Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[C:10]2[NH:14][C:13]([C:15]([C:49]3[C:54]([OH:55])=[CH:53][CH:52]=[CH:51][C:50]=3[OH:56])=[C:16]3[N:48]=[C:19]([C:20]([C:40]4[C:45]([OH:46])=[CH:44][CH:43]=[CH:42][C:41]=4[OH:47])=[C:21]4[NH:39][C:24](=[C:25]([C:31]5[C:36]([OH:37])=[CH:35][CH:34]=[CH:33][C:32]=5[OH:38])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2.[C:57]([OH:63])(=O)[C:58]([CH3:61])([CH3:60])[CH3:59]>O1CCCC1.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:57]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])[C:3]=1[C:9]1[C:10]2[NH:14][C:13]([C:15]([C:49]3[C:50]([O:56][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:51][CH:52]=[CH:53][C:54]=3[O:55][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[C:16]3[N:48]=[C:19]([C:20]([C:40]4[C:45]([O:46][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:44][CH:43]=[CH:42][C:41]=4[O:47][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[C:21]4[NH:39][C:24](=[C:25]([C:31]5[C:32]([O:38][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:33][CH:34]=[CH:35][C:36]=5[O:37][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2)(=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)C(=O)O
Reactant: Oc1cccc(O)c1-c1c2nc(c(-c3c(O)cccc3O)c3ccc([nH]3)c(-c3c(O)cccc3O)c3nc(c(-c4c(O)cccc4O)c4ccc1[nH]4)C=C3)C=C2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1cccc(OC(=O)C(C)(C)C)c1-c1c2nc(c(-c3c(OC(=O)C(C)(C)C)cccc3OC(=O)C(C)(C)C)c3ccc([nH]3)c(-c3c(OC(=O)C(C)(C)C)cccc3OC(=O)C(C)(C)C)c3nc(c(-c4c(OC(=O)C(C)(C)C)cccc4OC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2

Procedure:
50 ml of a solution of 1.0 g of 5,10,15,20-tetra(2',6'-dihydroxyphenyl)porphyrin in dry tetrahydrofuran was refluxed at the boiling point in an atmosphere of nitrogen. 5.0 g of anhydrous pivalic acid and then 0.17 g of 4-dimethylaminopyridine were added to the solution, and the mixture was heated under reflux for about 20 hours. The reaction solution was evaporated and the residue obtained was dissolved in 250 ml of chloroform. The chloroform solution was washed with dilute hydrochloric acid and with water. The solution was dehydrated by using anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness. The residue obtained was fractionated and purified by chromatography on a column of silica gel (chloroform / ether (10/1) (volume/volume)). The object fractionated was collected and evaporated to dryness under reduced pressure. Thus, 5,10,15,20-tetra(2',6'-dipivaloyloxyphenyl)porphyrin was obtained as violet needle crystals. Yield: 1.15g (60%).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl[C:10]([C:12]1[C:16]([CH:17]2[CH2:19][CH2:18]2)=[CH:15][N:14]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:13]=1)=[O:11]>COCCOC.C(Cl)(Cl)Cl.CO>[CH:17]1([C:16]2[C:12]([C:10]([NH:7][C:6]([NH2:8])=[NH:5])=[O:11])=[CH:13][N:14]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH2:19][CH2:18]1
Reactant: O=C(Cl)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: N=C(N)NC(=O)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
1.19 g (22 mmol) of sodium methoxide are added to 25 mL of methanol at a temperature in the region of 20° C. under an argon atmosphere. After total dissolution, 2.2 g (23 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 20° C. for 0.5 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is suspended in 50 mL of 1,2-dimethoxyethane and then concentrated to dryness again. The residue is suspended in a mixture of 100 mL of tetrahydrofuran and 100 mL of dichloromethane at a temperature in the region of 20° C. under an argon atmosphere, and 1.12 g (3.78 mmol) of 3-chlorocarbonyl-4-cyclopropyl-1-(quinolin-4-yl)-1H-pyrrole dissolved in 25 mL of chloroform are then added. After stirring for 17 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is triturated in 100 mL of water. After filtration, a gum is obtained, which is dissolved in 50 mL of methanol. The solution is partially concentrated to a volume of from 5 to 10 mL and then purified by chromatography on silica gel [eluent: chloroform/methanol (75/25 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure, the residue is dissolved in 20 mL of methanol, and 2 mL of 6 N hydrochloric dioxane are added. The solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is then triturated in a mixture of dichloromethane and diethyl ether and filtered, giving 0.77 g of 4-cyclopropyl-3-guanidinocarbonyl-1-(quinolin-4-yl)-1H-pyrrole in the form of a yellow solid melting at 185° C. Mass spectrum (EI): m/e 319 (M+.) (base peak), m/e 260, m/e 231.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6](#[N:9])[CH:7]=[CH2:8].[CH:10]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:9][C:6](=[O:2])[CH:7]=[CH2:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C=CC#N
Reactant: O=S(=O)(O)O
Reactant: OC1CCCCC1
Product: C=CC(=O)NC1CCCCC1
Temperature: 45 °C
Yield: 88 %

