Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1.CN(C(O[N:33]1N=N[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=CC=CN=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.O>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([NH:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:39]=3)=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[CH:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccccn1)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)[nH]c12
Temperature: 75 °C
Yield: 33.2 %

Procedure:
A mixture of 4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-8-carboxylic acid 44 (250 mg, 0.750 mmol), HATU (570 mg, 1.5 mmol), 2-aminopyridine 21 (141 mg, 1.5 mmol) and diisopropylethylamine (392 μl, 2.25 mmol) in DMAC (5 mL) was heated at 75° C. for 16 h. The reaction mixture was poured in H2O (25 mL) and the resulting precipitate was collected by filtration. The crude residue was purified by MPLC Compound 401 (102 mg, 33% yield). MS (ESI) calc. for C22H14F3N3O2: 409.10. found: 410 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH3:27].C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH3:27])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Cl)ccc2F)nc2nccnc12
Reactant: Cc1cnccc1N
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Cc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-amino-3-methylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[Br:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cccc(Br)c2)c(-c2ccccc2)n1
Yield: 41.9 %

Procedure:
6-(3-Bromophenyl)-5-phenyl-1,2,4-triazin-3-amine (218 mg, 52%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.4 g, 1.59 mmol) and 3-bromophenylboronic acid (0.32 g, 1.59 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:15][C:16]([OH:18])=[O:17])[O:3]1.[C:19](OC(=N)N(C(C)C)C(C)C)([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.Cl[Cu]>[CH3:1][N:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[O:3]1
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: CN1O[C@@H](CC(=O)O)C[C@H]1c1ccc(C#N)cc1
Agent: Cl[Cu]
Solvent: ClCCl
Product: CN1O[C@@H](CC(=O)OC(C)(C)C)C[C@H]1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a solution of [2-methyl-3(S)-(4-cyanophenyl)-isoxazolidin-5(R)-yl]acetic acid (480 mg, 1.95 mmol) in CH2Cl2 (30 ml) cooled in an ice-water bath was added a 1.6M solution of O-tert-butyl-N, N-diisopropylisourea, cat. CuCl (3.7 ml). The resulting mixture was stirred at rt for 48 hrs. After filtration, the fitrate was concentrated in EtOAc and the residue dissolved in EtOAc. The EtOAc solution was washed with brine and then dried over Na2SO4. After contration, the residue was chromatographed with a mixture of EtOAc and hexane to afford 550 mg of the product as a white solid (93%). 1H NMR (300 MHz, CDCl3) δ1.44(s, 9H), 1.98(m, 1H), 2.50(dd, 1H), 2.60(s, 3H), 2.80(dd, 1H), 2.98(dt, 1H), 3.70(t, 1H), 4.64(m, 1H), 7.50(d, 2H0, 7.66(d, 2H); MS(ESI) Calc. for (M+1)+: 303. Found: 303.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[CH2:50]([O:52][P:53]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([NH:65][C:66]2[N:71]=[C:70]([NH:72][C:73]3[CH:81]=[CH:80][C:79]([C:82]4[CH:83]=[N:84][N:85]([CH2:87][C@H:88]([OH:91])[CH2:89][OH:90])[CH:86]=4)=[C:78]4[C:74]=3[C:75](=[O:93])[N:76]([CH3:92])[CH2:77]4)[C:69]([C:94]([F:97])([F:96])[F:95])=[CH:68][N:67]=2)=[C:61]([O:98][CH3:99])[CH:60]=1)(=[O:57])[O:54]CC)[CH3:51]>>[OH:91][C@H:88]([CH2:89][OH:90])[CH2:87][N:85]1[CH:86]=[C:82]([C:79]2[CH:80]=[CH:81][C:73]([NH:72][C:70]3[C:69]([C:94]([F:97])([F:96])[F:95])=[CH:68][N:67]=[C:66]([NH:65][C:62]4[CH:63]=[CH:64][C:59]([CH2:58][P:53](=[O:54])([OH:57])[O:52][CH2:50][CH3:51])=[CH:60][C:61]=4[O:98][CH3:99])[N:71]=3)=[C:74]3[C:78]=2[CH2:77][N:76]([CH3:92])[C:75]3=[O:93])[CH:83]=[N:84]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C[C@H](O)CO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C[C@H](O)CO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1
Yield: 75.4 %

