH2:18][C:12]=3[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1CCCC2C(c3ccc(Cl)c(Cl)c3)=NOC2(N2CCCC2)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1CCCc2c(-c3ccc(Cl)c(Cl)c3)noc2C1
Temperature: 120 °C
Yield: 17.9 %

Procedure:
5 g (0.012 mol) of methyl 3-(3,4-dichlorophenyl)-3a,5,6,7,8,8a-hexahydro-8a-pyrrolidino-4H-cyclohept[d]isoxazole-7-carboxylate were dissolved in a mixture of 5 ml of water, 5 ml of concentrated sulfuric acid and 5 ml of glacial acetic acid and heated at 120° C. for 1.5 hours. The mixture was cooled, whereupon the crystals which formed were filtered off and washed firstly with glacial acetic acid and then with water. After drying in a vacuum and crystallization from methanol, there was obtained 0.7 g of 3-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 183°-185° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:34][N:35]1[C:39]([CH2:40][CH2:41][C:42](O)=O)=[N:38][C:37]([N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[N:36]1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:63][N:64]1[C:69](=[NH2+:70])[C:68]([CH3:71])=[CH:67][N:66]=[C:65]1[CH2:72][CH3:73]>CN(C)C=O>[CH2:72]([C:65]1[N:64]2[N:63]=[C:42]([CH2:41][CH2:40][C:39]3[N:35]([CH3:34])[N:36]=[C:37]([N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[N:38]=3)[N:70]=[C:69]2[C:68]([CH3:71])=[CH:67][N:66]=1)[CH3:73]
Reactant: Cn1nc(N2CCCC2)nc1CCC(=O)O
Reactant: CCc1ncc(C)c(=[NH2+])n1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ncc(C)c2nc(CCc3nc(N4CCCC4)nn3C)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
HATU (40.5 mg, 106 μmol, Eq: 1.5) and N,N-diisopropylethylamine (27.5 mg, 37.2 μL, 213 μmol, Eq: 3) were added to 3-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)propanoic acid in dimethylformamide (1 ml). The mixture was stirred for 10 min at room temperature. 3-Amino-2-ethyl-5-methylpyrimidin-4(3H)-iminium 2,4,6-trimethylbenzenesulfonate was added, and the mixture was stirred at 100° C. for 1 h. The product (2.7 mg, 100%) was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[CH:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1.[Cl-].[Na+]>[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(C)C2C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(C)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of diisopropylamine (3.0 mL, 22 mmol) in THF (34 mL) at 0° C. under nitrogen was added n-BuLi (8.8 mL, 22 mmol, 2.5M in hexanes). A solution of ethyl 2,3,4,8-tetra-methyl-2-azabicyclo[2.2.2]octane-6-carboxylate (4.8 g, 20 mmol) in THF (46 mL) was added to the mixture and the reaction was stirred at 0° C. for 1 hour. Ethyl chloroformate (2.3 mL, 24 mmol) in THF (3 mL) was then added and the mixture was stirred for 15 minutes. The reaction mixture was diluted with saturated sodium chloride and partitioned between water and ether. The aqueous layer was extracted with ether (2X) and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ether/hexanes (15/85) to afford 3.9 g (63%) of diethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate as a yellow oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[C:18]2[CH:23]=[CH:22][N:21]=[C:20](S(CCC)=O)[N:19]=2)[CH2:3]1.Cl.[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)=[O:35])[CH3:32].C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:20]2[N:19]=[C:18]([N:13]3[C:14]4[C:10](=[C:9]([O:8][CH2:7][CH:4]5[CH2:5][CH2:6][S:2](=[O:29])(=[O:1])[CH2:3]5)[CH:17]=[CH:16][CH:15]=4)[CH:11]=[CH:12]3)[CH:23]=[CH:22][N:21]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CCCS(=O)c1nccc(-n2ccc3c(OCC4CCS(=O)(=O)C4)cccc32)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCC5CCS(=O)(=O)C5)cccc43)n2)CC1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
To a solution of 4-(1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethoxy)-1-[2-(propane-1-sulfinyl)-pyrimidin-4-yl]-1H-indole 1.2 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (1.12 g) in NMP (5 mL) was added diisopropylethylamine (1.4 mL). The mixture was heated to 80° C. for 18 hours, then cooled and poured into 75 mL water. The mixture was extracted with methylene chloride, and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexanes) to give 1.069 g of 4-{4-[4-(1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:30]2=[O:31])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCCCc1cccnc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 6-(pyridin-3-yl)hexanoate (2.0 eq., prepared in Synthetic Example 12) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(pyridin-3-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 184.4 to 185.2° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15](Cl)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([NH2:28])[CH:20]([OH:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.Cl.[OH-].[K+]>C(O)C.O>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15]([NH:28][CH:19]([CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[OH:27])[CH3:18])=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)C(O)c1ccccc1
Reactant: Clc1nc(Cl)c2cnn(-c3ccccc3)c2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Nc1nc(Cl)nc2c1cnn2-c1ccccc1)C(O)c1ccccc1
Reaction time: 4 h
Yield: 90 %

Procedure:
390 mg of 1-phenyl-4,6-dichloropyrazolo[3,4-d]pyrimidine was suspended in 15 ml 95% ethanol. 828 mg norephedrine HCl was dissolved in 100 ml H2O, made basic with 10% KOH, and the free base extracted with 100 ml ether. The organic was dried over MgSO4, filtered, and concentrated to yield an oil which was added to the stirred reaction. After 4 hours the solution became clear and the solvent was removed under vacuum. The crude oil was then purified by radial chromatography (5-10-20% isopropyl alcohol/hexane, 4 mm plate) to yield 535 mg of [R-(S*,R*)]-α-[1-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl) amino]ethyl]benzenemethanol (90%).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[N:5]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH:6]=[CH:7][N:8]=1.Cl.S1C=CC=C1.[H][H]>CO.[Pd].O>[CH3:2][S:3][C:4]1[N:5]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CSc1nccn1C(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: c1ccsc1
Product: CSc1nccn1C(c1ccccc1)c1ccc(N)c(N)c1
Yield: 100 %

Procedure:
(a-5) A mixture of 5.5 parts of (+)-4-[[2-(methylthio)-1H-imidazol-1-yl]-phenylmethyl]-2-nitrobenzenamine monohydrochloride, 24 parts of concentrated hydrochloric acid, 2 parts of a solution of thiophene in methanol 4%, 120 parts of methanol and 100 parts of water was hydrogenated at normal pressure and at 0° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and treated with an ammonium hydroxide solution. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated, yielding 5.6 parts (100%) of (+)-4-[[2-(methylthio)-1H-imidazol-1-yl]phenylmethyl]-1,2-benzendiamine as a residue (int. 143).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[OH:34][CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([N:41]4[CH2:42][CH2:43][CH:38]([O:37][CH2:36][CH2:35][OH:34])[CH2:39][CH2:40]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: OCCOC1CCNCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(OCCO)CC4)c3)n2)n1
Yield: 49.1 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with 4-(2-hydroxyethoxy)piperidine [CAS-no. 40256-14-2] (0.297 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.120 g, 49%) as a white foam. MS (ISP) 598.3 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH2:18][CH2:19][CH3:20].C1CCC(N=C=NC2CCCCC2)CC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[CH2:17]([NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNC(=O)[C@H](C)N
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CCCC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 58.4 %

Procedure:
Tertiarybutoxycarbonyl-L-norleucine (13.2 g) in CH2Cl2 (200 ml) was treated at 0° with L-alanine N-butylamide (5.25 g), DCC (7.77 g) and 1-hydroxybenzotriazole (5 g). The pH of the reaction mixture was adjusted to 7 with N-methyl morpholine and allowed to warm to room temperature overnight. The precipitated urea was filtered off and the filtrate washed successively with saturated aqueous sodium hydrogen carbonate, water and 1M citric acid. The organic phase was dried over sodium sulphate and the solvent evaporated in vacuo. The residue was chromatographed on silica in a gradient of 30-70% ethyl acetate in dichloromethane. Elution with 50% ethyl acetate in dichloromethane afforded the title compound (7.6 g) which crystallised from ethyl acetate as needles m.p. 108°-112°; (Found: C,60.8; H,9.8; N,11.8. C18H35N3O4 requires C,60.5; H,9.9; N,11.75%); νmax (Nujol) 3280, 3340 1675 and 1640 cms-1 δ (CDCl3) 0.9 and 0.91 (each 3H, each t, each J=5 Hz,2xCH3); 1.1-1.9 (10H,m,(CH 2)3 and (CH2)2); 1.38 (3H,d,J=5 Hz,6H2CHCH3); 1.44 (9H,s, C(CH3)3); 3.24 (2H,tt,J=5 Hz NHCH2) and 4.1 and 4.48 (each 1H, each m, 2x CH).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:40]=[C:41](F)[CH:42]=1)[CH2:5][C@H:6]([C:25](N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H:7]([C@H:9]1[CH2:13][C@@H:12](OCC=C)CN1C(OC(C)(C)C)=O)O.[F:44][C:45]1[CH:46]=[C:47]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:48][C@H:49]1[C@@H:53]([CH:54]2[CH2:59][O:58][CH2:57][CH2:56][N:55]2C(OC(C)(C)C)=O)[O:52][C:51](=[O:67])[NH:50]1.FC1C=C(C=C(F)C=1)C[C@@H]([C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[F:71][C:69]1[CH:68]=[C:47]([CH:46]=[C:45]([F:44])[CH:70]=1)[CH2:48][C@H:49]1[C@@H:53]([C@H:54]2[CH2:59][C@H:57]([OH:58])[CH2:56][N:55]2[CH:5]([C:4]2[CH:3]=[CH:2][CH:42]=[CH:41][CH:40]=2)[C:6]2[CH:7]=[CH:9][CH:13]=[CH:12][CH:25]=2)[O:52][C:51](=[O:67])[NH:50]1
Reactant: CC(C)(C)OC(=O)N1CCOCC1[C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Step L (5): tert-Butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)morpholine-4-carboxylate. To a solution of (2S,3S)-2-(3,5-difluorobenzyl)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-3-hydroxypropanoic acid (step L (6), 1.6 g, 4 mmol) in toluene (100 mL) was added diphenylphosphoryl azide (1.65 g, 6 mmol) and triethyl amine (1.01 g, 10 mmoL). This reaction mixture was stirred at 80° C. for 4 h. Ethyl acetate (500 mL) was added. The mixture was washed with sodium carbonate solution, H2O, dried over Na2SO4 and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 800 mg of the title compound: MS (ESI) (M−H)− 397.12.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])(C)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[OH-].