Procedure:
Sulfuric acid (46.0 g) was placed in a 3-liter 3-neck flask and heated to 45° C. A mixture of acrylonitrile (94.5g) and cyclohexanol (180.2g) was prepared and added to the flask simultaneously with additional sulfuric acid (95.8%, 322.3 g) keeping the temperature at 45°-55° C. At the end of the addition, the brown solution was heated to 60° C. for 3 hours. The mixture was then poured into 3 liters of ice water with constant stirring. The white precipitate formed was filtered, washed with water until filtrate is no longer acidic and dried in a vacuum oven at 55° C. to yield N-cyclohexylacrylamide (242.4 g, 88%); m.p. 109°-110° C.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[NH:23][C:24]([NH:26][C:27]([O:29][CH3:30])=[O:28])=[S:25].[OH-].[Ca+2].[OH-].S(OC)(O[CH3:37])=O>CN(C)C=O.O>[NH:1]=[C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[NH:23][C:24](=[N:26][C:27]([O:29][CH3:30])=[O:28])[S:25][CH3:37]
Reactant: COC(=O)NC(=S)NC1C(=N)C=C(C(=O)c2ccccc2)C=C1Cc1ccccc1
Reactant: COS(=O)OC
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N=C(NC1C(=N)C=C(C(=O)c2ccccc2)C=C1Cc1ccccc1)SC
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-5-benzoylbenzene (4.33 g.; 0.01 mol) in dimethylformamide (50 ml.) and water (5 ml.) there is added calcium hydroxide (0.74 g.; 0.01 mol). The mixture is stirred at 30° C. for 2 hours and to it there is added dimethyl sulfite (1.1 g.; 0.01 mol). The mixture is stirred at room temperature for 3 hours and the precipitate collected and dried to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-5-benzoylbenzene.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[F:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.[CH3:20][O-:21].[Na+]>CO>[F:9][C:10]1[CH:11]=[C:12]([S:16]([NH:8][C:3]2[C:2]([O:21][CH3:20])=[N:7][CH:6]=[CH:5][N:4]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1nccnc1Cl
Reactant: C[O-]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1NS(=O)(=O)c1cccc(F)c1

Procedure:
By the method outlined in Example 1 (reaction performed at room temperature) using 3-chloro-2-pyrazinamine (1.29 g), 3-fluorobenzenesulphonyl chloride (2.13 g). The crude adduct was reacted with a solution of sodium methoxide (10 mL of a 25% solution in methanol) in methanol (20 mL) to afford the sub-titled compound (2.36 g) as a solid.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]21[CH:14]1[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]1)[CH2:10]2.[N+:17]([O-])([OH:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[N+:17]([C:8]1[CH:9]=[C:4]2[CH2:3][C:2]3([CH:14]4[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]4)[CH2:10]3)[O:1][C:5]2=[N:6][CH:7]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: c1cnc2c(c1)CC1(CN3CCC1CC3)O2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cnc2c(c1)CC1(CN3CCC1CC3)O2
Temperature: 0 °C
Yield: 51 %

