Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:27][CH:28]=2)[N:3]=1.Cl.[NH:37]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH3:38].C(N(CC)CC)C>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:22][C:4]3[N:3]=[C:2]([N:37]([CH3:38])[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:7]([C:8]#[N:9])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:5]=3[C:20]#[N:21])[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CN(C)c1nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
230 mg (about 0.45 mmol) of the crude product from Example 50A were dissolved in 3 ml of absolute THF, and 127 mg (0.91 mmol) of methyl sarcosinate hydrochloride and 138 mg (1.36 mmol) of triethylamine were added. The reaction mixture was stirred at RT for 10 h. After removal of the solvent on a rotary evaporator, the residue was purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Removal of the solvent on a rotary evaporator gave the product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([NH:22][C:23](OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:38]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:43]=[CH:42][C:41]([CH:44]2[CH2:48]C(OC)O[CH:45]2OC)=[CH:40][CH:39]=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([N:22]1[CH:23]=[CH:45][C:44]([C:41]2[CH:42]=[CH:43][C:38]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:39][CH:40]=2)=[CH:48]1)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(C)(C)O
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 11 %

Procedure:
According to the procedure described in Example 1(c) for N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octa-deca-11(18), 12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2hydroxy-1-(S)-hydroxymethyl-2-methylpropyl)succinamic acid benzyl ester was deprotected with trifluoroacetic acid. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to give in 11% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (acetone-d6): δ 7.67-7.61 (m, 6H), 7.48 (t, 2H, J=7.7 Hz), 7.39 (t, 1H, J=1.8 Hz), 7.37-7.27 (m, 6H), 7.09 (bd, 1H, J=9.2 Hz), 6.96 (t, 1H, J=2.6 Hz), 6.53 (dd, 1H, J=1.7, 2.8 Hz), 5.35 (t, 1H, J=7.4 Hz), 5.11 (s, 2H), 3.81-3.62 (m, 3H), 3.39 (dd, 1H, J=6.8, 16.4 Hz), 3.12 (dd, 1H, J=7.7, 16.6 Hz), 1.24 (s, 3H), 1.21 (s, 3H). Anal. Calculated for C32H34N2O5: C, 72.98; H, 6.51; N, 5.32. Found: C, 72.83; H, 6.60; N, 5.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]2[CH2:18][CH:17]([OH:19])[CH:16]([OH:20])[CH2:15]2)=O)[CH2:8][CH2:7]1.CO>B.O1CCCC1>[NH3:9].[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:14]2[CH2:18][CH:17]([OH:19])[CH:16]([OH:20])[CH2:15]2)[CH2:8][CH2:7]1
Reactant: O=C(C1CC(O)C(O)C1)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: N
Product: OC1CC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1O
Yield: 213.6 %

Procedure:
The more polar isomer of 4-[[4-(3,4dichlorophenoxy)-1-piperidinyl]carbonyl]-1,2-cyclopentanediol (0.71 g) was dissolved in a solution of borane in tetrahydrofuran (16 mL of 1M solution) and the mixture was heated to reflux for 1.5 h. Methanol (10 mL) was added and the solution was heated under reflux for 1 h. The volatile components were evaporated and the residue was loaded onto an HPLC SCX cartridge in methanol and eluted with methanol, then with 0.7M ammonia in methanol to give the title compound (0.73 g) as an oil.
