Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH:34]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:32])[N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH3:24])[CH:17]=2)O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH:34]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:32])[N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH3:24])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)c1cccc(C(O)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1)c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CN(C(=O)c1cccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A mixture of 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methyl-carbamoyl]phenyl}hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (3.59 g) and p-toluenesulfonic acid monohydrate (3.5 g) in benzene (200 mL) was refluxed overnight in a round bottom flask equipped with Dean-Stark trap. The reaction solution was cooled to room temperature. Saturated Na2CO3 solution (50 mL) was added to the solution, followed by the addition of 100 mL of H2O. The resulting mixture was extracted by EtOAc (300 mL). It was observed that solids were floating between the two layers. Consequently, 75 ml of 0.5 M NaOH solution was added to the mixture. After being stirred for 30 minutes, the mixture became clear. The organic layer and water layer were separated. The water layer was extracted by EtOAc (100 mL×1). The combined organic layer was washed by water (75 mL×2) and brine (75 mL×1), dried by Na2SO4 and concentrated to give 4-([3-(tert-butyl-dimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methylcarbamoyl]phenyl}-methylene)piperidine-1-carboxylic acid tert-butyl ester (2.83 g; crude). TLC and 1H NMR of the crude product indicated a mixture of compounds, apparently including the desired dehydration product with the loss of N-Boc and/or O-TBDMS protecting groups. The crude product was carried to next step without purification.
Reaction SMILES: [C:1]1([P:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2([Li])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]([NH:28][Si:29](Cl)([CH3:31])[CH3:30])([CH3:27])[CH3:26]>C1COCC1>[CH3:24][C:25]([NH:28][Si:29]([CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([P:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9]1)([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: [Li]C1(P(c2ccccc2)c2ccccc2)C=Cc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C=C(P(c2ccccc2)c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 98 %

Procedure:
(1-(Diphenylphosphino)-1H-indenyl)lithium (4.45 g, 14.53 mmol) dissolved in 40 mL of THF was added within 15 minutes to a 100 mL THF solution of N-(tert-butyl)-N-(1-chloro-1,1-dimethylsilyl)amine (3,37 g, 20.34 mmol). After stirring overnight a red solution resulted. Solvent was removed under vacuum to give a red oil. The residue was extracted with 35 mL of hexane and filtered. Hexane was removed leaving 6.12 g of red oil. Yield 98 percent.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33](OC)=O)=[CH:26][C:25]=2[O:24]1>>[O:31]1[C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33]3[NH:22][C:20](=[O:21])[C:3]4[N:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:2]=4[N:1]=3)=[CH:26][C:25]=2[O:24][CH2:23]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: CC(O)C(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(O)C(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21

Procedure:
Analogously to the procedure of Example 29, the title compound is prepared from 10 mg (0.024 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-[1,2,3]triazole-4-carboxamide and 20 mg (0.107 mmol) of methyl 3,4-methylenedioxyphenylacetate.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:26])[C:24]=1[F:25]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[C:24]([F:25])=[C:23]([F:26])[CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: Cc1c2n(c3c(-c4cc(F)c(F)c(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (79 mg, 87%), MS (ISP) m/z=365.5 [(M+H)+], mp 253° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([CH2:12][OH:13])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][C:26]([CH3:28])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:25][C:26]1([CH3:28])[O:11][CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)([CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:12][O:13]1
Reactant: CC(C)=O
Reactant: COc1ccc(COCC(CO)(CO)c2ccc(F)c(F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(COCC2(c3ccc(F)c(F)c3)COC(C)(C)OC2)cc1