Procedure:
A mixture of spiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (325 mg, 1.5 mmol) and fuming nitric acid (0.27 mL, 5.74 mmol) in sulfuric acid (0.75 mL) was heated at 70° C. to 80° C. for 24 hours. The resulting viscous solution was poured onto 15 g of ice and basified to pH>10 with solid sodium carbonate. The resulting mixture was extracted with chloroform (4×15 mL), dried (MgSO4), filtered, and evaporated under reduced pressure. Purification by flash chromatography through silica gel, eluting with ammoniated chloroform/methanol (95:5), provided the title compound (200 mg, 0.765 mmol, 51%) as a light yellow solid: electrospray MS 262 ([MH]+, 100).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C@@:18]3([CH:32]=[CH2:33])[CH2:26][CH2:25][C@:24]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:23][C@@H:19]3[CH2:20][CH2:21][O:22][C:3]=12.[Br:34][C:35]1[C:43]2[N:42]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[N:41]=[CH:40][C:39]=2[CH:38]=[C:37]2[C@:51]3([CH:65]=[CH2:66])[CH2:59][CH2:58][C@@:57]([C:61]([F:64])([F:63])[F:62])([OH:60])[CH2:56][C@H:52]3[CH2:53][CH2:54][O:55][C:36]=12>[Pd].C1COCC1>[Br:1][C:2]1[C:10]2[N:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C@@:18]3([CH2:32][CH3:33])[CH2:26][CH2:25][C@:24]([C:28]([F:29])([F:31])[F:30])([OH:27])[CH2:23][C@@H:19]3[CH2:20][CH2:21][O:22][C:3]=12.[Br:34][C:35]1[C:43]2[N:42]([C:44]3[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=3)[N:41]=[CH:40][C:39]=2[CH:38]=[C:37]2[C@:51]3([CH2:65][CH3:66])[CH2:59][CH2:58][C@@:57]([C:61]([F:62])([F:64])[F:63])([OH:60])[CH2:56][C@H:52]3[CH2:53][CH2:54][O:55][C:36]=12
Reactant: C=C[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCOc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Reactant: C=C[C@]12CC[C@@](O)(C(F)(F)F)C[C@@H]1CCOc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Agent: [Pd]
Solvent: C1CCOC1
Product: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCOc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Product: CC[C@]12CC[C@@](O)(C(F)(F)F)C[C@@H]1CCOc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Reaction time: 4 h
Yield: 92 %

Procedure:
To 10% Pd/C (wet, 0.162 g) was added a solution of (3R,4aR,12bS)-8-bromo-9-(4-fluorophenyl)-3-(trifluoromethyl)-12b-vinyl-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol; compound with (3S,4aS,12bR)-8-bromo-9-(4-fluorophenyl)-3-(trifluoromethyl)-12b-vinyl-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol (107, R1=4-Fluorophenyl, R2=Vinyl, R3=Trifluoromethyl) (0.443 g, 0.843 mmol) and THF (8.0 mL). The mixture was placed under an hydrogen atmosphere using a balloon. After about 4 h, the hydrogen atmosphere was evacuated and the mixture was filtered through Celite® rinsing with THF (50 mL). The volatiles were removed under reduced pressure. The residue was purified on silica gel (24 g) using a gradient of 0-5% EtOAc in DCM. The fractions containing the product were combined and concentrated under reduced pressure to afford (3R,4aR,12bR)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol; compound with (3S,4aS,12bS)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol (108, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.410 g, 92% yield) as an ivory solid. LC/MS, method 3, Rt=2.63 min, MS m/z 527 and 529 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 7.81 (s, 1H), 7.58-7.51 (m, 2H), 7.39-7.29 (m, 2H), 5.92 (s, 1H), 4.47-4.38 (m, 1H), 3.48-3.38 (m, 1H), 2.41-2.28 (m, 1H), 2.25-1.51 (m, 10H), 0.41 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:26])[N:15]([CH3:25])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(C)c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Yield: 96.9 %

Procedure:
Cyclohexylamine (2.85 mL, 24.95 mmol) was added to a solution of Compound 17 (3.26 g, 12.47 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 3.8 g (97%) of white solids. M.P. 218° C. 1H NMR (DMSO-d6): δ 1.28 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.87 (m, 2H), 2.40 (s, 3H), 3.59 (s, 3H), 3.87 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.86 (s, 1H), 10.49 (s, 1H). EIMS m/z 315 (M+1), 337 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.Cl.Cl.Cl.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[S:25][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]2)=[CH:27][N:28]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([C:11]([NH:37][CH2:36][CH:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:26]3[S:25][C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[F:17])=[N:28][CH:27]=3)[CH2:31][CH2:32]2)=[O:13])[CH:3]=1
Reactant: NCC1CCN(Cc2cnc(-c3ccccc3F)s2)CC1
Reactant: N#Cc1c(N)cc(C(=O)O)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)nc1Cl
Reaction time: 1 h

