Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:30]=1)[NH:27][CH:26]=[CH:25]2.C([SiH](CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:4]1[CH2:5][CH2:6][CH2:7][S:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCCSCC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCCSCC3)c[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-thiepanone (900 mg, 6.9 mmol, 1.1 eq) in dry dichloromethane (30 mL) was added activated molecular sieves (4 Å, beads, spatula tip full) and the solution was cooled to 0° C. using an ice water bath. Trimethylsilyl trifluoromethanesulfonate (1.25 mL, 6.9 mmol, 1.1 eq) was added dropwise to the ketone solution, followed by the dropwise addition of ethyl 5-bromo-1H-indole-7-carboxylate (1.69 g, 6.3 mmol, 1 eq) as a solution in dichloromethane (10 mL). The reaction mixture was stirred at rt for 2 h, then warmed to 35° C. for 45 minutes. The deep red reaction mixture was cooled to 0° C. and triethylsilane (2 mL, 12.6 mmol, 2 eq) was added. The mixture was warmed to rt for 30 minutes, then was quenched by the addition of saturated aq. sodium bicarbonate. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic extracts were dried over sodium sulfate, filtered through a thin pad of silica gel (to remove baseline impurities), eluting with 50% ethyl acetate in hexanes, and concentrated to afford the crude product as a yellow residue. The crude material was purified by Isco Combiflash, eluting with 0-30% ethyl acetate in hexanes (120 gram column). The title compound was obtained as a yellow residue (540 mg, 24%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:2]1.[CH3:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]3[CH:27]=[C:28]([C:30](O)=[O:31])[S:29][C:22]=13)=[CH:15][CH:14]=2>>[CH3:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]3[CH:27]=[C:28]([C:30]([N:1]4[CH2:4][CH:3]([N:5]5[CH2:9][CH2:8][CH2:7][CH2:6]5)[CH2:2]4)=[O:31])[S:29][C:22]=13)=[CH:15][CH:14]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Reactant: C1CCN(C2CNC2)C1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC(N6CCCC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 1-azetidin-3-yl-pyrrolidine and 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid by a procedure analogous to Example 21B. MS: 312 (MH+); HPLC Rf: 3.211 min; HPLC purity: 96%.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:33]I>[Ag]=O.C(Cl)(Cl)Cl>[CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH:30]([O:32][CH3:33])[CH3:31])=[CH:23][CH:24]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CI
Reactant: CCCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC)cc2)nc1
Yield: 52 %

Procedure:
At room temperature, 4.0 g (9 mmol) of the (-)-5-undecyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine obtained in Example 14, 40 ml of methyl iodide and 6.3 g (27 mmol) of silver oxide were stirred for 40 hours. Then, the reaction mixture was washed with 1 N hydrochloric acid and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography gave 2.1 g (yield 52%) of (-)-5-undecyloxy-2-{4-(6-methoxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.6 (c=1.0, CHCl3).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)[CH2:13][CH2:14]CC>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCCCC(=O)CC(=O)OC
Yield: 95.5 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 138.7 g (1.15 mol) of valeryl chloride. The pH in this gave 151 g (GC purity 82.5%) of methyl valerylacetate (yield 79.0%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[S:21]([OH:23])=[O:22].Cl>O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[S:21]([OH:23])=[O:22]
Reactant: Sc1ccccc1Br
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2Br)c(S(=O)O)c1
Temperature: 125 °C

Procedure:
To a solution of NaOH (80.18 g, 2.004 mol) in water (600 ml sonicated and degassed) was added 2-bromothiophenol (108.23 ml, 1.002 mol) and 2-chloro-5-nitro-benzenesulfinic acid (222.11 g, 1.002 mol). The mixture was stirred and heated at 125° C. for 19 hours. The reaction was cooled down at 0° C., and concentrated HCl added dropwise from a dropping funnel while stirring until pH<1. The precipitate formed was filtered, dried in a desiccators overnight and was used without any further purification (417.77 g). m/z (LC-MS, ESP), RT=3.51 min, (M−−1)=372-374, (1:1, bromine isotope ratio present).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH2:11])[CH2:8]2.Cl.[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH:14]1[NH2:23])[CH2:20]2.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>O1CCCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:24]([NH:23][CH:14]1[CH:15]3[CH2:21][CH:19]4[CH2:18][CH:17]([CH2:22][CH:13]1[CH2:20]4)[CH2:16]3)=[S:25])[CH2:8]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: S=C(NC1C2CC3CC(C2)CC1C3)NC1C2CC3CC(C2)CC1C3

