Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:14]=[C:15]([C:19]([C:24]2[N:25]=[CH:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=2)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:17][CH:18]=1>>[OH:23][C:19]([C:15]1[CH:14]=[C:13]([C:4]2[C:3]([CH:1]=[O:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][CH:16]=1)([C:24]1[N:25]=[CH:26][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=Cc1ccccc1B(O)O
Product: CC(C)C(O)(c1cccc(-c2ccccc2C=O)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 87.1 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 2-formylphenylboronic acid (0.50 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.02 g), the amorphous title compound (0.93 g) was obtained.
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:20][CH:19]=1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Reactant: Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)c1ccccc1O

Procedure:
The 4′-chloro-salicylanilide was prepared by condensing phenyl salicylate with 4-chloroaniline then purified as described in Example 2a.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([CH:58]=[CH:59][C:60]=1[NH:61][CH2:62][CH2:63][CH:64]([CH3:66])[CH3:65])[C:51]([N:53]([CH2:56][CH3:57])[CH2:54][CH3:55])=[O:52]>>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[N:61]([CH2:62][CH2:63][CH:64]([CH3:66])[CH3:65])[C:60]3[CH:59]=[CH:58][C:50]([C:51]([N:53]([CH2:56][CH3:57])[CH2:54][CH3:55])=[O:52])=[CH:49][C:48]=3[N:47]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(NCCC(C)C)c(N)c1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)ccc3n2CCC(C)C)cc1
Yield: 90 %

Procedure:
Following general procedure 13B, (4-ethoxyphenyl)acetic acid (0.110 g, 0.612 mmol), HATU (0.233 g, 0.611 mmol), DIPEA (0.15 m, 0.86 mmol), and 3-amino-N,N-diethyl-4-(isopentylamino)benzamide (0.154 g, 0.556 mmol) were combined. The crude product was purified by column chromatography (19:1 CH2Cl2:MeOH) to provide the title compound (0.211 g, 90%). 1H-NMR (CD3OD): δ 7.67 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.30 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.16 (d, J=9.2 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.28 (s, 2H), 4.12 (m, 2H), 3.98 (q, J=7.6 Hz, 2H), 3.57 (br s, 2H), 3.34 (br s, 2H), 1.62–1.48 (m, 1H), 1.34 (t, J=7.6 Hz, 3H), 1.36–1.07 (overlapping 2×br s and m, 8H), 0.88 (d, J=6.8 Hz, 6H). MS (ES) (M+H)+=422. Anal. Calcd for C26H35N3O2.1.7 TFA.0.2H2O: C, 57.05; H, 6.04; N, 6.79. Found: C, 57.11; H, 6.09; N, 6.69.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([CH3:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].[Cl:18][C:19]1[N:20]=[C:21](Cl)[C:22]2[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23]=2[N:24]=1>CN(C=O)C>[Cl:18][C:19]1[N:20]=[C:21]([O:1][CH2:2][C@H:3]2[C@H:7]([CH3:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4]2)[C:22]2[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23]=2[N:24]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1COc1nc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a stirred solution of tert-butyl trans-3-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (0.58 g, 2.7 mmol) in DMF (15 mL) was added NaH (60% in oil, 162 mg, 4.05 mmol) at 0° C. After stirring at rt for 30 min, 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.85 g, 2.7 mmol) was added to the mixture. The resulting mixture was stirred at rt for 1 hr. TLC (petroleum ether/EtOAc=5:1) showed the reaction was complete. The reaction mixture was quenched by water (10 mL) and extracted with EtOAc (two×20 mL). The combined organic layers were washed with brine (four×20 mL), dried over Na2SO4 and concentrated to yield the title compound (1.34 g, 100% yield) as a brown oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH:23]=[N:22][C:21]=2[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[N:16][C:17]2[CH:18]=[CH:19][C:20]3[O:24][CH:23]=[N:22][C:21]=3[CH:25]=2)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: Nc1ccc2ocnc2c1
Reactant: CC(=O)N1c2ccccc2C(=O)CC1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2C(=Nc2ccc3ocnc3c2)CC1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[Step 1] 177 mg of 1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline and 77 mg of 5-aminobenzoxazole were dissolved in 2 mL of methylene chloride, and 0.32 mL of triethylamine and 0.57 mL of titanium tetrachloride (1.0 M dichloromethane solution) were added to the solution under ice cooling. The mixture was stirred for 16 hours at room temperature. After completion of the reaction, the reaction liquid was filtered through Celite, and was concentrated under reduced pressure. Thus, a crude product of 1-acetyl-4-[(benzoxazol-5-yl)imino]-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a pale brown solid.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+]>CO>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:19])=[O:11])=[CH:5][CH:6]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(CCCC(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution of 4-(p-tolyl)-butyric acid (10.0 g, 56.11 mmol) in methanol (680 mL) was treated with concentrated sulfuric acid (5.4 mL). The reaction was stirred at room temperature for 18 hour. Sodium bicarbonate (˜15 g) was added and the mixture was stirred for 15 minutes, then concentrated. The residue was dissolved in ethyl acetate/water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (10.8 g, 100% crude) as an oil which was used for the next reaction.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:19]=[CH:20][CH:21]=1)C.[NH2:31][NH:32][C:33](=O)[CH2:34][N:35]([CH3:37])[CH3:36].C[O-].[Na+]>CO>[CH3:36][N:35]([CH2:34][C:33]1[NH:32][N:31]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:37]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)c4cccnc4)c3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)c5cccnc5)c4)c3c2)n[nH]1

