Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]([F:44])([F:43])[O:31][C:32]1[CH:42]=[CH:41][C:35](/[CH:36]=[CH:37]/[C:38](O)=[O:39])=[CH:34][CH:33]=1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:38](=[O:39])/[CH:37]=[CH:36]/[C:35]4[CH:34]=[CH:33][C:32]([O:31][C:30]([F:43])([F:44])[F:29])=[CH:42][CH:41]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-4-(trifluoromethoxy)cinnamic acid, by the method of Example 1, step K, giving a solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C31H35F3N4O3: 569 (M+H). Found: 569
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C([Si](C)(C)[O:26][C@H:27]1[CH2:31][CH2:30][N:29](/[CH:32]=[CH:33]/[NH:34][C:35](=[NH:38])[CH:36]=[CH2:37])[CH2:28]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([N:29]4[CH2:30][CH2:31][C@H:27]([OH:26])[CH2:28]4)=[CH:33][N:34]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: C=CC(=N)N/C=C/N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC[C@H](O)C4)cn3)nc2n1C1CCCC1
Yield: 64.3 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (101 mg, 0.35 mmol) and N-{(E)-2-[(S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-vinyl}-acrylamidine (153 mg, 0.52 mmol), followed by deprotection with TBAF to give 7-cyclopentyl-2-[5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (98 mg, 65%). MS(ESI) m/z 436.3 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7](N)[S:6][N:5]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:19].[K+].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:8]=[C:7]([I:19])[S:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)ns1
Reactant: [I-]
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Ic1cc(C2CC2)ns1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a water (1.4 mL) and ice (5.0 cc) suspension was added 3-cyclopropylisothiazol-5-amine (500 mg, 3.57 mmol) followed by concentrated sulfuric acid (1.4 mL). A solution of sodium nitrite (258 mg, 3.74 mmol) in water (5.0 mL) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hour. Next, a solution of potassium iodide (622 mg, 3.74 mmol) in water (3.5 mL) was added dropwise at 0° C., and the mixture was heated at 80° C. for 1 hour. Ethyl acetate at 0° C. was added and the mixture was neutralized with potassium carbonate. The organic layer was separated, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (19:1) to give the title compound as green oil (356.5 mg, 40%). 1H NMR (500 MHz, CDCl3) δ ppm 0.92-0.98 (m, 2H), 0.98-1.04 (m, 2H), 2.13-2.20 (m, 1H), 7.06 (s, 1H).
Reaction SMILES: C(O)C.[CH2:4]1[CH2:9][CH:8]([C:10]([OH:12])=[O:11])[NH:7][CH2:6][CH2:5]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>O>[CH2:4]1[CH2:9][C@@H:8]([C:10]([OH:12])=[O:11])[NH:7][CH2:6][CH2:5]1
Reactant: O=C(O)C1CCCCN1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CCCCN1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a mixture of about 600 mL of 95% ethanol and 200 mL water at 80° C. was added about 40 g of DL-pipecolic acid followed by the addition of 49 g of D-tartaric acid. The reaction mixture was stirred at 80° C. for about an hour to get a clear solution. The solution was allowed to stand at about 25° C. for about 48 hrs and the solid precipitated was filtered. The filtrate was reduced to 260 mL by evaporation and allowed to stand at about 25° C. for 24 h. At the end of that period, more solid had precipitated out and was removed by filtration The filtrate was evaporated to dryness and the residue was dissolved in 1 L water. The water solution recovered was then treated with Amberlite Ion-Exchange resin IR-120 H+ form (Hydrous form) to remove the tartaric acid followed by 10% NH4OH solution treatment of the resin to give L-pipecolic acid of optical purity of about 85-90%. After drying 22 g of a solid was obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72](=[NH:75])[NH:73]O)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C.O1CCOCC1>[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72]2[N:73]=[C:11]([C:8]3[CH:7]=[C:6]([CH3:14])[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:10][N:9]=3)[O:13][N:75]=2)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]
Reactant: Cc1cc(C(=O)O)ncc1CC(C)C
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 5-isobutyl-4-methyl-pyridine-2-carboxylic acid (246 mg, 1.07 mmol) and DIPEA (415 mg, 3.21 mmol) in DMF (4 mL), PyBOP (589 mg, 1.13 mmol) is added at 0° C. The mixture is stirred for 15 min at 0° C. before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester (328 mg, 1.07 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched by adding water, the mixture is diluted with sat. aq. NaHCO3-solution and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxy-amidine ester intermediate; LC-MS: tR=1.10 min, [M+H]+=482.27. This material is dissolved in dioxane (10 mL) and the mixture is stirred at 80° C. for 15 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid tert-butyl ester (420 mg) as a colourless oil; LC-MS: tR=1.26 min, [M+H]+=464.34.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:14][C:15]1[C:24]([CH2:25][P:26]([O:31]CC)([O:28]CC)=[O:27])=[CH:23][C:22]2[C:17](=[CH:18][C:19]([O:34][CH2:35][CH3:36])=[CH:20][CH:21]=2)[N:16]=1)[C:10]([O:12]C)=[O:11])=O)(C)(C)C.Cl>>[NH2:8][C@H:9]([CH2:14][C:15]1[C:24]([CH2:25][P:26]([OH:31])([OH:28])=[O:27])=[CH:23][C:22]2[C:17](=[CH:18][C:19]([O:34][CH2:35][CH3:36])=[CH:20][CH:21]=2)[N:16]=1)[C:10]([OH:12])=[O:11]
Reactant: CCOc1ccc2cc(CP(=O)(OCC)OCC)c(CC(NC(=O)OC(C)(C)C)C(=O)OC)nc2c1
Agent: Cl
Product: CCOc1ccc2cc(CP(=O)(O)O)c(C[C@@H](N)C(=O)O)nc2c1