Procedure:
2-(3,4-Difluorophenyl)-2-(4-methoxybenzyloxymethyl)propane-1,3-diol (16.5 g, 50 mmol), acetone (7.5 ml) and p-toluene sulphonic acid (100 mg) were heated to reflux in benzene (100 ml) and water was removed using Dean and Stark apparatus. After refluxing overnight the cooled solution was washed with saturated aqueous sodium bicarbonate solution and was dried over anhydrous magnesium sulphate. Evaporation gave 2,2-dimethyl-5-(3,4-difluorophenyl)-5-(4-methoxybenzyloxymethyl)-1,3-dioxane as a yellow oil (17.7 g, 97%, Nmr δ 7.2-6.8 (7H,m), 4.4 (2H,s), 4.05 (2H,d), 3.95 (2H,d), 3.8 (3H, s), 3.7 (2H,s), 1.4 (6H,s).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][N:3]1[CH2:15][C:16]#[N:17].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[C:16]([CH2:15][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:10][CH2:9]2)=[CH:4]1)#[N:17]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: N#CCn1cc(C2CCC(=O)CC2)ccc1=O
Product: N#CCn1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)ccc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of [2-oxo-5-(4-oxo-cyclohexyl)-2H-pyridin-1-yl]-acetonitrile (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[NH2:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=O.CCN(C(C)C)C(C)C.[F:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1>O.CN(C=O)C>[NH2:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:49][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=1)=[O:28]
Reactant: Nc1ccc(F)cc1
Reactant: Nc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncccc1C(=O)Nc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
A 1 L round-bottomed flask was charged with HOBT-H2O (20.37 g, 133.0 mmol), EDCI (25.50 g, 133.0 mmol), 2-aminonicotinic acid (12.25 g, 88.69 mmol), and DMF (750 mL). The reaction mixture was stirred for 30 minutes, then Hunig's base (30.90 ml, 177.4 mmol) and 4-fluorobenzenamine (10.65 ml, 110.9 mmol) were added. The reaction mixture was stirred for 18 hours, then diluted with water. After 30 minutes the resulting precipitate was collected by filtration and dried to provide the product. LRMS M+1 (231.9) observed.
Reaction SMILES: [CH2:1]1[C@@H:5]([C:6]([OH:8])=[O:7])[NH:4][CH2:3][C@@H:2]1[OH:9].C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1.Cl>O.C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([N:4]2[CH2:3][C@H:2]([OH:9])[CH2:1][C@H:5]2[C:6]([OH:8])=[O:7])=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a clear solution of L-trans-4-hydroxy-proline (10 g) (0.076 mol) and K2CO3 (15.7 g) (1.1 eq.) in 100 mL of water and 10 mL of THF, was added by portions 3,5-dichlorophenyl isocyanate (15.7 g) (1.1 eq.). The white suspension was stirred at RT overnight. The aqueous mixture was acidified with conc. HCl, ,then extracted with EtOAc. The organic extracts were combined, washed with water, dried over MgSO4, filtered, and the solvent removed in vacuo to afford the titled compound (19 g) (yield 78.5%). 1H NMR (DMSOd6): 8.7 (1H,COOH), 7.65 (2H,d), 7.1 (1H,m), 5.2 (1H,NH), 4.4 (2H,m), 3.6 (1H,dd), 3.45 (1H,d), 2.1–2.25 (1H, m), 1.85–2.05 (1H,m).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[O:4][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH3:19])=[O:17])[CH:2]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCl)c1ccc(F)cc1
Product: COC(=O)c1cc(-c2ccc(F)cc2)oc1C
Yield: 42.7 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-4′-fluoroacetophenone (13.4 g) and methyl acetoacetate (8.6 g) to give the title compound (7.4 g, 63%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
4,6-Dichloro-nicotinic acid (10.3 g, 53.4 mmol) was suspended in CH2Cl2 (200 mL). Oxalyl chloride (14 mL, 158 mmol) was added and the reaction was placed in an ice bath. DMF (1.0 mL) was added and the reaction was fitted with an air cooled condenser. The reaction was stirred for 3 h and allowed to warm to 25° C. The volatiles were removed in vacuo and the crude residue was resuspended in THF (200 mL) and cooled to 0° C. To this stirred suspension was added concentrated aqueous ammonia (75 mL) dropwise and the reaction was allowed to stir for 1 h. The volatiles were removed and the crude was redissolved in EtOAc and poured into brine. The aqueous phase was separated and extracted twice with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated to afford 4,6-dichloro-nicotinamide as a beige solid (7.27 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[OH:21][C@@H:22]([CH3:40])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([O:38][CH3:39])[CH:31]=2)[CH2:26][CH2:25]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([CH:27]4[CH2:28][CH2:29][N:24]([CH2:23][C@@H:22]([OH:21])[CH3:40])[CH2:25][CH2:26]4)=[CH:31][C:32]=3[O:38][CH3:39])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cc(C2CCN(C[C@H](C)O)CC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(C2CCN(C[C@H](C)O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 70 %