Procedure:
This material was prepared analogously to Compound 3A using diethyl[4-({4-[(7-{1-[(2S)-2,3-dihydroxypropyl]-1H-pyrazol-4-yl}-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate (Compound 5B, 254 mg, 353 μmol) to yield 184 mg of the desired product (75%). 1H NMR (400 MHz, CD3OD) δ 8.42 (br. s., 1H), 8.20 (br. s., 1H), 8.08-8.16 (m, 1H), 8.06 (br. s., 1H), 7.80 (s, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.09 (br. s., 1H), 6.95 (d, J=7.8 Hz, 1H), 4.37 (dd, J=4.17, 14 Hz, 3H), 4.16-4.26 (m, 1H), 4.07 (dd, J=4.6, 7.3 Hz, 1H), 3.88-3.97 (m, 2H), 3.87 (s, 3H), 3.58 (d, J=5.3 Hz, 2H), 3.10 (br. s., 3H), 3.01-3.08 (m, 2H), 1.21 (t, J=7 Hz, 3H). MS (ESI): m/z 692.21 [M+H]+. UPLC: tR=1.10 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37](Br)=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:74])(=O)=O)=CC=1>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([F:74])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2F)CCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the intermediate 17 (1.01 g, 1.2 mmol) in anhydrous THF (12.0 mL) were added dropwise n-BuLi (2.5 M in hexane, 0.77 mL, 1.92 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 20 min at the same temperature. Then a solution of N-fluorobenzenesulfonimide (0.68 g, 2.16 mmol) in THF (3.0 mL) was added dropwise, and the mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated NaCl solution (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 19, which was used without further purification (0.95 g, 1.21 mmol, 101%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])[CH3:2].[Br:18]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:16])[CH2:15][Br:18])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a cooled (0° C.) solution of (2-acetyl-4-bromophenoxy)acetic acid ethyl ester (2.5 g, 8.3 mmol) in CHCl3 (25 mL) was slowly added bromine (425 uL, 8.3 mmol). After completion the reaction mixture was allowed to stir at room temperature for 1 hour. The mixture was partitioned between CH2Cl2 and brine. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (2.97 g, 7.8 mmol, 94%): 1H NMR (CDCl3): δ 1.35 (t, 3H), 4.32 (q, 2H), 4.75 (s, 2H), 4.76 (s, 2H), 6.77 (d, 1H), 7.60 (dd, 1H), 7.97 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[N:17]1[O:18][N:19]=[C:20]2[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][C:21]=12>>[N:17]1[O:18][N:19]=[C:20]2[CH:25]=[C:24]([C:2]3[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=3)[C:14]([OH:16])=[O:15])[CH:23]=[CH:22][C:21]=12
Reactant: OB(O)c1ccc2nonc2c1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc3nonc3c2)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-2,1,3-benzoxadiazol-5-yl-boronic acid, (CAN 426268-09-9) as starting materials; LC-MS (UV peak area/ESI) 48%, 338.0 (M−H)−.
Reaction SMILES: CO[C:3]([CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]([OH:17])=O)=[O:7])=O.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>>[NH:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:25]=[C:3]1[C:5]1[C:6](=[O:7])[NH:8][C:9]2[C:14]([C:15]=1[OH:17])=[CH:13][CH:12]=[N:11][CH:10]=2
Reactant: COC(=O)CC(=O)Nc1cnccc1C(=O)O
Reactant: Nc1ccccc1N
Product: O=c1[nH]c2cnccc2c(O)c1-c1nc2ccccc2[nH]1
Temperature: 150 °C