Procedure:
Deprotection of the amino acid was effected in refluxing 6M HCl for 6 h. Evaporation of the solvent gave a residue which was put onto an acidic ion-exchange resin and eluted with water. Collection of ninhydrin-sensitive fractions and evaporation of solvent gave (R)-α-amino-3-phosphonomethyl-7-ethoxy-2-quinolinepropanoic acid. 13C-NMR (D2O plus NH3 vapours): δ (ppm) 174.7, 158.7, 156.3, 146.3, 138.0, 137.9, 128.6, 122.6, 118.8, 106.2, 64.4, 54.1, 34.2, 34.0, 32.8, 13.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1)#[N:28].C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]([C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([CH:30]=3)[C:27]#[N:28])[CH:7]=[CH:6][CH:5]=2)([C:19]2[CH:20]=[C:21]([CH3:26])[N:22]=[C:23]([CH3:25])[CH:24]=2)[N:9]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc(C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(C2(c3cccc(-c4cncc(C#N)c4)c3)N=C(N)c3c(F)cccc32)cc(C)n1
Yield: 53 %

Procedure:
The title compound was synthesized as described for Example 12 in 53% yield starting from 1-(3-bromophenyl)-1-(2,6-dimethylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (104.8 mg, 0.26 mmol), 5-cyanopyridin-3-ylboronic acid (37.8 mg, 0.26 mmol), PdCl2(dppf)-CH2Cl2 adduct (20.9 mg, 0.03 mmol), and K2CO3 (aq) (0.38 mL, 0.77 mmol).
Reaction SMILES: C(NC([C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O)=O)CCCCCCCCCCCCCCCCC.C=CO.[CH3:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH:50]([OH:58])[C@H]1OC[C@H](O)[C@H]1O)=[O:47]>>[CH3:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH2:50][OH:58])=[O:47]
Reactant: CCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Agent: C=CO
Agent: CCCCCCCCCCCCCCCCCCNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCCCCCCC(=O)OCCO

Procedure:
Comparative experiments were carried out in which in place of N-octadecyl gluconamide, the suspension stabilizers Gohsenol KP 08, Armotan® MP (sorbitan monopalmitate), Armotan® ML (sorbitan monolaurate) Tween® 20 (polyoxyethylene (20) monolaurate) and Tween® 21 (polyoxyethylene (4) monolaurate) were used. Only the results obtained with Tween® 21 (polyoxyethylene (4) monolaurate) compared with those obtained with N-octadecyl gluconamide. When only Gohsenol KP 08 was used, the results obtained were distinctly poorer. In all other cases destabilization of the suspension was observed after 1 to 2 hours polymerization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[S:29]
Reactant: COc1ccc(OC)c(NC(=O)C2CCCCC2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(NC(=S)C2CCCCC2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
1.46 g (5.54 mmol) of N-(2,5-dimethoxyphenyl)cyclohexanecarboxamide is put into solution in 40 ml of anhydrous toluene. The solution is taken to 100° C., and 3.34 g (8.26 mmol; 1.5 eq.) of Lawesson's reagent are added to the reaction medium which is then maintained under stirring at 100° C. for 4 hours. After returning to ambient temperature, the solution is poured into 50 ml of iced water and extracted using toluene. The organic phases are dried over magnesium sulphate and the solvent is evaporated off. The N-(2,5-dimethoxyphenyl)cyclohexanecarbothioamide is then purified by chromatography on a silica column (eluent: dichloromethane/heptane: 1/1 then 3/2). 1.26 g (yield=81%) of product is obtained in the form of yellow oil.
Reaction SMILES: [F:1][C:2]([N+:13]([O-:15])=[O:14])([C:8](OCC)=[O:9])[C:3](OCC)=[O:4].C=O.[OH-].[Na+]>O>[F:1][C:2]([N+:13]([O-:15])=[O:14])([CH2:8][OH:9])[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(C(=O)OCC)[N+](=O)[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])C(F)(CO)CO
Temperature: 2 °C
Reaction time: 1.67 h
Yield: 45.8 %

