Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[N:14]=3)=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:10]=[CH:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.O.[CH3:36][S:37]([CH3:39])=O>C(OCC)(=O)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:11]2[N:10]=[CH:9][N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:36][S:37][CH3:39])[CH2:3][CH2:4]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[N:14]=2)=[CH:26][CH:25]=1
Reactant: CS(C)=O
Reactant: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@H]2CC[C@H](O)CC2)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@H]2CC[C@H](OCSC)CC2)n1
Temperature: 25 °C

Procedure:
The product of example 11 (7.76 g, 21 mmol) was dissolved with warming in DMSO (105 mL) while stirring under argon. Cooling to room temperature and addition of triethylamine (29 mL, 208 mmol) resulted in two phases. The mixture was cooled with stirring to 18° C. in a water bath. The sulfur trioxide pyridine complex (13.4 g, 84 mmol) in DMSO (42 mL) was added dropwise over 15 min. The mild exotherm was controlled by adding ice to the water bath. The maximum internal temperature was 20° C. After the addition was complete, the mixture was stirred for 15 min., diluted with ethyl acetate (800 mL) and extracted four times with water (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated on a rotary evaporator to give 7.9 g of a crude product which NMR indicated contained −5% of the title compound. The remainder of the crude material was mostly 5-[4-(2-methoxy)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-oxocyclohexyl)imidazole. Careful chromatography on silica gel (700 g) eluted with 0.5-3% methanol in methylene chloride gave the title product as a white solid (0.368 g, 4%). MS(ES+) [M+H]+, 429.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:24](O)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)C1CCCCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCCC4)cc23)CC1

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 13.0 mg (0.10 mMol) cyclohexanecarboxylic acid, 20.6 mg (100+%) of the title compound were recovered.
Reaction SMILES: O.[O:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:12][CH:13]([OH:15])[CH3:14])[CH:6]=[CH:5][C:4]1=2>COCCOCCOC.[Pd]>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC(O)Cn1ccc2c1CCCC2=O
Agent: [Pd]
Solvent: O
Solvent: COCCOCCOC
Product: CC(O)Cn1ccc2c(O)cccc21
Yield: 78.5 %

Procedure:
10 g of 5% by weight palladium-on-charcoal, containing 50% of water, were added to a solution of 19.3 g of 4-oxo4,5,6,7-tetrahydro-1-N-(β-hydroxy-propyl)indole, obtained in the preceding stage, in 300 cm3 of diglyme. The temperature of the reaction mixture was brought to the reflux temperature of the diglyme for 5 hours, after removal of the water by azeotropic distillation. The catalyst was then filtered off on Celite and the diglyme was then evaporated. 17 g of crude product were obtained. After chromatography on silica gel (heptane/ethyl acetate=1/4), 15 g of a viscous product were obtained, which product crystallized on addition of 15 cm3 of dichloromethane. After filtering, washing with petroleum ether and drying under vacuum and over phosphorus pentoxide, 10 g of 4-hydroxy-1-N-(β-hydroxypropyl)indole were recovered, the melting point of which was between 93 and 95° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[N+:28]([O-])=O)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].[NH4+].[Cl-].C1COCC1.O>CCO.[Fe]>[NH2:28][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:18]=1[S:17][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])=[C:2]([F:1])[CH:3]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)c(F)c2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)c(F)c2)c(N)c1
Yield: 49.6 %

Procedure:
The product of Example 449C (2.8 g, 5.6 mmol), Fe powder (1.6 g, 28 mmol) and NH4Cl (1.5 g, 28 mmol) in a mixture of EtOH (28 mL), THF (14 mL) and water (28 mL) was gently refluxed for 1 hour. The reaction mixture was cooled and filtered through celite pad. The filtrate was concentrated. The aqueous residue was partitioned between ethyl acetate and water, and adjusted to pH 8-9 with NaHCO3. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated. The oily residue was separated by column chromatography (SiO2, n-hexane/ethyl acetate=3/1) to give the title compound as pale yellow crystal (1.3 g, 48%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[C:25](O)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:27].CC1C=CC=C(C)N=1>ClCCl>[Br:16][C:17]1[C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:27]
Reactant: O=C1CCc2c1ccc(O)c2Br
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (4.0 mL) is added dropwise to a solution of 4-bromo-5-hydroxy-indan-1-one (5.0 g) and 2,6-dimethylpyridine (5.1 mL) in dichloromethane (50 mL) cooled to 0° C. The cooling bath is removed and the mixture is stirred for 2 h at room temperature. The solution is partitioned between saturated aqueous NH4Cl solution and dichloromethane. The organic phase is separated, washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. LC (method 2): tR=1.08 min; Mass spectrum (ESI+): m/z=359/361 (Br) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41])=[O:29]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2CC(=O)N[C@H]2c3ccccc3C[C@H]2O)cc1OC