Procedure:
The title compound was prepared according to example Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3-pyridylcarboxamide hydrochloride (0.400 g, 0.873 mmol), N-amino-2-(dimethylamino)acetamide (0.306 g, 2.62 mmol) and sodium methoxide in methanol (0.609 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.037 g, 10% yield): 1H NMR (CD3OD) δ 9.16 (dd, 1H), 8.79 (d, 1H), 8.75 (dd, 1H), 8.43 (dt, 1H), 8.39 (s, 1H), 8.09 (dd, 1H), 7.89–7.83 (m, 2H), 7.72 (d, 1H), 7.65–7.56 (m, 2H), 4.06 (br s, 2H), 2.61 (br s, 6H); ES-MS (m/z) 439 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1)=[O:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:10]([CH2:35][CH:34]=[CH2:33])[C:11]([O:13][CH3:14])=[O:12])[C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@H](C(=O)OC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product from Step A (4.51 g, 14.2 mmol) in THF (150 mL) was added potassium hexamethyldisilazide (65.0 mL, 0.5M in toluene, 32.5.0 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 min. Allyl bromide (6.2 mL, 71.7 mmol) was then added. After stirring at −78° C. for 2 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (30:70 hexanes/ethyl acetate) afforded the desired product (major diastereoisomer from the reaction).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]2([OH:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[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>>[CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]2([OH:16])[CH2:14][CH2:13][CH:12]([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)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(C2(O)CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CN(C)c1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(3-dimethylamino-phenyl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: CS(Cl)(=O)=O.C(OC(=O)[NH:12][C:13]([C:15]1[S:16][C:17]([S:38][CH3:39])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([C:29]3[C:34]([CH2:35]O)=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:37])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])(C)(C)C.C(N(C(C)C)CC)(C)C.C[N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C(Cl)Cl>[CH3:37][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[C:29]=1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20]([C:18]2[CH:19]=[C:15]([C:13]([NH2:12])=[NH:14])[S:16][C:17]=2[S:38][CH3:39])(=[O:21])=[O:22])[CH:24]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Reactant: CN1CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (100 μL) was added over 1 min to a 0° C. solution of {[4-(6′-hydroxymethyl-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 5: step c) (30 mg)) and diisopropylethylamine (0.25 mL) in DCM (10 mL). The solution was stirred for 1 h at 0° C. and warmed to rt. 4-Methylmorpholine (0.5 mL) was added and the solution was stirred for 3 h at rt. The volatile components were removed in vacuo and the residue was treated with 1:1 TFA/DCM (10 mL) for 2 h at rt. The solvent was removed in vacuo and the residue was purified by preparative HPLC (C18-column, 10–70% CH3CN over 30 min) which yielded the title compound as a opaque glass (6.8 mg). 1H-NMR (CD3OD): δ 8.40 (s, 1H), 8.13 (ddd, 1H, J=1.2, 1.9, 7.9 Hz), 7.97 (t, 1H, J=1.6 Hz), 7.82 (t, 1H, J=7.9 Hz), 7.61 (m, 2H), 7.49 (m, 2H), 4.15 (d, 1H, J=13.5 Hz), 4.07 (d, 1H, J=13.5 Hz), 3.82 (br s, 4H), 2.75 (s, 3H), 2.18 (s, 2H), 2.03 (s, 3H), 1.31 (s, 2H). ESI-MS (m/z): Calcd. for C24H27N3O3S3 (M+H): 502.1; found: 502.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[C-:13]#[N:14].[Na+].O>CN(C=O)C>[C:13]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])#[N:14]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-(bromomethyl)benzoic acid methyl ester (25 g, 109 mmol) in DMF (250 mL) was added NaCN (5.4 g, 109 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into water (1.5 L), followed by the extraction with TBME (2×500 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and evaporated under reduced pressure to yield methyl 3-(cyanomethyl)benzoate 1 (17 g, 89%). 1H-NMR (400 MHz, CDCl3) 3.82 (s, 2H), 3.94 (s, 3H), 7.48 (m, 1H), 7.57 (m, 1H), 8.03 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:14][C:15]1[C:20]([O:21][C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1ncccc1O
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1cc(C(F)(F)F)ccc1C#N
Temperature: 50 °C
Yield: 93.4 %

