Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.Br[CH2:14][CH2:15][CH2:16][Cl:17].O>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2
Reactant: Oc1cccc2cc[nH]c12
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (0.8 g, 17 mmol of a 50% oil dispersion) in dimethylformamide (20 ml), under nitrogen, was added dropwise 7-hydroxyindole (2.1 g, 15.7 mmol) in dimethylformamide (20 ml). After complete addition, the reaction was stirred at ambient temperature for 0.5 hour and then cooled to 15° C. To this cooled solution was added, dropwise, 1-bromo-3-chloropropane (2.5 g, 15.7 mmol) in dimethylformamide (5 ml). The reaction was then stirred at ambient temperature for 16 hours. The reaction was poured into water, and the aqueous suspension extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the solvent was concentrated to afford a dark brown oil. Following flash chromatography on silica gel, 7-(3-chloropropoxy)indole was obtained as a colorless oil, 1.0 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (1.0 g, 5.4 mmol) and 2-amino-N-methylbenzamide (0.98 g, 6.5 mmol) in THF (5.0 mL) was charged with DIPEA (1.42 mL, 8.18 mmol) and the mixture allowed to stir at rt for 16 h. The reaction was quenched with NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL), dried over NaSO4, filtered, and concentrated in vacuo to yield a yellow solid which was recrystallized from EtOAc to afford 422 mg of 2-[(2,5-dichloropyrimidin-4-yl)amino]-N-methylbenzamide (yield: 26% yield*). Further material could be recovered from the mother liquors if desired. 1H NMR (CD3OD, 400 MHz): δ=2.93 (s, 3 H), 7.21 (td, J=7.64, 1.14 Hz, 1 H), 7.56 (ddd, J=8.53, 7.26, 1.64 Hz, 1 H), 7.71 (dd, J=7.83, 1.26 Hz, 1 H), 8.30 (s, 1 H) 8.63 (dd, J=8.59, 0.76 Hz, 1 H). MS (ES+): m/z 296.90 [MH+] (ZQ3, polar—5 min).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][N:15]([CH3:17])[CH3:16])([OH:13])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:16][N:15]([CH2:14][C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:17]
Reactant: CN(C)CC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1(O)CCNC1

Procedure:
9.4 g (39 mmol) of 1-benzyl-3-dimethylaminomethyl-3-hydroxypyrrolidine in 60 ml of methanol are hydrogenated using 2 g of palladium/active carbon (5%) at 100° C. and 90 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[CH2:28][C@H:27]([C:31](O)=[O:32])[CH2:26]2)=[CH:21][CH:20]=1>O1CCCC1>[F:13][C:14]1[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[CH2:28][C@H:27]([C:31]([NH2:3])=[O:32])[CH2:26]2)=[CH:21][CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 18 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
1,1′-carbonyldiimidazole (8.27 g, 51.0 mmol) was suspended and partly dissolved in tetrahydrofuran (110 mL) at 18° C. (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (14.0 g, 42.5 mmol; enantiomeric purity (S):(R)=99.5:0.5) was added as a solid together with tetrahydrofuran (30 mL) used for rinsing. The turbid solution, which turned into a white suspension after 15 min, was stirred 1 h at 16-20° C. and then transferred into a stirred 25% aqueous ammonia solution (7.95 mL) in tetrahydrofuran (80 mL). The last part of the white suspension was transferred with the aid of tetrahydrofuran (10 mL) for rinsing. After stirring for 0.5 h the reaction mixture was concentrated in vacuo to a volume of ˜70 mL and diluted with water (300 mL). Some ice was added to keep the temperature at 20-25° C. The white precipitate was collected by filtration, washed with water/tetrahydrofuran 80:20 and with heptane. Drying in vacuo at 20-45° C. afforded (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (13.5 g, 96%) as a white solid. The purity of the material by HPLC was 96.9% (area) and the enantiomeric ratio (S):(R) was determined as 99.7:0.3.
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]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:10]1=[N:41][OH:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:49][C:50](OC(C)=O)=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:50]([O:42][N:41]=[C:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:12][C@@H:11]1[CH2:32][P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])(=[O:51])[CH3:49]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1=NO)OCC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1=NOC(C)=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of diethyl (((2S,4R,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-(hydroxyimino)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (2.0 g, 3.35 mmol, 1.0 equiv) in dry DCM (40 mL) was added catalytic DMAP, pyridine (2.1 mL, 26.8 mmol, 8.0 equiv) and Ac2O (1.26 mL, 13.4 mmol, 4.0 equiv) slowly. The mixture was stirred at room temperature for 16 hours and then the concentrated in vacuo. The product thus obtained was then purified by silica gel chromatography, eluting with MeOH:acetone:chloroform:petroleum ether (0.5:0.5:1:8), to give diethyl (((2 S,4R,5 S,6R)-3-(acetoxyimino)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate as a colorless oil (1.5 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dddd, J=21.0, 10.3, 8.1, 6.0 Hz, 13H), 7.20 (ddq, J=8.2, 5.4, 3.0 Hz, 2H), 5.48-5.38 (m, 1H), 4.90 (d, J=11.6 Hz, 1H), 4.72 (d, J=11.5 Hz, 1H), 4.62-4.44 (m, 5H), 4.18-4.02 (m, 4H), 3.95-3.83 (m, 2H), 3.63 (qd, J=10.1, 4.8 Hz, 2H), 2.61-2.46 (m, 1H), 2.26-2.15 (m, 4H), 1.32 (td, J=7.1, 1.9 Hz, 6H). MS ESI (M+1) 639.8; calc for C34H42NO9P 639.3.
Reaction SMILES: O[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(O)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2[nH]c(Cl)nc2c1
Yield: 40 %