Procedure:
3-[2-(Methoxycarbonyl)acetylamino]pyridine-4-carboxylic Acid (1.1 equivalents) was combined with 1,2-phenylenediamine (1.0 equivalent) and heated at 150° C. for 3 hours. The crude product was purified by reversed-phase HPLC (DMSO/5% TFA). LC/MS m/z 279.3 (MH+), Rt 1.73 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1SC=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23]1C=CC(C=O)=[CH:24]1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:22]=[CH:21][S:23][CH:24]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccsc1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Product: COC(=O)/C(=C/c1ccsc1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that 3-thiophenecarboxaldehyde (762 mg) was used as the aldehyde component to afforded the desired product (549 mg). 1H NMR (300 MHz, CDCl3) δ 3.795 (s, 3H), 5.19 (s, 2H), 5.99 (br., 1H), 7.07 (m, 1H), 7.34(m, 7H), 7.49(d, 1H, J=5 Hz), 7.77(s, 1H). LC/MS: 2.32 min.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (1.21 g, 4.95 mmol) was added thionyl chloride (5.5 mL, 74.2 mmol). The mixture was heated at 50° C. for 2 h before it was allowed to cool to room temperature and stirred at room temperature overnight. The mixture was poured into ice and stirred for 5 min before it was extracted with dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as an oil (1.16 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.55-1.63 (m, 2H), 1.69-1.77 (m, 2H), 1.82-1.90 (m, 2H), 2.05-2.13 (m, 2H), 3.37 (quintet, J=8.59 Hz, 1H), 4.58 (s, 2H), 7.46 (d, J=8.00 Hz, 1H), 7.52 (d, J=8.00 Hz, 1H), 7.61 (d, J=1.52 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:35]([OH:38])[C:36]#[CH:37].[NH4+].[Cl-]>CN(C=O)C.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.[Cu]I.O>[OH:38][CH2:35][C:36]#[C:37][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:17][C:18]([CH3:24])([CH3:25])[CH2:19][C:20]([CH3:22])([CH3:23])[CH2:21]2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(I)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#CCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a degassed solution of 4-[(4-iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144) (0.17 g, 0.38 mmol) in DMF (3 mL) were added Pd(PPh3)2Cl2 (27 mg, 0.04 mmol), CuI (8 mg, 0.04 mmol), N,N-diisopropylethylamine (0.30 mL, 1.71 mmol) and propargyl alcohol (45 μL, 0.76 mmol). The reaction mixture was stirred at room temperature overnight, poured into saturated aqueous NH4Cl (15 mL) and water (5 mL), extracted with EtOAc (3×50 mL). The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 30% EtOAc:hexanes to give 0.106 g (74%) of compound 145 as pale yellow solid. mp 141-142° C. 1H NMR (400 MHz, DMSO-d6): δ 0.85 (s, 6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.85 (s, 2H), 1.89 (s, 2H), 4.25 (d, J=5.9 Hz, 2H), 5.28 (t, J=5.9 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 9.29 (s, 1H). LCMS (ESI): m/z 375 (M+H)+, 373 (M−H)−. Anal. Calcd for C26H30O2.0.1H2O: C, 82.98; H, 8.09; Found: C, 82.88; H, 8.19.
Reaction SMILES: CN1CCOCC1.C1(C2C=CC=CC=2)C=CC(S([N:17]2[CH2:21][CH2:20][S:19][CH:18]2[C:22](O)=[O:23])(=O)=O)=CC=1.ClC(OCC(C)C)=O.[NH2:39][C@H:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:41][CH2:42][OH:43]>C1COCC1>[OH:43][CH2:42][CH2:41][C@H:40]([NH:39][C:22]([CH:18]1[NH:17][CH2:21][CH2:20][S:19]1)=[O:23])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H](CCO)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(N[C@@H](CCO)c1ccccc1)C1NCCS1
Temperature: -25 °C
Reaction time: 0.08 h

Procedure:
N-methyl morpholine (NMM) (3.24 g, 2.5 eq, 32.15 mmol) was added to a solution of a compound of general formula (VIII) (Intermediate 8, 4.50 g, 1 eq, 12.86 mmol), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid, in dry THF (100 ml) and the reaction mixture was cooled down to −25° C. To the reaction mixture was then added drop wise, over a period of 5 minutes, isobutyl chloroformate (1.84 g, 1.05 eq, 13.50 mmol) in solution in dry THF (20 ml). The resulting mixture was stirred at −25° C. for 30 minutes, after which time an amine of general formula (IV) or (IV*) (commercial or Intermediate 2, 2.14 g, 1.1 eq, 14.15 mmol), e.g., (3S)-3-amino-3-phenyl-1-propanol, was added in dry THF (20 ml) over a period of 5 minutes. The mixture was allowed to gradually warm to room temperature and stirred overnight at room temperature. The solvent was removed and the residue re-dissolved in ethyl acetate (200 ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml). The combined organic phases were dried with magnesium sulfate and concentrated in vacuo, yielding the crude product of general formula ([), e.g., 3-(1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide, as a white solid (6.21 g, 96%). Silica gel chromatography, eluting in isocratic conditions (50% ethyl acetate in hexanes), which gave the separation of the desired two pure diastereoisomers of general formula (I), e.g., (2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (more polar compound, 3.1 g), and (2R)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (less polar compound, 3.0 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC(C)([O-])C.[Na+].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1>COCCOC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 110 °C