Procedure:
A suspension of 89.2 g (0.40 mole) of diethyl fluoronitromalonate in 80 ml (1.0 mole) of 37% aqueous formaldehyde was cooled in an ice-bath to 2° C. A solution of 66.0 g (1.60 mole) of sodium hydroxide in 400 ml of water was then added dropwise with vigorous stirring over 100 minutes, below 10° C. After the reaction mixture was stirred overnight in the ice-bath, it was filtered and the filtrate was extracted with ethyl acetate (3×1000 ml). The ethyl acetate solution was dried over sodium sulfate and distilled (0.17 mm/170° bath) to give 25.5 g (45.9%) of 2-fluoro-2-nitro-1,3-propanediol; mp 86°-87° C.; 1HNMR (acetone-d6) δ3.90 (d, J=6Hz, 2 H, --CH2 --), 4.20 (t, J=6Hz, 2 H, --CH2 --), 4.80 (t, J=6Hz, 2 H, --OH); 19FNMR (acetone-d6) φ145.6 (quintuplet J=16Hz). IR (CH2Cl2) 3620 (--OH), 1575, 1335 (--NO2), 1040 cm-1 (C=F).
Reaction SMILES: [C:1]([CH:9]([CH2:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:29]>C(O)(=O)C>[C:2]1([C:1]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:29]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1-c1ccccc1
Yield: 92.1 %

Procedure:
A mixture of 2.30 g of compound G, 8.20 g of ammonium acetate and 8.43 g of ferric chloride hexahydrate in 50 cc of acetic acid was heated under reflux for 7 hours. After cooling, the insoluble materials were removed by filtration through Celite and the filtrate was distilled to remove the solvent. The residue was adjusted to pH 8 with an aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/5) to obtain 1.98 g of compound H. Yield: 92.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:36]=[C:5]2[N:6]=[CH:7][C:8]3[CH2:12][N:11]([C@@H:13]4[CH2:18][C@H:17]([NH:19]C(=O)OC(C)(C)C)[C@@H:16]([C:27]5[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=5[F:35])[CH2:15][CH2:14]4)[CH2:10][C:9]=3[N:4]2[N:3]=1.[ClH:37]>>[ClH:37].[ClH:37].[CH3:1][C:2]1[CH:36]=[C:5]2[N:6]=[CH:7][C:8]3[CH2:12][N:11]([C@@H:13]4[CH2:18][C@H:17]([NH2:19])[C@@H:16]([C:27]5[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=5[F:35])[CH2:15][CH2:14]4)[CH2:10][C:9]=3[N:4]2[N:3]=1
Reactant: Cc1cc2ncc3c(n2n1)CN([C@H]1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OC(C)(C)C)C1)C3
Agent: Cl
Product: Cc1cc2ncc3c(n2n1)CN([C@H]1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](N)C1)C3
Reaction time: 0.5 h