Procedure:
According to the procedure of A. T. James, et al., J. Chem. Soc., 1515 (1950), a mixture of 2-hydroxy-5-nitro-1H-benzimidazole (10.0 g, 0.0558 mol) and phosphoryl chloride (100 mL) was heated under reflux for 3 hours. The mixture was cooled, concentrated, and ice water was added. The resulting precipitate was collected by filtration. NMR analysis showed the material to be a 1:1 mixture of starting material and product. (Note: Longer heating does not improve the conversion.) Purification by flash chromatography (material preadsorbed onto silica; eluent 40% EtOAc/hexane) gave 4.4 g (40%) of the off-white solid product m.p. 215°-217° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:25]=[C:24]([C:26]([NH:28][NH2:29])=[O:27])[N:23]=[CH:22]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:29][NH:28][C:26]([C:24]1[N:23]=[CH:22][O:21][CH:25]=1)=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cocn1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1cocn1
Yield: 61.7 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and oxazol-4-carbohydrazide (613 mg, prepared following a procedure analogous to Reference Example 2), 335.2 mg of the title compound was afforded (yield 61.7%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:16][O:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[C:20]([O:25][CH3:26])[N:19]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:24][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[N:19]=[C:18]([O:17][CH3:16])[N:23]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1cc(N)nc(OC)n1
Solvent: c1ccncc1
Product: COc1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc(OC)n1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 2,6-dimethoxypyrimidin-4-amine (31 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 343.3, found 344.1 (M+1)+. Retention time 2.87 minutes.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>CC#N>[OH:4][CH2:3][C@H:2]([N:1]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1[C@@H](CO)c1ccccc1
Temperature: 150 °C
Yield: 93.9 %

Procedure:
To a 2.0-5.0 mL microwave vial was added (R)-2-amino-2-phenylethan-1-ol (1.53 g, 0.0112 mol) and phthalic anhydride (1.65 g, 0.0112 mol). The reaction mixture was capped and heated to 150° C. for 2 minutes in a microwave reactor. The mixture was cooled and diluted with CH3CN (2 mL), recapped and heated in the microwave reactor a second time at 140° C. for 20 minutes. The volatiles were removed under reduced pressure and the resulting solid was suspended in EtOAc (50 mL). The organic layer was washed with 5% NaHCO3 (aq), H2O, and brine, dried with anhydrous MgSO4 and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with CH3OH in CH2Cl2 (0 to 5%) to yield 2.81 g (94%) of the title compound. LC/MS: m/z (ES+) 268 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(Cl)cc(=O)n(C)c2=O)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (16.2 g, 101 mmol), p-methoxybenzyl chloride (16.5 mL, 122 mmol) and potassium carbonate (7.0 g, 50.7 mmol) in anhydrous DMF (200 mL) is heated at 60° C. for 3 hours. Additional potassium carbonate (3.0 g, 21.7 mmol) is added, and the reaction mixture heated at 60° C. for another 3 hours. After hot filtration, the filtrate is evaporated to dryness under reduced pressure. The obtained oil is directly used for the synthesis in the next step. A small amount of product is further purified by silica-gel flash chromatography to give pure product as crystals. 1H NMR (400 MHz, MeOH-d4) δ3.37 (s, 3H), 3.83 (s, 3H), 5.24 (s, 2H), 5.96 (s, 1H), 6.91 and 7.32 (AB, 4H, J=6.8 Hz). MS (FAB) m/z 281.23 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:28]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:33]([C:32]4[CH:36]=[CH:37][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=4)=[O:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CO
Product: COC(=O)c1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 92 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxycarbonylbenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 92%. Melting point: 220-223° C. (Methanol).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[CH2:5]([C:7]([C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=1)([OH:10])[CH2:8][CH3:9])[CH3:6]>>[CH2:5]([C:7]([C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=1)([O:10][CH3:3])[CH2:8][CH3:9])[CH3:6]
Reactant: CI
Reactant: CCC(O)(CC)c1ccc2ccc3cccnc3c2n1
Agent: [H-]
Agent: [Na+]
Product: CCC(CC)(OC)c1ccc2ccc3cccnc3c2n1
Yield: 64 %

