Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:28][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH2:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>CN(C=O)C>[CH3:30][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH:60][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 868 mg (4.59 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e), 1.64 g (8.58 mmol) of EDC and 773 mg (5.72 mmol) of HOBT are dissolved in 24.5 ml of DMF. After 15 min, 2.39 ml (1 7.2 mmol) of TEA and 1.64 g (2.86 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 12 ml of DMF are added. After 20 hours, the mixture is concentrated by evaporation, and water and methylene chloride are added to the residue; the aqueous phase is separated off and extracted 2× more with methylene chloride. The organic phases are washed with 10% citric acid solution, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. [Digestion from DIPE yields the title compound: HPLC20-100 : tRet =18.6; FAB MS (M+H)+ =743.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH3:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:24][C:21]1[S:22][CH:23]=[C:19]([CH3:18])[N:20]=1)=[O:8]
Reactant: Cc1csc(N)n1
Reactant: CN(c1cncnc1)c1cccc(C(=O)O)c1
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
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cccc(N(C)c3cncnc3)c2)n1
Yield: 16.1 %

Procedure:
Compound 17 (0.1 g, 0.4 mmol, 1 eq), 4-methylthiazol-2-amine (60 mg, 0.53 mmol, 1.2 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (348 mg, 0.915 mmol, 2.10 eq), and DIEA (160 μL, 0.915 mmol, 2.10 eq) were dissolved in CH2Cl2 (5 mL) and DMF (1 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 21 mg (15%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.68 (s, 2H), 7.58 (m, 1H), 7.45 (m, 1H), 7.18 (m, 1H), 6.81 (s, 1H), 3.39 (s, 3H), 2.28 (s, 3H); [M+1]+: 326.2.
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23](O)=[O:24])([CH3:20])[CH2:3][C@:4]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])([C:8]([F:11])([F:10])[F:9])[CH2:5][C:6]#[CH:7].[N:31]1C=CC=CC=1.S(Cl)(Cl)=O.N>C(Cl)Cl>[CH3:1][C:2]([C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([NH2:31])=[O:24])([CH3:20])[CH2:3][C@:4]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])([C:8]([F:11])([F:10])[F:9])[CH2:5][C:6]#[CH:7]
Reactant: c1ccncc1
Reactant: C#CC[C@@](CC(C)(C)c1ccc(F)cc1C(=O)O)(O[Si](CC)(CC)CC)C(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C#CC[C@@](CC(C)(C)c1ccc(F)cc1C(N)=O)(O[Si](CC)(CC)CC)C(F)(F)F
Reaction time: 0.42 h
Yield: 53.1 %

Procedure:
To a solution of 14.2 g of 2-((S)-1,1-dimethyl-3-triethylsilanyloxy-3-trifluoromethylhex-5-ynyl)-5-fluorobenzoic acid (0.030 mol) in 400 mL of DCM was added 4.6 mL of pyridine (0.057 mol) followed by 3.3 mL of thionyl chloride (0.045 mol). The reaction was stirred for 25 minutes then carried on to next step. The crude acid chloride was cannulated into a flask containing ammonia (7 M in MeOH, 185 mL, 1.30 mol). The mixture was stirred for 40 minutes then quenched with saturated aqueous sodium bicarbonate solution. The mixture was then diluted with 20 mL of ethyl acetate, washed with two 100 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was chromatographed on silica gel using 0-50% ethyl acetate/hexanes to afford 7.1 g (50%) of 2-((S)-1,1-dimethyl-3-triethylsilanyloxy-3-trifluoromethylhex-5-ynyl)-5-fluorobenzamide.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]1[O:10][CH2:9]1>>[CH2:1]([N:4]([CH:9]([OH:10])[CH3:8])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: C1CO1
Product: C=CCN(CC=C)C(C)O