Reaction SMILES: [F:1][C:2]1[C:25]([F:26])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[N:22]O)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[C:27]([OH:30])(=O)[CH3:28].[CH2:31](O)C>O.[Zn]>[CH:27]([O:30][CH:25]([CH3:24])[CH3:2])([CH3:28])[CH3:31].[F:26][C:25]1[C:2]([F:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]([NH2:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]=2[CH:24]=1
Reactant: CCO
Reactant: CC(=O)O
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(F)c(F)cc2[nH]1
Agent: [Zn]
Solvent: O
Product: CC(C)OC(C)C
Product: NC1c2ccccc2-c2c(-c3nc4cc(F)c(F)cc4[nH]3)cccc21

Procedure:
The procedure used in Example 216 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, dissolve 830 mg of 4-(5,6-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 5.5 ml of ethanol and 5.5 ml of water and 5.5 ml of acetic acid, at room temperature, add 624 mg of zinc in three stages, and, between each addition, stir for approximately one hour to two hours. Add Celite and filter. The filtrate is concentrated under pressure. The crude product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (98/2 by volume). After formation of a paste with diisopropyl ether, in this way we obtain 653 mg of 4-(5,6-difluoro-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a white powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:13][C:14]1[CH:15]=[C:16]([N:31]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:32]([C:34]2([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]2)=[O:33])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>O.CCO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:28]2[S:29][C:22]3[C:23](=[N:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]3[CH:18]=[CH:17][C:16]([N:31]([C:40]4[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:15][C:14]=3[F:13])[CH:27]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)cc1
Temperature: 80 °C
Yield: 12.5 %

Procedure:
A sealable vial, was charged with 4-carbamoylphenylboronic acid (0.0312 g, 0.189 mmol), N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 0.100 g, 0.0947 mmol), Cs2CO3 (0.0309 g, 0.0947 mmol), toluene (2 mL) and EtOH (1 mL). Under nitrogen Pd(PPh3)4 (0.00547 g, 0.00473 mmol) was added and the reaction heated to 80° C. for 18 hours. The mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL) and MeOH (2 mL). The organics were dried over sodium sulfate, filtered and concentrated to get crude product. The crude product was purified by reverse phase C-18 column chromatography to get product (6.9 mg, 13%) as a white solid. LRMS (esi+) 585 m/z (M+1) detected. 1H NMR (d6-DMSO, 400 MHz) δ 8.48 (d, J=6 Hz, 1H), 7.96 (m, 5H), 7.87 (m, 1H), 7.57 (m, 2H), 7.37 (m, 2H), 7.07 (t, J=9.0 Hz, 2H), 6.65 (d, J=6 Hz, 1H), 1.64 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH2:5]2.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH:5]2[C:19](=[O:20])[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CCN1C(=O)Cc2cc(Cl)cnc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C(=O)c2cccs2)c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1-ethyl-7-azaoxindole (400 mg, 2.03 mmol) and 4-dimethylaminopyridine (537 mg, 4.4 mmol) in DMF (10 mL) at 0° C. was added thiophene-2-carbonyl chloride (0.24 mL, 2.24 mmol). The reaction mixture was stirred at room temperature for 2 hours and then poured into ice/water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried (magnesium sulfate) and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with chloroform. Fractions containing only the desired product were combined and concentrated to afford the title compound as a solid which was recrystallized from hexanes. The yield of recrystallized material was 29 mg (50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)Oc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
In a dry flask 5-amino-indazole-1-carboxylic acid t-butyl ester (1.4 g, 6.0 mmol) was dissolved in tetrahydrofuran (20 mL) and triethylamine (1.0 g, 9.9 mmol) were added and the reaction mixture cooled to 0° C. Phenyl chloroformate (1.0 g, 6.4 mmol) was added dropwise and the mixture was stirred an additional 15 minutes after the addition was complete. The reaction mixture was diluted with ethyl acetate, washed with water, and concentrated in vacuo. The crude material was purified by flash chromatography with 35% ethyl acetate in hexanes to give a white solid (1.9 g, 90%). 1H NMR (300 MHz, CDCl3), δ: 8.14 (d, J=10, 1H), 8.12 (s, 1H), 8.02 (bs, 1H), 7.40 (m, 3H), 7.24 (m, 4H), 1.73 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:34]5[C:29]([O:28][CH3:27])=[N:30][CH:31]=[CH:32][CH:33]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncccc1B(O)O