Procedure:
In a similar fashion as for the synthesis of III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-[1-((S)-2-hydroxypropyl)-piperidin-4-yl]-2-methoxy-benzaldehyde were reacted to produce the title compound (70%). 1H NMR (d-chloroform): 10.81 (br s, 1H), 8.33 (d, J=9 Hz, 1H), 8.01 (s, 1H), 7.03 (d, J=9 Hz, 1H), 6.94 (s, 1H), 6.42 (s, 1H), 6.35 (m, 2H), 5.55 (d, J=8 Hz, 1H), 5.27 (br s, 1H), 5.20 (t, J=9 Hz, 1H), 4.07 (s, 3H), 3.89 (m, 1H), 3.58 (m, 1H), 3.18 (m, 2H), 2.97 (d, J=11 Hz, 1H), 2.92 (s, 1H), 2.87 (d, J=11 Hz, 1H), 2.61 (m, 1H), 2.49-2.24 (m, 4H), 2.08 (t, J=11 Hz, 1H), 1.94-1.71 (m, 5H), 1.18 (d, J=7 Hz, 3H). MS: 551.2 (M+H). HPLC retention time: 1.84 minutes (G Method).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:8](=[O:11])[O:9][CH3:10].[C:40]([Cu])#[N:41].O>CN(C=O)C>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:40]#[N:41])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(I)ccc1-c1cc(C(C)C)ccc1OC
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C#N)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl [3,5-bis(trifluoromethyl)benzyl][(4-iodo-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]carbamate from Example 10 (0.03 g, 0.045 mmol) and CuCN (0.008 g, 0.09 mmol) in DMF (1 ml) was stirred at 100° C. overnight. Water (10 ml) was added and the mixture was extracted with EtOAc (3×15 ml). The combined EtOAc layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after preparative thin layer chromatography using 2:8 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.74 (m, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.49 (m, 1H), 7.38 (m, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.28 (m, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.91 (m, 1H), 4.26-4.49 (m, 4H), 3.81 (m, 3H), 3.70 (s, 3H), 2.92 (m, 1H), 1.22 (s, 6H). LC-MS (M+1) 565.3 (4.42 min).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19]>>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][P:21](=[O:25])([O:22][CH2:23][CH3:24])[O:20][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(COc2ccc(CBr)cc2)CCCCC1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(OCC2(C)CCCCC2)cc1)OCC
Temperature: 145 °C

Procedure:
A mixture of the 4-[((1-methyl)cyclohexyl)methoxy]benzyl bromide and 1.7 g (10 mmol) of triethylphosphite was heated at 145° C. for 0.2 hour. The reaction was cooled to room temperature and flash chromatographed to give 1.3 g of product as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][N:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:15][CH2:14][C:13]([N:11]1[CH:12]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH:9]=[N:10]1)([CH3:17])[CH3:16])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)CO)c1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)COS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)carbamate (3.4 g) obtained in Step A of Example 114 were added successively triethylamine (2.4 mL) and methanesulfonyl chloride (1.2 mL) in an ice bath, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (2.2 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:18]([O-])([O-:20])=[O:19].[Na+]>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Cc1ccc2c(c1)CCN2C(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc2c(c([N+](=O)[O-])c1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
Compound 2 (467 mg, 2 mmol) was added to a stirred solution of sodium nitrate (170 mg, 2 mmol) in trifluoroacetic acid (5 mL) and the mixture was stirred at rt for 4 h. The solution was poured into ice-cold water (100 mL) and extracted with EtOAc. The combined organic phases were washed with saturated aq. NaHCO3 and brine, dried and evaporated. Recrystallization (EtOAc-hexanes) afforded 16 as orange needles (395 mg, 71%), mp 136-137° C.; IR: νmax/cm−1 1740, 1670, 1530; 1H NMR: δH (90 MHz) 7.52 (br s, 1H), 7.36 (br s, 1H), 4.23 (t, J=8.3 Hz, 2H), 3.70 (s, 3H), 3.62 (s, 2H), 3.20 (t, J=8.3 Hz, 2H) and 2.24 (s, 3H). Anal. Calcd for C13H14N2O5: C, 62.94; H, 6.27; N, 4.59. Found: C, 63.00; H, 6.16; N, 4.59.
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4](O)[C@H:2]1[OH:3].C(Cl)(=O)C(C)(C)C.CS(Cl)(=O)=O.C[O-].[Na+].[BH4-].[Na+].Cl>N1C=CC=CC=1.O.CO.CC(C)=O>[C@@H:1]1([N:10]2[CH:11]=[N:12][C:13]3[C:14](=[O:15])[NH:16][C:17]([NH2:18])=[N:19][C:20]2=3)[O:9][C@H:6]([CH2:7][OH:8])[CH2:4][C@@H:2]1[OH:3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CC(C)(C)C(=O)Cl
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)C[C@@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27.7 %