Procedure:
The 2-adamantylamine obtained from 5.0 g. (0.0266 mole) of 2-adamantylamine hydrochloride is reacted with 2.5 g. (0.014 mole) of 1,1'-thiocarbonyldiimidazole in 100 ml. of tetrahydrofuran for 20 hr. The solvent is evaporated and the residue partitioned between 5 percent hydrochloric acid and ether. The organic layer is washed with water, dried over potassium carbonate, evaporated and the residue is recrystallized from benzene-Skellysolve B: 3.65 g. (79 percent), m.p. 254-258.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][N:25](CC)[CH2:26][C:27]1C=CC=CC=1)([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][CH2:26][CH3:27])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: CCN(Cc1ccccc1)CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Yield: 98.9 %

Procedure:
A solution of 5-amino-N-(2-{[ethyl(phenylmethyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.39 g, 0.813 mmol) in ethanol (35 ml) was stirred under an atmosphere of hydrogen over Pearlman's catalyst (45 mg) for 7 hours (32 ml of hydrogen taken up). The catalyst was filtered off and the filtrate was evaporated to give the title compound (0.313 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][C:20]([OH:31])([C:22]([CH3:30])([CH3:29])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH3:21]>>[CH3:21][C:20]([OH:31])([C:22]([CH3:30])([CH3:29])[CH2:23][C:24]1[S:25][C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:27][CH:28]=1)[CH3:19]
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(O)C(C)(C)Cc1cccs1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CC(C)(C)C(C)(C)O)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2,3,3-trimethyl-4-thiophen-2-yl-butan-2-ol (prepared from 2,2-dimethyl-3-thiophen-2-yl-propionic acid by esterification with diazomethane and treatment with MeMgBr (Step A of Method A)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([Li])CCC.CI>C(OCC)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][C:13]=1[CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCOCC
Product: Cc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
(6-Chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (14.11 g) was dissolved in dry diethyl ether (310 mL), N,N,N′,N′-tetramethyl-ethylene-1,2-diamine (23.1 mL) was added. The solution was cooled to −78° C., n-butyl lithium (97 mL, 1.59 M in hexane) was added, the cool bath replaced by an ice/sodium chloride cool bath and the suspension was stirred for 2 h at −10° C. The suspension was cooled again to −78° C. and methyl iodide (5.8 mL) was added slowly. The cool bath was removed and the reaction was quenched after 1 h by addition of water. Ethyl acetate was added and the mixture was neutralized by addition of 2 M hydrochloric acid. The layers were separated and the aqueous layer was extracted 2× with ethyl acetate, the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate 5:1, Rf=0.10) to afford 4.24 g of the title compound of the formula
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].Br[C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:16]2[CH:24]=[CH:23][C:22]3[N:21]([CH3:25])[C:20]4[CH2:26][CH:27]5[NH:31][CH:30]([C:19]=4[C:18]=3[C:17]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]5)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(C(F)(F)F)cc4)ccc31)C1CCC(C2)N1
Yield: 24 %

Procedure:
Intermediate 17 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) to give tert-butyl 2-(4-trifluoromethylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (130 mg, 24%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.19 (s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.67-7.78 (m, 3H), 7.31-7.33 (m, 1H), 5.30 (br s, 1H), 4.70 (br s, 1H), 3.58 (s, 3H), 3.37-3.41 (m, 1H), 2.51 (d, J=16.3 Hz, 1H), 2.16-2.31 (m, 2H), 1.90-1.96 (m, 1H), 1.56-1.65 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[C:15]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:27]([CH2:31][C:32]#[CH:33])[C:28](=O)[CH3:29])(C)(=O)=O>CO.C(Cl)(Cl)Cl>[CH3:21][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17]([O:19][CH3:20])=[O:18])[C:10]=1[CH2:9][NH:8][C:7]1[C:2]2[N:3]([C:27]([CH2:31][C:32]#[CH:33])=[C:28]([CH3:29])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Reactant: COC(=O)Nc1cccc(C)c1CNc1cccnc1N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC)cccn12
Yield: 55.7 %