Procedure:
Diallylamine was reacted with ethylene oxide to give diallylaminoethanol and this was reacted with thionyl chloride to give an aqueous solution of diallylaminoethyl chloride in accordance with the method disclosed by J. B. Wright et al., J. Amer. Chem. Soc., 72, pp. 3556-3559, 1950.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][CH:21]=[CH2:22])[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:24][N:25](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.CN.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[CH3:24][NH:25][C:10](=[O:11])[C@@H:9]([N:8]([CH2:20][CH:21]=[CH2:22])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NC

Procedure:
Combine (S)-2-[N-(t-butoxycarbonyl)-allylamino]-3-phenyl-propionic acid (0.7 g, 2.29 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.50 g, 2.52 mmol), 1-hydroxybenzotriazole (0.38 g, 2.52 mmol), methylamine hydrochloride (0.17 g, 2.52 mmol) and diisopropylethylamine (0.59 mL, 2.52 mmol) in dichloromethane (23 mL) and stir for 18 hours. Dilute with ethyl acetate and extract with 1M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. Dry the separated organic layer over MgSO4, filter and evaporate in vacuo. Chromatograph on silica gel eluting sequentially with 5% methanol/dichloromethane and 10% methanol/dichloromethane to give the title compound: TLC Rf =0.44 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH2:46][CH2:47][NH:48][CH2:49][CH:50]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:57][S:58](Cl)(=[O:60])=[O:59].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH2:46][CH2:47][N:48]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:49][CH:50]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:37])([F:36])[F:38])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5=CCNCC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5=CCN(S(C)(=O)=O)CC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (320 mg, 0.413 mmol) in CH2Cl2 (5.0 mL) was added methanesulfonyl chloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), and the reaction was stirred for 1.5 h at RT and then concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2Cl2 to 90:9:1 CH2Cl2:MeOH:conc. NH4OH) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:29][N:30]=[C:31]=[O:32]>C(#N)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:29][NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)NS(=O)(=O)c1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NS(=O)(=O)c1ccc(NC(=O)NCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
A solution of methyl 4-aminophenylsulfonylcarbamate (50 mg, 0.2 mmol), N,N-diisopropylethylamine (35 L, 0.2 mmol), 3,4-dichlorobenzylisocyanate (30 L, 0.2 mmol) in acetonitrile was stirred under an N2 atmosphere for 19 h. The mixture was concentrated and the residue purified by reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give methyl 4-(3-(3,4-dichlorobenzyl)ureido)phenylsulfonylcarbamate. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=431.01; tR=2.9 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25]CC)=[O:24]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][C:23]([OH:25])=[O:24])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.6 %

Procedure:
The mixture of 4-nitro-3-trifluoromethylphenol (414 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 8 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml of dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 2, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was separated by column chromatography (eluent: ethyl acetate: EtOH 9:1) to give 35 mg 4-nitro-3-trifluoromethylphenoxyacetic acid as white solid, mp 92-95° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:39])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][O:26][C:25]5=[O:31])=[CH:20][C:19]=4[N:32]4[CH2:36][CH2:35][CH2:34][S:33]4(=[O:38])=[O:37])=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:40]I>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:39])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH3:40])[CH2:27][O:26][C:25]5=[O:31])=[CH:20][C:19]=4[N:32]4[CH2:36][CH2:35][CH2:34][S:33]4(=[O:37])=[O:38])=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2N2CCCS2(=O)=O)CC1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 73.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-(1,1-dioxoisothiazolidin-2-yl)phenyl}-4-hydroxymethyloxazolidin-2-one (778 mg) described in Example 317 and methyl iodide (238 mg), the title compound (586 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[N:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:24]=[CH:25][CH:26]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[N:23]([CH2:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[S:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cn1cccc1-c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc(-c3cccn3CC(=O)O)sc2-c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
Ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]-pyrrole-1-acetate (prepared in Example 14) (3.59 g, 8 mmole) and potassium hydroxide (0.90 g, 16 mmoles) are added to ethanol (80 ml), and the mixture is refluxed for 5 minutes. After distilling off ethanol, the resulting residue is dissolved in water. To the aqueous solution is added 10% hydrochloric acid, and the precipitated crystals are separated by filtration and dried to give crude crystals (3.20 g). The crude crystals are recrystallized from benzene to give 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]-pyrrole-1-acetic acid (2.69 g, yield: 80%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:21])([C:14]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][CH2:5]2.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:23][C:7]([CH3:21])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:22])[C:14]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC(C)C)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCC(C)C)=C(C)C1=O
Yield: 87.3 %