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1ccccc1F
Solvent: CCN(CC)CC
Product: Fc1ccccc1CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(2-fluorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-fluorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:18])[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH3:7].[I-].[Na+].[CH:21]([C:24]1[NH:25][CH:26]=[CH:27][N:28]=1)([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C=O)C.O>[CH:21]([C:24]1[N:25]([CH2:2][CH2:3][O:4][C:5](=[O:18])[C:6]([CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH3:7])[CH:26]=[CH:27][N:28]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(C(=O)OCCBr)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)c1ncc[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1nccn1CCOC(=O)C(C)(C)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 19.5 %

Procedure:
To a solution of 2-methyl-2-(3-nitro-phenyl)-propionic acid 2-bromo-ethyl ester (1.5 g, 4.74 mmol) in DMF (8 mL) was added sodium iodide (0.73 g, 4.87 mmol) and heated at 100° C. for 1 h. 2-Isopropyl-imidazole (2.15 g, 19.5 mmol) and triethylamine (2 mL, 14.6 mmol) were added and then refluxed for 4 h. The reaction was diluted with water and extracted with DCM. The organic layer was washed thoroughly with water, dried over sodium sulfate and evaporated to obtain crude compound. Purification by column chromatography on silica gel (60-120 mesh), eluting with 30% ethyl acetate/hexane gave 2-methyl-2-(3-nitro-phenyl)-propionic acid 2-(2-isopropyl-imidazol-1-yl)-ethyl ester (320 mg, 20%) as a solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([N+:25]([O-])=O)=[C:6]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:5]=1>CO.C(Cl)Cl.O.[Ni](Cl)Cl>[CH3:3][C:4]1[N:9]=[C:8]([N:10]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([NH2:25])=[C:6]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:5]=1
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(N(Cc2ccccc2)Cc2ccccc2)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1cc(NCC(C)C)c(N)c(N(Cc2ccccc2)Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Sodium borohydride (585 mg, 16 mmole) was added to a solution of nickel (II) chloride hydrate (1.02 g, 4.3 mmole) in methanol (100 mL). The addition caused a black solid to form along with gas evolution. The resulting heterogeneous mixture was stirred at ambient temperature for 30 minutes. A solution containing 6-methyl-N4 -(2-methylpropyl)-3-nitro-N2,N2 -bis(phenylmethyl)pyridine-2,4-diamine (3.47 g, 8.6 mmole) in methylene chloride (20 mL) was added followed by the addition of sodium borohydride (1.37 g, 36 mmole). The reaction mixture was stirred at ambient temperature for about 30 minutes then eluted through a layer of silica gel with a methanol/methylene chloride mixture. The filtrate was concentrated under vacuum. The resulting residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried with magnesium sulfate and concentrated under vacuum to provide 2.74 g of the desired product as a green foam.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(S(C)(=O)=O)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 70.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(methylsulfonyl)phenylboronic acid (20.8 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 2′-amino-1′-methyl-6-(3-(methylsulfonyl)phenyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (16.89 mg, 70%). 1H-NMR (MeOD): 2.01 (m, 1H), 2.31 (m, 1H), 3.14 (m, 3H), 3.21 (m, 3H), 5.22 (m, 0.2H), 5.83 (m, 0.7H), 6.89 (m, 1H), 7.18 (m, 1H), 7.23 (m, 1H), 7.32 (m, 2H), 7.39 (m, 2H), 7.45 (m, 1H), 7.57 (m, 1H), 7.76 (m, 2H), 7.96 (m, 1H).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:26]2[C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:23](=[O:36])[C:22]=2[C:21]([OH:37])=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45]N(C=O)C.C([O-])([O-])=O.[K+].[K+].CI>O>[CH:1]([O:14][C:15]1[C:26]2[C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:23](=[O:36])[C:22]=2[C:21]([O:37][CH3:45])=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1c2c(c(O)c3c(ncn3Cc3ccccc3)c2OC(c2ccccc2)c2ccccc2)C(=O)N1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 73 %