Procedure:
A solution of 1,1′-carbodiimidazole (0.15 g) and 4-amino-6-chloro-5-cyanopicolinic acid (0.14 g, prepared according to the reported preparation in Zhao, Hongyu, et al.; J. Med. Chem. 2006, 49(15), 4455-4458) in N,N-dimethylformamide (3.5 mL) was stirred one hour at room temperature. The compound prepared in Example 392 (0.30 g) and triethylamine (0.60 mL) were added and the reaction was stirred for one hour more. A saturated sodium bicarbonate solution was added and the mixture was vigorously stirred overnight. The mixture was diluted with water and then filtered. The solids were evaporated from acetone and then a 1:1 dichloromethane:toluene solution. The solids were triturated with dichloromethane to furnish the title compound (0.22 g) having the following physical data.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C.O>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1F
Reactant: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(F)cccc1Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 106.9 %

Procedure:
To a 20 mL vial containing a magnetic stir bar was added sodium hydride (103.7 mg, 4.32 mmol, 60% in mineral oil) followed by anhydrous DMF (2 mL) resulting in gas evolution. To this stirring reaction mixture was added 2-naphthol (623 mg, 4.32 mmol) as a solid in small portions over 5 min. The mixture was stirred at room temperature for 3 min and then 2,6-difluorobenzonitrile (601 mg, 4.32 mmol) in anhydrous DMF was added in one portion. The reaction mixture was heated in an oil bath at 100° C. for a total of 2 h and allowed to cool to room temperature. The reaction mixture was diluted with water (15 mL) and the resulting mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (3×20 mL), dried (Na2SO4), filtered and concentrated to give I-189 as brown solid (1.216 g) of sufficient purity (contains 2-naphthol) to be used in the subsequent step. 1H NMR.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([O:18][P:19]([O-:22])([O-:21])=[O:20])[O:16][C@@H:15]([CH3:17])[C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@@H:9]1[OH:10].C([NH+](CC)CC)C.C([NH+](CC)CC)C.C1CCC(NC(N2CCOCC2)=NC2CCCCC2)CC1.C1N([P:64]([O:67][CH2:68][C@H:69]2[O:73][C@@H:72]([N:74]3[C:78]4[NH:79][C:80]([NH2:84])=[N:81][C:82](=[O:83])[C:77]=4[N:76]=[CH:75]3)[C@H:71]([OH:85])[C@@H:70]2[OH:86])([OH:66])=[O:65])CCOC1.N1C=NN=N1>N1C=CC=CC=1>[CH3:17][CH:15]1[O:16][CH:8]([O:18][P:19]([O:21][P:64]([O:67][CH2:68][CH:69]2[O:73][CH:72]([N:74]3[C:78]4[NH:79][C:80]([NH2:84])=[N:81][C:82](=[O:83])[C:77]=4[N:76]=[CH:75]3)[CH:71]([OH:85])[CH:70]2[OH:86])([OH:66])=[O:65])([OH:22])=[O:20])[CH:9]([OH:10])[CH:11]([OH:12])[CH:13]1[OH:14]
Reactant: C[C@@H]1OC(OP(=O)([O-])[O-])[C@@H](O)[C@H](O)[C@@H]1O
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@H](COP(=O)(O)N4CCOCC4)[C@@H](O)[C@H]3O)c2[nH]1
Agent: C1CCC(N=C(NC2CCCCC2)N2CCOCC2)CC1
Agent: CC[NH+](CC)CC
Agent: c1nnn[nH]1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1OC(OP(=O)(O)OP(=O)(O)OCC2OC(n3cnc4c(=O)nc(N)[nH]c43)C(O)C2O)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.9 %