Procedure:
By using General Procedure II, NaH (0.035 g, 1.5 mmol), methyl iodide (0.092 mL, 1.5 mmol), and 2-[(1-ethyl-1-hydroxypropyl)]-1,10-phenanthroline (0.098 g, 0.368 mmol), prepared as described by Example 2, were reacted to yield 0.066 g (65% yield) of the title methyl ether as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.24 (dd, J=4.50, 1.80 Hz, Hp9), 8.23 (dd, J=8.40, 1.80 Hz, Hp7), 8.20 (d, J=8.40 Hz, Hp4), 7.97 (d, J=8.40 Hz, Hp3), 7.78 and 7.72 (two d, J=8.80 Hz, Hp5 and Hp6), 7.60 (dd, J=7.80, 4.50 Hz, Hp8), 3.24 (s, OCH3), 2.34 and 2.24 (two dq, J=7.5 Hz, (CH2CH3)2), 0.73 (t, J=7.50 Hz, (CH2CH3)2); 13C NMR (75 MHz) δ164.85, 150.31, 146.45. 145.28, 136.10, 135.54, 128.89. 127.24, 126.55, 125.88, 122.48, 121.52, 84.26, 49.80, 28.17, 7.54; IR (CHCl3) 2969 (C—H Ar), 2935 (CH), 910 (C—H Ar) cm−1; HRMS m/e Calcd for C18H21N2O (MH+): 281.164, found, 281.1646.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][P:16]([CH2:19][CH:20]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21](O)=[O:22])([OH:18])=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:44]1([NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:57])[CH3:56])[NH2:53])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[C:44]1([NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:56])[CH3:57])[NH:53][C:21](=[O:22])[CH:20]([CH2:19][P:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])([OH:18])=[O:17])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)C(CCc1ccccc1)CP(=O)(O)CCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)C(CCc1ccccc1)CP(=O)(O)CCCCN1C(=O)c2ccccc2C1=O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
The crude product from Step G was dissolved in tetrahydrofuran (80 mL) and the solution was cooled in an ice bath. A slurry of 1,1'-carbonyldiimidazole (4.09 g, 25.2 mmol) in tetrahydrofuran (10 mL) was added over 10 min with additional tetrahydrofuran (3×5 mL) to complete the transfer. After 30 min, a solution of L-leucine N-phenylamide (5.60 g, 27.1 mmol) in tetrahydrofuran (10 mL) was added over 10 min with additional tetrahydrofuran (5 mL) to complete the transfer. The homogeneous solution was allowed to slowly warm to room temperature and stirred for 16 h. The mixture was concentrated on a rotary evaporator to remove most of the tetrahydrofuran and the residue was partitioned between ethyl acetate (150 mL) and 2N aqueous hydrochloric acid (75 mL). The ethyl acetate layer was washed with saturated aqueous sodium chloride (2×25 mL). The crystals which spontaneously formed in the organic layer were separated by filtration and partioned between chloroform (300 mL) and 2N aqueous hydrochloric acid, and the chlorform layer was washed with saturated aqueous sodium chloride (50 mL). The sodium chloride layer was extracted with chloroform (2×25 mL). The combined chlorform extracts were dried (magnesium sulfate), filtered, and evaporated. The residue was dissolved in boiling tetrahydrofuran (100 mL), allowed to cool to 25° C., evaporated to a mass of 40 g, and dissolved in ethyl acetate (150 mL). After 2 h at 25° C., the crystals were separated by filtration,washed with ethyl acetate (2×20 mL) and ether (20 mL), and dried under vacuum to give 6.17 g of almost colorless crystals. Evaporation of the mother liquor and recrystallization produced a second crop of 1.62 g (total yield 54% for steps F-H) of (2-(((4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl)hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine N-phenylamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.N>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]2[S:18][C:17]([NH2:19])=[N:16][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1
Agent: BrBr
Agent: N
Solvent: ClC(Cl)Cl
Product: Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A solution of (3-benzyloxy-5-bromo-phenyl)-thiourea (2.0 g, 5.93 mmol) in CHCl3 (80.0 mL) was cooled to −60° C. followed by drop wise addition of a solution of bromine (0.30 mL, 5.93 mmol) in CHCl3 (20.0 mL). The resulting reaction mixture was stirred at room temperature for 15 minutes followed by refluxing at 70° C. for 1 h. The reaction mass was then cooled and basified with 25% aqueous ammonia solution to pH 8-9 and then extracted with EtOAc (3×150.0 mL). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 40% EtOAc-Hexane) to get the desired compound (1.35 g, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(OCC)(O[CH2:13][CH3:14])(=O)=O>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13][CH3:14]
Reactant: Oc1ccccc1Br
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccccc1Br
Temperature: 25 °C