Procedure:
A mixture of 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)pyridine (180 mg) and 3-mesyloxy-5-hexyn-2-one (120 mg) in methanol (0.36 ml) and chloroform (0.36 ml) was refluxed for 20 hours. After cooling, chloroform was added to the mixture and the resultant mixture was washed with an aqueous solution of sodium carbonate and water. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (4 g), eluting with chloroform to give an oily product. The residue was triturated with diethyl ether to give 8-(2-methyl-6-methoxycarbonylaminobenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (127 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH3:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:11]1([C:17]2[O:18][C:19]3[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:10][N:9]1[CH:7]2[CH2:6][CH2:5][CH:4]1[CH2:3][CH:2]([NH:1][C:26]([C:25]1[C:19]3[O:18][C:17]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:21][C:20]=3[CH:22]=[CH:23][CH:24]=1)=[O:27])[CH2:8]2
Reactant: CN1C2CCC1CC(N)C2
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Product: CN1C2CCC1CC(NC(=O)c1cccc3nc(-c4ccccc4)oc13)C2
Yield: 57 %

Procedure:
N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-7-carboxamide was prepared from 3-amino-8-methyl-8-azabicyclo[3.2.1]octane and 2-phenylbenzoxazole-7-carboxylic acid using conditions similar to those described for Step C in Example 7. This compound was obtained in 57% yield as a white solid: mp 164-166° C.; 1H NMR (300 MHz, CH3OD) δ 8.25 (dd, J=8.1, 1.8 Hz, 2H), 7.90 (dd, J=8.1, 1.2 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.64-7.58 (m, 3H), 7.50 (t, J=7.8 Hz, 1H), 4.25 (t, J=5.0 Hz, 1H), 3.63 (br s, 2H), 2.63 (s, 3H), 2.53-2.35 (m, 6H), 2.22-2.17 (m, 2H); MS (ESI) m/z 362 [M+H]+.
Reaction SMILES: Cl[C:2](=[CH2:6])[C:3](O)=[O:4].Cl.Cl.[CH3:9][O:10][C:11](=[O:20])[C@H:12]([CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)[NH2:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:20])[C@H:12]([CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)[NH:13][C:3](=[O:4])[CH:2]=[CH2:6]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: C=C(Cl)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)OC
Yield: 44.8 %

Procedure:
After chloroacrylic acid (1.6 ml, 20 mmol) was dropped, with ice cooling, into a solution of histidine methyl ester dihydrochloride (6.05 g, 25 mmol) and triethylamine (14 mL, 100 mmol) in methylene chloride (200 mL), the same operation as in the synthesis of N(α)-acryloyl-N(π)-methyl-L-histidine methyl ester was conducted to give N(α)-acryloyl-L-histidine methyl ester (2.0 g, 36%) as an oily product.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])O.[Na+].[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([O:17][C:18]2[C:19]([CH:28]([CH3:30])[CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[C:23]#[N:24])=[CH:12][N:11]=1>C(O)C.O>[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([O:17][C:18]2[C:19]([CH:28]([CH3:30])[CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[C:23]([NH:2][OH:3])=[NH:24])=[CH:12][N:11]=1
Reactant: NO
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(=N)NO
Yield: 82.8 %