Procedure:
To the more polar product from Step A was added 1 mL of hydrochloric acid (4.0 M in 1,4-dioxane) and the solution was stirred for 30 min and the solvent evaporated in vacuo to afford the title compound as a white solid. LC/MS 402.1 (M+1).
Reaction SMILES: C([Li])CCC.[CH:6]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[CH2:7].CN(C)CCN(C)C.[Cl:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CCCCCC.C(O)(=O)C.O.O1CCCC1>[Cl:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)([C:9]2[N:8]([CH:6]=[CH2:7])[CH:12]=[CH:11][N:10]=2)[OH:27])=[CH:24][CH:23]=1
Reactant: C=Cn1ccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=Cn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
At a temperature of -60° to -70° C. and under a nitrogen atmosphere, 25 ml. (0.04 mol) of 15% butyl lithium in n-hexane were added to a solution of 3.2 g (0.034 mol) of 1-vinylimidazole and 4.6 g (0.04 mol) of N,N,N',N'-tetramethylethylenediamine in 75 ml. of anhydrous tetrahydrofuran. The mixture was stirred for 2 hours and then 8.5 g (0.034 mol) of 4,4'-dichlorobenzophenone, dissolved in 75 ml. of anhydrous tetrahydrofuran were added dropwise under the same conditions. The reaction mixture was stirred for 2 hours at -60° to -70° C. and kept standing overnight at room temperature under the nitrogen atmosphere. Then 25 ml. of water and a small amount of acetic acid were added to the reaction mixture and the liquid was distilled off. Water was added to the residue and the solid matter was filtered off. The product was crystallised from a mixture of isopropyl alcohol, dimethylformamide and petroleum ether (boiling range 60°-80° C.). α,α-Bis(p-chlorophenyl)-1-vinylimidazole-2-methanol was obtained. Melting point 173.5°-174° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17]>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 65 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
4-Morpholin-4-ylmethyl-benzene-1,2-diamine (1 mol. eq.) and 4-nitro-1H-pyrazole-3-carboxylic acid (1 mol. eq.) were dissolved in dimethylformamide (DMF) (10 vol.). O-(Benzot πazol-1-yl)-N,N,N′,N1-tetramethyluronium tetrafluoroborate (TBTU) (1.2 mol. eq.) was added and the mixture was stiffed at ambient temperature for 24 hours. The mixture was concentrated in vacuo until no further solvent was seen to distil. The residue was then dissolved in glacial acetic acid (10 vol.) and heated at 65° C. for ˜12 hours. The mixture was concentrated in vacuo and then dissolved in water (6 vol.) at 75° C. The black solution was cooled to 0-5° C. over 2 hours during which time a solid was formed. The solid was removed by filtration and the aqueous filtrate was diluted with ethyl acetate (4 vol.) and tetrahydrofuran (2 vol.). Solid NaHCO3 was added slowly to the stirred mixture until no further effervescence was observed and a pII of 6.8 was reached. The mixture was then stirred until a precipitation was observed. After standing the mixture at 0-5° C. for 2 hours, the solid was collected by filtration and washed with water (2 vol.) and ethyl acetate (2 vol.) and dried to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)1H-benzimidazole as a brown solid (40%). (LC/MS (basic method): Rt 1.93, [M−H+]− 327).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2.[H][H].O.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:36])=[O:37])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1COCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCCCCC[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reaction time: 16 h
Yield: 53.6 %

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(i)pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate (0.028 g, 0.038 mmol) and Rh/Al (5%) (0.0079 g, 0.0038 mmol) in Ethyl acetate (5 mL) was charged with 1 atmosphere of hydrogen and stirred for 16 hrs. Water (3 mL) and saturated potassium hydrogen sulfate (3 mL) was added and stirred for 10 minutes. The organic phase was separated and aqueous phase extracted with ethyl acetate (10 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:4) to give (2R,6S,13aR,14aR,16aS)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxohexadecahydro-1H-cyclopropa(i)pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.015 g, 53%). MS: Calcd.: 735; Found: [M+H]+ 736. 1H NMR (400 MHz, CD2Cl2) δ9.65 (s, 1H), 7.22-7.28 (m, 2H), 6.96-7.08 (m, 2H), 5.55 (m, 1H), 5.39 (m, 1H), 4.74 & 4.69 (s, 4H), 4.54 (m, 1H), 3.97 (m, 1H), 3.84 (m, 1H), 3.77 (m, 1H), 3.67 (m, 1H), 3.55 (m, 1H), 3.47 (m, 1H), 2.92 (m, 1H), 2.65 (m, 1H), 2.35 (m, 1H), 1.06-1.68 (m, 25H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Yield: 91 %

Procedure:
A suspension of 25.0 g (0.055 mol) of [2-(2-nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (see Example 4A) in 200 ml of methanol was treated with a cold suspension of 2.5 g of 5% palladium on charcoal in 50 ml of methanol (under nitrogen) and placed on the Parr apparatus at 58 lbs. of hydrogen. The theoretical amount of hydrogen was consumed in about 30 minutes and this mixture was then heated at 50°-55° C. for one hour to assure that all of the nitro compound had dissolved. The mixture was removed from the Parr and allowed to stand at room temperature overni-ght. The flask was heated to dissolve the crystallized product, and the hot solution was filtered through Celite (under nitrogen) and washed with hot methanol. The colorless filtrate was concentrated on a rotary evaporator to give 22.2 g of a nearly colorless solid. The latter was triturated with 100 ml of hexane and then with 50 ml of hexane. The solvent was decanted and the entrained solvent removed on a rotary evaporator to give 21.3 g of product, melting point 124°-127° C. A sample of this material, after crystallization from methanol, melted at 125°-127° C.