Procedure:
Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione 258 (103 mg, 0.177 mmol, 1 equiv.) was added to a flask containing DMF (4 mL) followed by K2CO3 (122 mg, 0.88 mmol, 5 equiv.). To this was added methyl iodide (MeI, 109 μL, 1.76 mmol, 10 equiv.) under a nitrogen atmosphere and stirred for 16 hours. To the reaction was added water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed several times with water (3×30 mL), saturated NaHCO3 (40 mL), brine solution (30 mL). It was dried over Na2SO4, filtered and concentrated in vacuo and purified by silica gel chromatography using 7/3 Hexanes/Ethyl acetate to obtain 4-benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-methoxy-1H-1,3,6-triaza-s-indacene-5,7-dione 259 (73%, 75 mg, 0.125 mmol). 1H NMR (300 MHz) CDCl3 δ 8.09 (s, 1 H), 7.94 (s, 1 H), 7.88 (s, 1 H), 7.64-7.43 (m, 4 H), 7.41-7.46 (m, 2 H), 7.17-7.43 (m, 10 H), 6.98-7.04 (m, 3 H), 5.56 (s, 2 H), 4.80 (s, 2 H), 3.84 (s, 3 H). MS: 620.1 (M+23). TLC Rf: 0.6 Hexanes/Ethyl acetate (1/1).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:29]=[CH:28][N:13]([C@@H:14]2[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12](=[O:30])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[C:34]([O:53][CH3:54])=[C:35]([CH:50]=[CH:51][CH:52]=1)[C:36](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([NH:9][C:10]1[CH:29]=[CH:28][N:13]([C@@H:14]2[O:27][C@H:24]([CH2:25][O:26][C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:35]3[CH:50]=[CH:51][CH:52]=[C:33]([O:32][CH3:31])[C:34]=3[O:53][CH3:54])[C@@H:22]([OH:23])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12](=[O:30])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 69.5 %

Procedure:
N4-Benzoyl-2'-O-pentylcytidine (3.0 g, 0.007 mol) was treated with dimethoxytrityl chloride (2.7 g, 1.1 eq) as per the procedure of Example 72 to give 3.5 g of pure product. Anal. Calcd. for C42H45N3O8.1/2H2O: C, 69.21; H. 6.36; N, 5.76. Found: C, 69.51; H, 6.30; N, 5.71.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[CH3:22][C:23]1[CH:37]=[CH:36][C:26]([CH:27](O)[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:22][C:23]1[CH:37]=[CH:36][C:26]([CH:27]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[O:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])=[CH:10][CH:9]=2)=[CH:25][CH:24]=1
Reactant: O=C(CCc1ccc(OCCSCCO)cc1)C(F)(F)F
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(OCCSCCOc2ccc(CCC(=O)C(F)(F)F)cc2)c2ccc(C)cc2)cc1
Yield: 94.2 %

Procedure:
A solution of 4-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone (1.20 g, 3.72 mmol), 4,4′-dimethylbenzhydrol (0.95 g, 4.47 mmol) and p-toluenesulfonic acid (0.035 g) in toluene (20 ml) was heated under reflux for 15 min. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution with a gradient of ethyl acetate 20-40% in hexane) gave 1.81 g (94%) of the title material as an oil.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH:12]2[N:16]3[C:17](=[O:36])[CH:18]([NH:23][C:24]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][N:27]=4)=[O:25])[CH2:19][CH:20]=[CH:21][CH2:22][CH:15]3[CH2:14][CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1)C.FC(F)(F)C(O)=O>O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:16]3[C:17](=[O:36])[C@@H:18]([NH:23][C:24]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][N:27]=4)=[O:25])[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:15]3[CH2:14][CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)C1CCC2CC=CCC(NC(=O)c3nccc4ccccc34)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CC(NC(=O)[C@@H]2CC[C@H]3CC=CC[C@H](NC(=O)c4nccc5ccccc45)C(=O)N32)C(O)O1
Yield: 78 %