Procedure:
2-Methoxyethanol (3.2 mL) was diluted with 1,2-dimethoxyethane (20 mL). To this was added sodium tert-butoxide (3.9 g) gradually and the reaction mixture was stirred under nitrogen until it was homogenous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.5376 g) was then added to the reaction mixture, followed by 1,2-dimethoxyethane (20 mL). The reaction mixture was then heated to reflux (110° C., external) overnight. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL, twice). The combined organic layers were then washed with brine (100 mL). The organic layer was then dried by passing through a hydrophobic frit and then evaporated under reduced pressure (followed by azeotroping with toluene (100 mL, twice)). This gave an amber oil that under high vacuo gave gummy foam. This material was triturated with diethyl ether (with cooling) until this gave the title compound, a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([NH2:27])([C:25]#[N:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])(O)=O.[Na+]>CCO>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]([C:25]#[N:26])([NH:27][C:6]([C:5]2[CH:9]=[CH:10][N:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:8])[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1cc(C(=O)O)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)ccn1
Reaction time: 46.5 h

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 2,7-hydrate (1.06 g, 3.26 mmol) was added to a solution of 2-methoxy-isonicotinic acid (500 mg, 3.26 mmol) and 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (669 mg, 2.97 mmol) in EtOH (8.0 ml) at room temperature, and the mixture was stirred for 46.5 hours. An aqueous NaHCO3 solution was added to the reaction mixture, followed by extraction with AcOEt three times. The organic layers were washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (CH2Cl2/MeOH=99:1 to 95:5) to give 4-cyano-4-[(2-methoxy-pyridine-4-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless form (901 mg, 84%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH2:8])=[N:3][CH:2]=1.N1C=CC=CC=1.CN(C)C=O.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>O>[NH2:8][C:4]1[C:5]([NH:7][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cncnc1N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: Nc1ncncc1NC(=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a stirred mixture of 20.2 parts of 4,5-pyrimidinediamine, 40 parts of pyridine and 144 parts of N,N-dimethylformamide was added dropwise a solution of 24.2 parts of 4-fluorobenzoyl chloride in 36 parts of N,N-dimethylformamide at 10° C. Upon completion, stirring was continued for 30 minutes at room temperature. 600 Parts of water were added. The product was filtered off and dried, yielding 30 parts (70%) of N-(4-amino-5-pyrimidinyl)-4-fluorobenzamide (interm. 11).
Reaction SMILES: [H-].[Li+].N[C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1.C(OC[C@@H]1[C@@H](COC(=O)C2C=CC=CC=2)CC2C(O2)C1)(=O)C1C=CC=CC=1.P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:6]1[N:5]=[CH:4][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2
Reactant: COCCOc1nc(N)nc2nc[nH]c12
Agent: O=C(OC[C@H]1CC2OC2C[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COCCOc1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
In an atmosphere of argon gas, lithium hydride (4.8 mg, 0.6 mmole) was added to a suspension of 2-amino-6-(2-methoxyethoxy)-purine (354.4 mg, 1.69 mmoles) in anhydrous DMF (15 ml). After stirring the mixture at room temperature for one hour, (3S,4S)-3,4-bis(benzoyloxymethyl)-7-oxabicyclo[4.1.0]-heptane (310.4 mg, 0.85 mmole) was added, and the reaction was further continued at 140° C. for 1.5 hours. Then, while cooling the reaction mixture, 0.2M phosphate buffer solution (pH 7.0) was added thereto and the mixture was stirred for a while, and then the mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water, washed with saturated aqueous solution of sodium chloride and dried on anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-amino-9-[1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-6-(2-methoxyethoxy)-purine (320 mg, Yield 65.6%).