Procedure:
Oxidation as described in protocol B, using 84 mg (0.278 mmol) of 6-hydroxy-N-isobutyl-2,5,7,8-tetramethylchroman-2-carboxamide and 335 mg CAN (0.612 mmol) yielded 78 mg of 2-hydroxy-N-isobutyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow-orange oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=2)[C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:5]([Cl:33])=[CH:4][N:3]=1.Cl>COCCO.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:33][C:5]1[CH:4]=[N:3][C:2]2[NH:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH:17]=3)[CH2:15][NH:14][C:12](=[O:13])[C:11]3[CH:10]=[C:9]([NH:8][C:6]=1[N:7]=2)[CH:32]=[CH:31][CH:30]=3
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COCCO
Product: O=C1NCc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Temperature: 150 °C
Yield: 62.5 %

Procedure:
To a solution of tert-butyl {3-[({3-[(2,5-dichloropyrimidin-4-yl)amino]benzoyl}amino)methyl]phenyl}carbamate (40.0 mg, 0.0819 mmol) in 2-methoxyethanol (0.452 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (100 μL). The resulting mixture was heated at 150° C. in the microwave for 15 min. The cloudy mixture was diluted with Na2CO3 (aq), filtered, washed with water. The crude cake was triturated with MeOH to give the desired product as an off-white powder (18 mg, 62%). LCMS for C18H14ClN5O (M+H)+: m/z=352.0. 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 10.05 (t, J=2.0 Hz, 1H), 9.66 (s, 1H), 9.05 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.62 (t, J=2.0 Hz, 1H), 8.25 (t, J=8.0 Hz, 1H), 8.00 (m, 1H), 7.76 (ddd, J=7.6, 2.0, 1.2, 1H), 7.52 (m, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.02 (m, 1H), 6.90 (m, 1H), 4.32 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccnc2)cc1N

Procedure:
Prepared from (2-nitro-4-pyridin-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example C10) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a grey powder (200 mg).
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH2:1]([NH:6][C:7]([NH:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN=C=O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use pentylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (45.5% yield). 1H NMR (400 MHz, CDCl3) δ 10.60, 7.82, 7.74, 7.13, 7.63, 7.56, 7.52, 7.36, 7.08, 4.29, 4.0-4.09, 3.85-3.95, 3.50-3.70, 3.40-3.47, 3.25-3.36, 1.50-1.60, 1.22-1.36, 0.80-0.92. MS (ES+) m/z 465 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C1([O:28][C:29](=O)[NH:30][C:31]2[CH:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:35][CH:36]=2)C=CC=CC=1>C(#N)C>[C:33]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=[C:31]([NH:30][C:29]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:8]3[CH2:7][CH2:6][C:3]4([CH2:4][CH2:5]4)[C@H:2]([OH:1])[CH2:9]3)[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:28])[CH:32]=1
Reactant: C[C@@H]1NCCN(CCCCN2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C(Nc1cccc(-c2ccccc2)c1)Oc1ccccc1
Solvent: CC#N
Product: C[C@H]1C(=O)N(CCCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1cccc(-c2ccccc2)c1
Yield: 82.7 %