Procedure:
The benzamidination carried out in this step follows the procedure reported by Meyer et al., Synthesis 2003, 6, pp. 899-905. To a stirred mixture of hydroxylamine hydrochloride (0.099 g, 1.43 mmol) and sodium hydrogen carbonate (0.119 g, 1.42 mmol) in ethanol (1.4 ml) and water (0.3 ml) was added 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.385 g, 1.29 mmol) and the mixture heated at reflux for 5 hours. A second portion of hydroxylamine hydrochloride (0.049 g, 0.71 mmol) and sodium hydrogen carbonate (0.060 g, 0.71 mmol) was added. After a further 2 hours the mixture was cooled, concentrated in vacuo, then diluted with water (10 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo to yield 5-(2,4-diamino-pyrimidin-5-yloxy)-N-hydroxy-4-isopropyl-2-methoxy-benzamidine (355 mg) as a yellow foam. This material was used directly without further purification.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:24][C:25]([OH:27])=[O:26])=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:7](CC(O)=O)=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[H-].[CH3:29][O:30]CCO[Al+]OCCOC.[Na+].[H-].C1(C)C=CC=CC=1>O1CCCC1>[CH:10]([C:8]1[C:7]([CH2:29][OH:30])=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:5]([CH2:24][C:25]([OH:27])=[O:26])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1)([CH3:11])[CH3:12]
Reactant: COCCO[Al+]OCCOC
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(-c2ccc(F)cc2)c1CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CC(=O)O)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of the intermediate obtained in Step C (37.3 g, 100 mmol) in anhydrous tetrahydrofuran (350 mL) stirred under argon at 0° C. was added a solution of 3.4M of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (Red-Al) (105 mL, 204 mmol, 65 wt % in toluene) via syringe over 20 min. The reaction mixture was allowed to stir at room temperature for 24 hr, then cooled again to 0° C. and carefully quenched by the dropwise addition of water. The solution was decanted from the solid which forms and the solvent removed in vacuo. The residue was purified by flash chromatography (500 g silica) via step gradient. Elution with 5% diethyl ether/hexane affords 9.8 g (26.3 mmol, 28%) of recovered starting material and elution with 40% diethyl ether (Et2O)/hexane affords the desired product as a white solid (26.8 g, 77.8 mmol, 78%). mp 124-126° C. Rf=0.2 (10% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3): δ 7.35 (s, 1H), 7.27 (m, 2H), 7.08 (m, 2H), 4.44 (d, J=5.5 Hz, 2H), 3.43 (m, 4H), 2.92 (sept, J=6.6 Hz, 1H), 1.59 (s, 1H), 1.28 (m, 12H). FAB-MS: calculated for (C21H25FO3) 344, found 345 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(=O)(=O)(O)O.[CH2:22](O)[CH2:23][CH3:24]>C1C=CC=CC=1.O>[CH2:22]([O:7][C:6](=[O:8])[C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([Cl:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=1)[CH2:23][CH3:24]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Yield: 88 %

Procedure:
Into a 50 l enamelled double-walled apparatus equipped with a stirrer and adjusted to azeotropic distillation 7.5 kg (0.125 kmole) of n-propanol, 19 kg of benzene, 25 kg (0.1 kmole) of 4-chloro-3,5-dinitro-benzoic acid and 1 kg of concentrated sulfuric acid are weighed in. The reactor is closed and the content thereof is heated to boiling by means of steam heating. The reaction mixture is heated to boiling (86°-90° C. until no more water leaves the system while the organic phase (a mixture of benzene and n-propanol) is continuously reintroduced into the reactor. Once the distillation of water is completed (5-7 hours) the mixture is cooled below 20° C., the precipitated crystals are isolated by centrifugation, washed with cold benzene and dried. Thus 25.4 kg of the desired compound are obtained, yield 88%, purity 97%.
Reaction SMILES: [NH:1]([C:3](=[O:15])[CH2:4][CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[NH2:2].[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33](O)=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.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>CN(C=O)C>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:2][NH:1][C:3](=[O:15])[CH2:4][CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:34])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(CCC(=O)NN)C(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a 0° C. solution of tert-butyl 3-hydrazinyl-3-oxopropyl(methyl)carbamate (4.3 g, 19.8 mmol) and (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (4.9 g, 0.0178 mol) in DMF (100 mL) was added HATU (8.2 g, 0.0218 mol), followed by dropwise addition of DIPEA (9.6 mL, 0.0594 mol) slowly. The mixture was stirred at 0° C. for 1 h, and then quenched with ice water. The aqueous layer was extracted with EtOAc (2×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (gradient elution 20˜60% EtOAc/petroleum ether) to afford tert-butyl 3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-3-oxopropyl(methyl)carbamate (6.7 g, 78%) as a white solid. ESI-MS (EI+, m/z): 476 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][OH:5].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:5][CH2:4][CH:3]([NH:6][C:7]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[C:2]([F:17])([F:18])[F:1])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC(CO)C(F)(F)F)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(NC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate (300 g, 1.14 mol) in dichloromethane (2500 mL) were added triethylamine (128 g, 1.27 mol) and methanesulfonylchloride (144 g, 1.26 mol). After 2 hours, the reaction mixture was quenched with water (1000 mL) and extracted with dichloromethane (3×300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2-{[(benzyloxy)carbonyl]amino}-3,3,3-trifluoropropyl methanesulfonate. The material was used without further purification.