Procedure:
Compound 26 (624 mg, 1.41 mmol; wherein R, R'=OH; Sigma) was dissolved in H2O (15 mL), applied to a Bio-Rad AG 50W-X2 cation exchange column (Et3N+, 2.5×8 cm), and eluted with H2O (150 mL). The solution was evaporated, coevaporated with MeOH (2×10 mL) and dried for 3 d under vacuum to give triethylammonium β-L-fucopyranosyl phosphate 29 (512 mg). The content of triethylamine was determined to be 1.16 equiv. (1H NMR) A mixture of 29 (57.5 mg, 159 μmol) and guanosine 5'-monophospho morpholidate 4-morpholine-N,N'-dicyclohexylcarboxamidine salt 27 (201 mg, 255 μmol) was coevaporated with dry pyridine (3×1.5 mL). 1H-Tetrazole (33 mg, 477 μmol) and dry pyridine (0.8 mL) were added, and the solution stirred at rt. After a while, product starts to precipitate. The reaction was monitored by TLC (2:1 i-PrOH/1M NH4OAc). After 2 d, the mixture was diluted with water (1.5 mL) to become a clear solution, evaporated, and coevaporated with water (2×1.5 mL). The residue was purified on a Bio-Gel P-2 column (2.5×70 cm), eluated with 250 mM NH4 HCO3 to give 30 (82.4 mg, 85%) as a white solid after lyophilization (Rf 0.43, 2:1 i-PrOH/1M NH4OAc). The 1H NMR spectral data were in agreement with the published ones (Nunez et al. Can. J. Chem. 1981, 59, 2086-2095; Gokhale et al. Can. J. Chem. 1990, 68, 1063-1071).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([N+]([O-])=O)=[CH:15][CH:14]=3)=[O:10])=[C:6]([F:23])[C:5]([F:24])=[C:4]([F:25])[C:3]=1[F:26].[N+:27](C1C=C2C(=CC=1)NC(C(O)=O)=C2)([O-:29])=[O:28]>>[F:1][C:2]1[C:7]([O:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([N+:27]([O-:29])=[O:28])[CH:14]=3)=[O:10])=[C:6]([F:23])[C:5]([F:24])=[C:4]([F:25])[C:3]=1[F:26]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc2ccc([N+](=O)[O-])cc2[nH]1

Procedure:
Compound 192 was synthesized as described for Compound 105 in Example 93, except instead of 104, 191 was used. It was used without isolation.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25](O)=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]([CH2:33][CH2:34][CH2:35][NH2:36])[CH3:32]>>[CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([NH:36][CH2:35][CH2:34][CH2:33][N:31]([CH3:32])[CH3:30])=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-benzyloxycarbamoyl-phenylamino)methyl]-2-fluoro-benzoic acid (Example 498) and 3-(N,N-dimethylamino)-1-propylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([F:16])([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+:18].O1CCCC1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([F:16])([C:13]([O-:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Li+:18]
Reactant: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)[O-])C1
Temperature: 45 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a solution of #168 (50 mg, 0.21 mmol, 1 eq.) in methanol (0.2 mL) was added a solution of lithium hydroxide (9.2 mg, 0.38 mmol, 1.8 eq.) dissolved in water (0.1 mL). Next, tetrahydrofuran (0.3 mL) was added and the reaction was stirred at 45° C. for 18 hours. The reaction was concentrated in vacuo and the material was azeotroped (3×) with toluene (2 mL) to obtain #170 (51 mg, 100%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([OH:26])=O)[CH:5]=[CH:6][C:7]=1[O: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][CH3:22].CN(C)C=O.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([Cl:35])=[O:26])[CH:5]=[CH:6][C:7]=1[O: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][CH3:22]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 69 h

Procedure:
To a mixture of 10 g of product from Example 64, 0.095 g of dimethylformamide and 150 ml of methylene chloride is added, dropwise, 3.42 ml of oxalyl chloride. The reaction is stirred at room temperature for 69 hours and then concentrated in vacuo. The residue is dissolved in diethyl ether, filtered and concentrated in vacuo to give 10.5 g of the desired product as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:30])[CH:13]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([F:29])[CH:22]=[C:23]([F:28])[CH:24]=3)[CH2:19]2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CS(C)=O>C(Cl)Cl>[CH3:4][C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:30])[CH:13]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([F:29])[CH:22]=[C:23]([F:28])[CH:24]=3)[CH2:19]2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:2]=[O:1]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)CO)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)C=O)s1

Procedure:
A mixture of 2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (60 mg) and Dess-Martin oxidizing agent (100 mg) in methylene chloride (1 mL) and DMSO(1 mL) was stirred at room temperature for 4 hr. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated and concentrated. The residue was purified by silica gel column chromatography using 20% to 50% ethyl acetate in hexane as eluent to give 2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide as a brown oil, LC-MS RT=2.1 min, M+1=436.9.0.