Procedure:
A mixture of 17.5 g of 2-bromophenol, 66 ml of diethyl sulfate and 170 ml of 10% NaOH solution is refluxed for 2 hours. After cooling the reaction mixture to RT, it is extracted with EtOAc, the organic phase is washed with 2N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 19.6 g of the expected product are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]([O:15]C(C)(C)C)=[O:14])(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)O
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of Intermediate 4A (0.048 g, 0.171 mmol) in 50% TFA/DCM (2 mL) was stirred at rt. After 1 h, the reaction was concentrated to give Intermediate 4 (0.038 g, 100%) as a yellow solid. The material was carried onto the next step without further purification. MS (ESI) m/z: 225.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([N:22]=[C:23]([NH2:25])[NH2:24])#[N:21].[OH-].[K+]>COCCO.O>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]3[N:24]=[C:23]([NH2:25])[N:22]=[C:20]([NH2:21])[N:13]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CN=C(N)N
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: Nc1nc(N)nc(C2CN(C(c3ccccc3)c3ccccc3)C2)n1
Temperature: 25 °C

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinecarbonitrile (500 mg, 2.01 mmol), dicyandiamide (220 mg, 2.62 mmol) and KOH (34 mg, 0.604 mmol) in 2-methoxyethanol (10 mL) was heated at reflux for 4 hours, diluted with water, and cooled to room temperature. The precipitate was rinsed with water and dried under vacuum to provide the title compound.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[Na+].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20].N1C=CC=CC=1.Cl>CN(C=O)C>[C:11]([C:9]1[O:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])([CH3:16])[CH3:15])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CS(=O)(=O)c1ccc(S(=O)[O-])cc1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)no1
Temperature: 50 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a solution of 160 mg (0.55 mmol) of 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide in DMF (3 mL) were added 181 mg (0.71 mmol) of 4-methanesulfonyl-benzenesulfinic acid sodium salt in one portion. Pyridine (48 μL) was added and the reaction was stirred at 50° C. for 18 h. The mixture was acidified with 1M aqueous HCl solution (1 mL) and extracted with diethyl ether (3×3 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified by column chromatography (silica, eluent heptanes, 0-20% ethyl acetate) to afford 47 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-propionamide.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/[CH:11]=O)=[CH:7]/N(C)C)=[O:5].Cl.[C:14]([NH2:22])(=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na]>CCO>[C:15]1([C:14]2[N:22]=[CH:11][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:7][N:21]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)/C(C=O)=C/N(C)C
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1
Yield: 76.2 %

Procedure:
A solution of ethyl 3-N,N-dimethylamino-2-formylacrylate (4.0 g, 23 mmol) (Arnold, Coll. Czech. Chem. Commun. 26:3051, 1961), benzamidine hydrochloride (4.0 g, 26 mmol) and sodium (0.65 g, 28 mmol) in EtOH (40 mL) was heated at reflux for 1 h. The solution was filtered and concentrated and the residue partitioned between EtOAc and dilute HCl (10%). The organic layer was dried (Na2SO4), and concentrated to give ethyl 2-phenylpyrimidine-5-carboxylate (4.0 g, 75% yield); m.p. >220° C. (dec.).