[Na+]>O1CCCC1.O>[F:10][C:9]([F:12])([F:11])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:18]([OH:23])[OH:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2 g (9.5 mmol) of 1-bromo-2-trifluoromethoxy benzene in 28 mL of tetrahydrofuran (THF) at −78° C., was carefully added 5.9 mL of a 1.7 M solution of t-butyl lithium in hexanes (9.5 mmol). This reaction mixture was stirred at −78° C. for 45 min. To this reaction mixture at −78° C. was added 2.58 mL (11.1 mmol) of tri-isopropyl borate, followed by slow warming of the mixture to room temperature (RT) over a period of 16 h. The reaction mixture was diluted with water and made basic with 2N NaOH solution. The mixture was then washed with EtOAc. The aqueous fraction was acidified with 2N HCl solution and stirred for 1 h at RT. The reaction mixture was extracted with EtOAc and the organic fractions were washed with water and saturated NaCl solution (brine), dried over Na2SO4 and filtered. The filtrate was concentrated to give the title compound as a white solid. 1H NMR (CDCl3) (δ, ppm): 7.96 (dd, J=7.2, 1.6 Hz, 1 H), 7.53 (ddd, J=9.1, 7.3, 1.8 Hz, 1 H), 7.38 (td, J=7.3, 0.7 Hz, 1 H), 7.28 (d, J=8.2 Hz, 1 H), 5.25 (br s, 2H). MS (M+H): 206.9.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:49]=[C:50](Cl)[O:51][C:52](Cl)(Cl)Cl.[O:57]1[CH2:62][CH2:61]C(O)[CH2:59][CH2:58]1>C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:50](=[O:49])[O:51][CH:52]7[CH2:61][CH2:62][O:57][CH2:58][CH2:59]7)[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: OC1CCOCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
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)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: Cc1ccccc1
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](NC(=O)OC5CCOCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
(cis)-4-(4-(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]pyridin-5-yl)phenyl)cyclohexanamine (40 mg) is dissolved in toluene (2 mL), treated dropwise with a solution of diphosgene (6.8 μL) in toluene (2 mL), stirred for 10 minutes at room temperature and for 1.5 hours at 60° C. Then tetrahydro-2H-pyran-4-ol (5.3 μL) is added and the mixture is stirred for 48 hours at 60° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The crude product is used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:23]([O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(CO)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)CC(=O)OCC(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
3.7 g of 3-[4-(tert-butyloxycarbonyl)-1-piperazinyl]-2,2-dimethylpropanol and 30 mg of 4-dimethylaminopyridine were dissolved in 10 ml of methylene chloride, and diketene was added while cooling the solution with ice. After stirring the solution for 30 minutes under cooling with ice, water was added and the solution was extracted with methylene chloride. The resulting extract was concentrated under reduced pressure to give 4.7 g of an oily product (yield: 97%). The IR and NMR data of the compound thus obtained are as follows: ##STR59##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[N:9]2[CH2:12][C:11](=[C:13]([S:34]([CH3:37])(=[O:36])=[O:35])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](OC4C(F)=C(F)C(F)=C(F)C=4F)=[O:21])[CH:15]=3)[CH2:10]2)=[CH:4][CH:3]=1.[NH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O.C(OCC)(=O)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([S:34]([CH3:37])(=[O:35])=[O:36])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[NH:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)[CH:15]=3)[CH2:10]2)=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c1
Reactant: NN1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)NN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.45 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine, 0.07 cm3 of 1-aminopiperidine in 4 cm3 of dimethylformamide is stirred for 18 hours at room temperature. The mixture is taken up in 30 cm3 of ethyl acetate. The organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of 1-[bis-(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine is obtained melting at 175° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (400 MHz): 1.40 (2H, m, CH2), 1.60 (4H, m, 2CH2), 2.85 (4H, m, 2NCH2), 3.00 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, m, 2CH arom.), 9.45 (1H, s, NH)].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].FC1C=CC(C(O)=O)=CC=1[N+]([O-])=O.S(Cl)(Cl)=O.[Br:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[CH:36]=[C:35]([C:49]([F:52])([F:51])[F:50])[C:33]=1[NH2:34]>>[Br:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:40]([F:42])([F:43])[F:41])[C:44]([F:45])([F:47])[F:46])[CH:36]=[C:35]([C:49]([F:50])([F:51])[F:52])[C:33]=1[NH:34][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Agent: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
According to the method of 1-3 of Example 1, a target compound was prepared from 4-fluoro-3-nitrobenzoyl chloride prepared from 4-fluoro-3-nitrobenzoic acid and thionyl chloride, and 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline obtained in 1-2 of Example 1.