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc(C)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
A solution of N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (38 mg, 0.1 mmol) in DME (1 mL) was added to a reaction tube containing 2-methoxypyridin-3-ylboronic acid (46 mg, 0.15 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol). Saturated Na2CO3 solution was added (100 μL) and the reaction was stirred at 80° C. overnight. The reaction was filtered, concentrated and purified by column chromatography (0-50% ethyl acetate in hexanes) to obtain 50 mg (55%) of a clear oil. ESI-MS m/z calc. 453.4. found 454.5 (M+1)+. Retention times: 1.9 minutes. H NMR (400 MHz, DMSO) 8.81 (s, 1H), 8.22 (dd, J=1.9, 5.0 Hz, 1H), 7.84 (s, 1H), 7.57-7.53 (m, 2H), 7.38-7.31 (m, 2H), 7.05 (dd, J=5.0, 7.2 Hz, 1H), 3.78 (s, 3H), 2.29 (s, 3H), 1.89 (s, 3H), 1.50-1.47 (m, 2H), 1.16-1.13 (m, 2H)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14](O)=[O:15])([CH3:10])[CH3:9].[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14]([NH:25][NH:26][C:27](=[S:28])[NH2:29])=[O:15])([CH3:10])[CH3:9]
Reactant: NNC(N)=S
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NNC(N)=S)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Oxalyl chloride (11.5 g, 0.091 mole) is added dropwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid (15.0 g, 0.059 mole) in methylene chloride (120 ml) and N,N-dimethylformamide (0.5 ml). After one hour, the solvent is removed in vacuo. The residue is dissolved in tetrahydrofuran (70 ml) and added dropwise to a stirred 0° C. suspension of thiosemicarbazide (10.9 g, 0.120 mole) in tetrahydrofuran (300 ml). After the addition is complete the mixture is allowed to warm to room temperature and stir 18 hours. The mixture is concentrated in vacuo and the residue filtered through a plug of flash silica gel using a 1:1 ethyl acetate/heptane mixture as eluent. Concentration and trituration with 1:1 isopropyl ether/hexane yielded 17.6 g (19.4 g theor., 91%) of 2-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazinecarbothioamide, mp 210°-211° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.O[N:19]1C2C=CC=CC=2N=N1.C(Cl)CCl>ClCCl>[C:1]([NH:8][C@H:9]([C:14]([NH2:19])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred mixture of 3.47 g (15 mmol) of BOC-norleucine (Bachem), 3.44 g (22.5 mmol) of 1-hydroxybenzotriazole monohydrate and 50 mL of dichloromethane at 0° C. was added 3.45 g (1.2 mmol) of EDC. The resulting mixture was stirred at 0° C. for 1 hour and then ammonia gas was bubbled through the mixture for 10 min. The cooling bath was allowed to warm to room temperature and the mixture stirred for 18 hours. The mixture was evaporated to dryness, triturated with 20% Na2CO3. The resulting solid was collected by filtration and washed wiith water to yield 2.69 g (11.7 mmol, 78%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)C(C)C)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 7.5 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added isopropylsulfonyl chloride (22 μl, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was chromatographed on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (2 mg, 7%). 1H NMR (300 MHz, DMSO-d6): δ 0.98 (d, J=6.62 Hz, 6 H) 1.28 (d, J=6.99 Hz, 6 H) 1.57 (m, 2 H) 1.71 (m, 1 H) 3.29 (m, 1 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.59 (dd, J=8.82, 2.57 Hz, 1 H) 7.67 (d, J=2.57 Hz, 1 H) 7.74 (d, J=9.18 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.60, 1.65 Hz, 1 H) 10.33 (s, 1 H) 14.11 (s, 1 H). MS (ESI−) m/z 532 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18]C)[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C2C=CC=CC=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](N[C:54](=[O:57])CC)[C@@H](O)[C@H]2O)=C(Cl)N=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(COC(=O)C)=[O:78])[C@@H](O)[C@H]2O)=C(Cl)N=1.C1(C(C2C=CC=CC=2)CN)C=CC=CC=1>>[CH2:25]([C@H:24]([NH:23][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][OH:78])[C@@H:13]([OH:21])[C@H:12]1[OH:22])[CH2:54][OH:57])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: NCC(c1ccccc1)c1ccccc1