Procedure:
6-[(Isoquinoline-1-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide, 15, (1.42 g, 2.80 mmol) is stirred in a solution of trifluroacetic acid 5 mL acetonitrile 5 mL, and water 2.5 mL for 2 hours. Solvents are removed in vacuo and the resulting residue dissolved in ethyl acetate and re-concentrated to remove any excess TFA. The crude product is purified over silica (ethyl acetate:0.1% acetic acid,) to afford 1.18 g (78% yield) of the desired product as a yellow foam. 1H NMR (CDCl3): δ 9.30 (m, 1H), 8.85 (d, 7.6 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H), 7.87–7.34 (m, 6H), 5.92–5.71 (m, 3H), 5.54 (m, 1H), 4.71–4.35 (m, 3H), 3.03 (m, 4H), 2.43 (m, 3H), 2.19 (m, 2H), 1.98 (m, 1H). 13C NMR (CDCl3): δ 173.9, 172.5, 171.4, 165.9, 147.9, 140.7, 137.6, 131.4, 130.8, 128.9, 127.5, 127.2, 125.6, 124.9, 61.7, 59.1, 50.4, 34.2, 33.4, 32.3, 27.0. ESI MS 479.11 (M+H). HRMS calc. 479.1931, found 479.1941.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH3:23])[CH:15]=O.[Si](C#N)(C)(C)C.[N:30]1([C:35](N2C=CN=C2)=[O:36])C=CN=[CH:31]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:15]([C:14]4[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][CH3:23])=[C:12]([F:11])[CH:13]=4)[CH2:31][NH:30][C:35]3=[O:36])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CCCOc1ccc(C=O)cc1F
Agent: C[Si](C)(C)C#N
Product: CCCOc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1F

Procedure:
The compound was further synthesized starting from 5-aminobenzimidazole (0.806 g, 6.1 mmol), 3-fluoro-4-propoxybenzaldehyde (1.0 g, 5.5 mmol), TMSCN (0.69 mL, 5.5 mmol), PdC (10%, 0.02 g), TEA 1.44 mL, 10.3 mmol), di-(imidazol-1-yl)methanone (0.92 g, 5.6 mmol) as described in method 2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]>CN(C)C=O.N1C=CC=CC=1.O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]
Reactant: Oc1ccccc1I
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(COc2ccccc2I)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
2-Iodophenol (0.18 g, 0.87 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried to yield 280 mg of 2-(2-iodophenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.C(N(CC)C(C)C)(C)C.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:45]2C(=O)C[CH:48]([C:52]([F:55])([F:54])[F:53])[CH2:47][C:46]=2[OH:56])[NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)=[O:33])=[CH:26][CH:25]=1)#[N:23]>ClCCl>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]([C:45]2[C:46](=[O:56])[CH2:47][CH:48]([C:52]([F:53])([F:55])[F:54])[CH2:12][C:11]=2[O:8][CH2:9][CH3:10])[NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)=[O:33])=[CH:28][CH:29]=1)#[N:23]
Reactant: CC[O+](CC)CC
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(C(F)(F)F)CC2=O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (1.82 g, 9.57 mmol) is added to a mixture of N,N-diisopropylethylamine (1.92 mL, 11.0 mmol) and 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 12, 2.38 g, 4.79 mmol) in dichloromethane (30 mL). The mixture is stirred at room temperature for 1 h and washed three times with water. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 1.66 g; ESI mass spectrum [M+H]+=525, Retention time HPLC: 1.25 min (V011_S01).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[NH2:24][CH2:25][CH2:26][OH:27].CC(O)C.CCN(C(C)C)C(C)C>O>[Br:1][C:2]1[C:3]([NH:24][CH2:25][CH2:26][OH:27])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCO)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 0.5 g, 1.264 mmol), 2-aminoethanol hydrochloride (0.123 g, 1.896 mmol), iPrOH (4 mL) and DIPEA (0.442 mL, 0.327 g, 2.53 mmol) were subjected to MW irradiation at 140° C. for 2 h. The vial was cooled to RT and the RM was poured into water (100 mL) and the resulting precipitate was collected by filtration. The obtained solid was washed with water (50 mL) and dried to afford the title compound without further purification. LC-MS (Condition 6) tR=1.14 min, m/z=419.8 [M+H]+.