Procedure:
A solution of (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one (intermediate 27; 50 mg, 0.17 mmol) and biphenyl-3-ylcarbamic acid phenyl ester (PCT Int. Appl. WO20050443810; 49 mg, 0.17 mmol) in acetonitrile (1 mL) was stirred at room temperature for 72 h, then concentrated under vacuum. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) furnished the title compound (69 mg, 83%). White foam, MS (ISP)=491.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10](B(O)O)=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.Cl[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([CH2:31][CH3:32])[N:19]2[CH:24]([CH:28]1[CH2:30][CH2:29]1)[CH:25]1[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:28]1([CH:24]([CH:25]2[CH2:27][CH2:26]2)[N:19]2[C:18]([CH2:31][CH3:32])=[N:17][C:16]3[C:20]2=[N:21][CH:22]=[N:23][C:15]=3[C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:8][CH2:7][CH2:6][C:5]=3[CH:9]=2)[CH2:30][CH2:29]1
Reactant: CCc1nc2c(Cl)ncnc2n1C(C1CC1)C1CC1
Reactant: Cc1cc2c(cc1B(O)O)CCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCc1nc2c(-c3cc4c(cc3C)OCC4)ncnc2n1C(C1CC1)C1CC1

Procedure:
Part G. A mixture of the boronic acid from Part F (298 mg, 1.67 mmol), 6-chloro-9-dicyclopropylmethyl-8-ethylpurine (309 mg, 1.12 mmol), 2 N aqueous sodium carbonate solution (1.7 mL, 3.4 mmol) and triphenylphosphine (61 mg, 0.233 mmol) in DME (20 mL) was degassed by repeated cycles of brief vacuum pumping followed by nitrogen purging. To this was added palladium (II) acetate (13 mg, 0.058 mmol), and the mixture was degassed again and then heated to reflux for 14 hours. It was cooled, and poured into water (100 mL). This mixture was extracted with ethyl acetate (2×100 mL), and the extracts were washed in sequence with brine (60 mL), combined, dried over sodium sulfate, filtered and evaporated. The residual material was separated by column chromatography (silica gel, 20:80 ethyl acetate-hexane) to afford the title product as a solid. This was recrystallized to purity from ether (253 mg, 0.77 mmol, 69%). m.p. 147-148° C. TLC RF 0.18 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 8.88 (1H, s), 7.60 (1H, s), 6.77 (1H, s), 4.61 (2H, t, J=8.6 Hz), 3.44 (1H, v br), 3.24 (2H, t, J=8.6 Hz), 2.94 (2H, br), 2.44 (3H, s), 2.03 (2H, v br), 1.45 (3H, br t, J=6 Hz), 0.89-0.79 (2H, m), 0.58 (2H, br), 0.50-0.40 (2H, m), 0.27-0.17 (2H, m). MS (NH3-CI): m/e 377 (4), 376 (27), 375 (100). Analysis calc'd for C23H26N4O: C, 73.77; H, 7.01; N, 14.96; found: C, 73.69; H, 7.08; N, 14.40.
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)OC1C=CC=CC=1)(=[O:4])=[O:3].[CH3:21][N:22]([CH2:31][C:32]1[O:36][C:35]([CH2:37][S:38][CH2:39][CH2:40][NH2:41])=[CH:34][CH:33]=1)[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6](=[N:41][CH2:40][CH2:39][S:38][CH2:37][C:35]1[O:36][C:32]([CH2:31][N:22]([CH3:21])[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24])=[CH:33][CH:34]=1)[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(Cc1ccc(CSCCN)o1)C(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN(Cc1ccc(CSCCN=C(NS(C)(=O)=O)Oc2ccccc2)o1)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 78 %

Procedure:
11.6 g of diphenyl methanesulfonylimidocarbonate was dissolved in 40 ml of methylene chloride. With ice-cooling, thereto was added 15 g of 2-[[5-[N-methyl-N-(2,2,2-trichloroethoxycarbonyl)aminomethyl]-2furyl]methylthio]ethylamine. The mixture was stirred for 10 minutes. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: benzene:ethyl acetate=2:1) to obtain 17.8 g (yield: 78%) of oily N-methanesulfonyl-N'-[2-[[5-[N-methyl-N-(2,2,2-trichloroethoxycarbonyl)aminomethyl]-2furyl]methylthio]ethyl]-O-phenylisourea.