Procedure:
A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (0.19 g, 1.0 mmol), 2-methylpyridin-3-ol (0.11 g, 1.0 mmol), and cesium carbonate (0.33 g, 1.0 mmol) in anhydrous DMF (5 mL) was heated at 50° C. for 16 h. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (0%-30% EtOAc-hexanes) to obtain 2-(2-methylpyridin-3-yloxy)-4-(trifluoromethyl)benzonitrile (0.26 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.7, 1.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.1, 0.7 Hz, 1H), 7.35 (dd, J=8.1, 1.4 Hz, 1H), 7.28-7.25 (m, 1H), 6.87 (s, 1H), 2.50 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[F:30][C:31]1[C:37]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][C:39]([F:40])([F:41])[F:42])[C:31]=2[F:30])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: Nc1cccc(OC(F)(F)F)c1F
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.83 g, 8.07 mmol) in dry THF (45 mL) at −20° C. under nitrogen atmosphere was added triethylamine (3.32 mL, 23.8 mmol) followed by ethylchloroformate (0.775 mL, 8.07 mmol) dropwise. The reaction mixture was stirred at −20° C. for 90 min and a solution of 2-fluoro-3-(trifluoromethoxy)aniline (prepared as described in Part C, 1.5 g, 7.69 mmol) in dry THF (5 mL) was added. The reaction mixture was further stirred at −20° C. for 1 h, warmed up to RT and stirred at 65° C. for 16 h until completion of the reaction. The reaction mixture was diluted with EtOAC, washed with a saturated aqueous solution of NaHCO3 (×3) and brine, dried (phase separator) and concentrated under reduced pressure. The crude residue was purified via flash column chromatography on silica gel (EtOAc/c-hexane 1:1) to give the desired material as a colorless oil. MS: 427 [M+Na]+, 304.9 [MH−Boc]+; tR (HPLC conditions c): 5.23 min.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:11][C@H:9]([CH3:10])[CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: C[C@@H](N)CSc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](CSc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.7 %

Procedure:
(R)-1-Phenylthio-2-propylamine (0.4 g, 1.96 mmol) was reacted with 9-(2,3.5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.2 g, 1.9 mmol) in dioxan (15 ml) in the presence of triethylamine (0.4 g, 4 mmol). The reaction mixture was stirred at room temperature for 72 h, heated at 50° C. for 24 h, cooled, filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro- N-[(R)-1-phenylthio-2-propyl]adenosine (after column chromatography) as a foam (0.47 g, 52%), 1H NMR (DMSO-d6)δ 1.34 (3H, d, --CH3), 3.01 (1H, dd, --C--H), 3.52-3.60 (1H, m, H-5'a), 3.62-3.72 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, m, H-3'), 4.30-4.45 (1H, m, --C--H), 4.53 (1H, m, H-2'), 5.09, 5.22, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.84 (1H, d, H-1'), 7.19 (1H, t, Ar--H), 7.30 (2H, t, Ar--H), 7.45 (2H, d, Ar--H), 8.29-8.45 (2H, s & m, H-8 and N--H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:37](=[O:38])[CH2:36][C:31]2[NH:30][C:29]3[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=3[S:33](=[O:34])(=[O:35])[N:32]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC=CCC1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CC=CCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.6 %

Procedure:
The crude 6-(4-fluoro-benzylamino)-cyclohex-3-enecarboxylic acid ethyl ester (113.7 mg, 0.41 mmol) was mixed with (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 150 mg, 0.45 mmol) and dissolved in N,N-dimethylformamide (3.4 mL). N-methylmorpholine (100 μL, 0.9 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for 16 h. LC-MS analysis indicated that the reaction was incomplete and thus additional (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (30 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17 mg) were added and the resulted mixture was stirred at 25° C. for 1.5 h. A 1.0 M aqueous hydrochloric acid solution (6.7 mL) was added. The product was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with water (10 mL) and saturated aqueous brine solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and further dried under high vacuum for 16 h to afford the crude product, 6-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohex-3-enecarboxylic acid ethyl ester (295.4 mg). LC-MS (ESI) calcd for C26H29FN4O7S2 592.15, found 593.4 [M+H+]. This crude product was directly used in next step without further purification.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[O:27]1[CH2:28][CH2:29][N:24]([C:21]([C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[O:23])[CH2:25][CH2:26]1
Reactant: O=C(O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylic acid, the product of Example 54 (40 mg, 0.121 mmol), morpholine (12 μL, 0.133 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (51 mg, 0.133 mmol) were combined in dichloromethane (2 mL). Triethyl amine (52 μL, 0.374 mmol) was added and mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane and washed with a 1 N aqueous sodium hydroxide solution. The organic layer was absorbed on silica gel and the mixture was purified by column chromatography eluting with a gradient of methanol and dichloromethane (2-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.41-1.54 (m, 2 H) 1.59-1.70 (m, 4 H) 1.94-2.12 (m, 1 H) 2.24-2.38 (m, 1 H) 2.39-2.60 (m, 4 H) 2.95-3.11 (m, 1 H) 3.37-3.48 (m, 1 H) 3.49-3.61 (m, 1 H) 3.61-3.80 (m, 9 H) 3.81-3.93 (m, 1 H) 7.33 (dd, J=8.31, 1.87 Hz, 1 H) 7.55 (d, J=8.14 Hz, 1 H) 7.73 (d, J=1.70 Hz, 1 H); MS (ESI+) m/z 401.1 (M+H)+.