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
N-{(1S,2R,3S,4R)-4-[6-((S)-1-Benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide by replacing N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide, with acetic acid [(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentylcarbamoyl]-methyl ester (Intermediate FA) and replacing 2,2-diphenylethylamine with (4Z,6Z)-(S)-phenylalinol.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([OH:21])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][C:6]=1[Cl:22])[CH2:2][CH2:3][CH3:4].C1([C@H](N)C)C2C(=CC=CC=2)C=CC=1>>[CH2:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([OH:21])=[O:20])[C@H:11]([C:15]([F:16])([F:17])[F:18])[O:12]2)=[CH:7][C:6]=1[Cl:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: C[C@@H](N)c1cccc2ccccc12
Product: CCCCc1cc2c(cc1Cl)C=C(C(=O)O)[C@H](C(F)(F)F)O2

Procedure:
A racemic mixture of the compound prepared in Example 9a, Step 5 was chirally resolved using the same protocol as for Example 609e, Step 1, R-enantiomer was identified as peak 1 with retention time 5.38 min: ESHRMS m/z 333.0489 (M−H, C15H13ClF3O3 Calc'd 333.0500). 1HNMR (DMSO-d6/400 MHz), 13.13 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.00 (s, 1H), 5.89 (q, 1H, J=7.1 Hz), 2.62 (t, 2H, J=7.5 Hz), 1.50 (m, 2H), 1.30 (m, 2H), 0.860 (t, 3H, J=7.3 Hz). 19FNMR (d6-benzene; 6 eq of (R)-(+)-1-(1-naphthyl)ethylamine) d −77.82 (d, 3F, J=6.8 Hz, R-enantiomer), −77.78 (d, 3F, J=6.8 Hz, S-enantiomer).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:25])=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:10]3[CH2:9][C:8](=O)[NH:7][C:6]=2[CH:24]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[C:3]([Cl:25])=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH:10]3[CH2:9][CH2:8][NH:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)c(Cl)cc3NC(=O)CC2C1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)c(Cl)cc3NCCC2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 15B (168 mg, 0.435 mmol) in tetrahydrofuran (1.5 mL) was added borane in tetrahydrofuran (1.74 mL, 1M solution). The resulting mixture was heated to 80° C. overnight. Methanol was then added, and the mixture was heated at 80° C. for 1 hour to destroy excess borane. The reaction was then cooled to room temperature and 1M HCl was added. The mixture was allowed to stir for another 30 minutes. Aqueous sodium bicarbonate was slowly added to the mixture until the solution was basic (pH=8). Ethyl acetate was then added, and the water layer was separated and washed two times with additional ethyl acetate. The organic layers thus obtained were combined and concentrated.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH2:21][CH2:22][CH2:23][N:24]1[C:28]([CH3:30])([CH3:29])[C:27](=[O:31])[NH:26][C:25]1=[O:32].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)=[N:4][C:5]([NH:21][CH2:22][CH2:23][N:24]2[C:28]([CH3:29])([CH3:30])[C:27](=[O:31])[NH:26][C:25]2=[O:32])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: CS(=O)(=O)c1ncc(Br)c(-c2nc3ccncc3s2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2nc3ccncc3s2)n1
Temperature: 160 °C
Yield: 4.5 %

Procedure:
A microwave tube was charged with 2-(5-bromo-2-(methylsulfonyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridine (300 mg, 0.81 mmol), 1-(2-Aminoethyl)-5,5-dimethyl-imidazolidine-2,4-dione (138 mg, 0.81 mmol), isopropanol (3 mL) and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol). The vessel was sealed and heated in a microwave reactor at 160° C. for 1000 seconds. The resulting solid was filtered off and washed with methanol (4×10 mL). The solid was then dissolved in dimethylsulfoxide (4 mL) and purified by reverse phase HPLC. Product fractions were combined and loaded onto an SCX cartridge, washed with methanol (4 mL), then free based and eluted with 2 M ammonia in methanol (4 mL). The solvent was evaporated in vacuo to yield 1-(2-(5-bromo-4-(thiazolo[5,4-c]pyridin-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (17 mg, 5%) as a yellow amorphous solid. 1H NMR 6 (d6-DMSO, 400 MHz) 1.50 (s, 6 H), 3.67 (br. s., 2 H), 3.75 (br. s., 2 H), 4.32 (br. s., 1 H), 6.89 (s, 1 H), 7.49 (s, 1 H), 8.33 (d, J=5.5 Hz, 1 H), 8.91 (d, J=5.1 Hz, 1 H), 9.71 (s, 1 H): HRMS (M+H)+ Calcd. C17H16BrN7O2S 462.0348, found 462.0339.