Procedure:
Guanosine (5.0 g, 17.7 mmol) was suspended in dry pyridine (50 ml). To the suspension was added pivaloyl chloride (9.8 ml) 79.6 mmol) under ice cooling, and the mixture was then stirred at room temperature for 45 minutes. After ice cooling, methanesulfonyl chloride (4.1 ml, 53.0 mmol) was added dropwise to the reaction mixture, after which it was first stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture was cooled with iced water and a small amount of water was added thereto and the mixture was stirred for 30 minutes. The reaction mixture was extracted with chloroform-ether and the organic layer was washed with saturated aqueous sodium bicarbonate and then with water, and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was evaporated. The residue was dissolved in toluene and the solvent was evaporated under reduced pressure. This procedure was repeated several times to completely remove the remaining pyridine.. The residue was dissolved in methanol (120 ml). Sodium methoxide (7.6 g, 140.7 mmol) and sodium borohydride (2.7 g, 71.4 mmol) were added to the solution, after which it was first stirred at room temperature for 1 hour and then at 50° C. for 5 hours. After ice cooling, a small amount of acetone was added to decompose an excess of NaBH4. Methanol (100 ml) was added to the mixture, after which it was concentrated to 1/2 volume. This procedure was repeated to remove methyl borate thus produced as a by-product. The reaction mixture was again cooled with ice, and concentrated hydrochloric acid was gradually added to neutralize. Then, water was added and the mixture was concentrated under reduced pressure. The residue from which alcohol had been removed completely was suspended in water (about 150 ml), and applied to HP-20 (DIAION: 600 ml made up with water, Mitsubishi Chemical Industries Ltd.) column. Water (about 1.5 l) was passed through the column to elute inorganic salts, and the product was then eluted with 5% methanol-water followed with 5% methanol--0.1M ammonia water. Fractions containing compound G3 were concentrated to dryness under reduced pressure and the-residue was recrystallized from methanol to give colorless crystals (1.31 g, 27.8%). The mother liquor was dried up under reduced pressure, again subjected to HP-20 column chromatography (300 ml) and followed by the same procedures mentioned above to give compound G3 (0.55 g, 11.6%).
Reaction SMILES: Br[CH:2]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([C:20](=[O:25])[C:21](Br)([CH3:23])[CH3:22])=[N:10]1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[P:26]([O:31]C)([O:29][CH3:30])[O:27][CH3:28]>>[P:26]([O:27][CH3:28])([O:29][CH3:30])([O:8]/[C:3](/[C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:2]\[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([C:20]([O:25][P:26]([O:29][CH3:30])([O:27][CH3:28])=[O:31])=[C:21]([CH3:23])[CH3:22])=[N:10]1)=[O:31]
Reactant: COP(OC)OC
Reactant: COc1ccc2c(C(=O)C(C)(C)Br)nn(C(Br)C(=O)C(C)(C)C)c2c1
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)nn(/C=C(\OP(=O)(OC)OC)C(C)(C)C)c2c1

Procedure:
The title compound was prepared from 1-bromo-1-[3-(2-bromo-2-methylpropanoyl)-6-methoxy-1H-indazol-1-yl]-3,3-dimethylbutan-2-one from Step A above and trimethyl phosphite using the method in Method I Step B of Example 1. It was purified by RP-HPLC using 10-80% MeCN gradient without TFA. 1H NMR (CDCl3, 500 MHz) δ 7.68 (d, 8.9 Hz, 1H), 6.865 (dd, 2.1 & 8.9 Hz, 1H), 6.71 (d, JH-P=3.0 Hz, 1H), 6.67 (d, 2.0 Hz, 1H), 3.89 (s, 3M), 3.63 (d, JH-P=11.2 Hz, 6H), 3.36 (d, JH-P=11.6 Hz, 6H), 2.02 (d, JH-P=2.5 Hz, 3H), 1.88 (d, JH-P=3.4 Hz, 3H), 1.38 (s, 9H). LC-MS: 3.26 min. (m/Z=407.1, 533.0, 555.0). It was noted that a faster-eluting undesirable isomeric side-product was also obtained during this reaction.
Reaction SMILES: N#[C:2][Br:3].C(N(CC)C[C:8]#[C:9][CH:10]([O:18][C:19](=[O:21])[CH3:20])[C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][CH2:14][CH3:15])C>CCOCC>[Br:3][CH2:2][C:8]#[C:9][CH:10]([O:18][C:19](=[O:21])[CH3:20])[C:11]([CH3:16])([CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(C)(C)C(C#CCN(CC)CC)OC(C)=O
Reactant: N#CBr
Solvent: CCOCC
Product: CCCCC(C)(C)C(C#CCBr)OC(C)=O
Reaction time: 16 h

Procedure:
A solution of cyanogen bromide (36.0 g., 0.340 mole) in ether (400 ml.) is treated with 1-diethylamino-4-acetoxy-5,5-dimethyl-2-nonyne (82.3 g., 0.293 mole) to give a mildly exothermic reaction. The clear solution is allowed to stand at room temperature for 16 hours.