Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl[CH:23]([CH2:28][CH2:29][C:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1)[C:24]([O:26][CH3:27])=[O:25]>CC(CC)C(=O)C>[C:30]1([CH2:29][CH2:28][CH:23]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)C(Cl)CCC1=CCCCC1
Agent: CCC(C)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C(CCC1=CCCCC1)Oc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.9 g (0.0138 mol) of potassium carbonate are added to a solution of 1.4 g (0.0069 mol) of 4′-methoxy-1,1′-biphenyl-4-ol in 30 ml of 3-methyl-2-pentanone (MIBK). The mixture is refluxed for 30 minutes and a solution of 1.5 g (0.0069 mol) of methyl 2-chloro-4-cyclohex-1-en-1-ylbutanoate in 10 ml of 3-methyl-2-pentanone is then added. Refluxing is continued for a further 6 hours. After cooling to room temperature, the reaction medium is concentrated, taken up in water and extracted with ethyl acetate. The extracts are washed with 1N sodium hydroxide and then with saturated aqueous NaCl solution, and dried over Na2SO4. After concentrating, a thick oil is obtained, which is purified by flash chromatography (95/5 heptane/ethyl acetate) 1.1 g of an oily product are thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](F)[CH:13]=[C:12]([F:20])[C:11]=1[F:21].C[O-].[Na+].[C:25](OCC)(=[O:27])C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([O:27][CH3:25])[CH:13]=[C:12]([F:20])[C:11]=1[F:21]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
A stirred solution of (2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine (1.23 g, 3 mmol) in dry THF (25 ml) under nitrogen was cooled to −78° C. and a solution of 25% sodium methoxide (0.68 ml, 0.3 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirring continued for another 16 hours. TLC indicated incomplete reaction. Ethyl acetate (100 mL) was added to the reaction mixture and the organic layer was washed with water, dried over sodium sulfate and further purified by column chromatography to provide the desired compound as a yellow solid (0.6 g, 47.6%). m/z=424 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11].Cl.O.[N+]([O-])([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>>[OH:1][C:2]1[C:7]([N:8]=[N+:27]=[N-:28])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11]
Reactant: Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
The N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea(274 mg, 0.85 mmol) was added to HCl/H2O (0.85 mL/1.7 mL), cooled to 0° C. Sodium nitrate (58.6 mg, 0.85 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. Sodium azide (55 mg, 0.85 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours then it was extracted with three times with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 5:1) gave product (210 mg, 71%). EI-MS m/z 349 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8]O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(Cl)Cl>[Br:33][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(F)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1CBr
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a solution of (5-Fluoro-2-nitrophenyl) methanol (0.3 g, 1.75 mmol) in methylene chloride (5 mL0 was added triphenylphosphine (0.52 g, 2.01 mmol) and carbon tetrabromide (0.66 g, 2.01 mmol). After 3 hours, the reaction was concentrated and chromatographed using 3:1 hexane:ethyl acetate as eluant to provide 0.38 g (93%) of the desired product as white crystals. mp 38-41° C. Anal Calc'd for C7H5N3O2FBr: C, 35.93; H, 2.15; N, 5.99. Found: C, 35.97; H, 2.12; N, 5.91.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[S:16][C:15]2[C:10](=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6].C(OC(=O)C)(=[O:21])C>>[S:5]([C:8]1[S:16][C:15]2[CH:14]=[CH:13][C:12](=[O:21])[NH:11][C:10]=2[CH:9]=1)(=[O:7])(=[O:6])[NH2:4]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C=NS(=O)(=O)c1cc2c(ccc[n+]2[O-])s1
Product: NS(=O)(=O)c1cc2[nH]c(=O)ccc2s1
Temperature: 140 °C
Yield: 33 %

Procedure:
A suspension of N,N-dimethyl-N'-(4-oxido-thieno[3,2-b]pyridine-2-sulfonyl)formamidine (6.23 g, 22.6 mmol) in acetic anhydride (70 ml), under a nitrogen atmosphere, was heated at 140° C. for 20-22 hours to give a dark solution. The excess acetic anhydride was removed on a rotary evaporator and 6 N HCl (90 ml) was added to the residue and it was warmed at 80° C. for four hours. This reaction mixture was cooled and ice was added as product began to precipitate. Upon standing several crops were collected by filtration. The combined crude product (2.2 g) was dissolved in a large volume of boiling water, filtered and allowed to cool. Pure product was obtained (1.72 g, 33% yield). This material was recrystallized by dissolution in a minimum volume of hot dimethylsulfoxide. This solution was treated with charcoal, filtered, and diluted with ethanol as product crystallized (1.3 g), m.p. >300° C.
Reaction SMILES: [CH2:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:5](=[O:17])[CH2:4]1)[CH3:2].[OH2:18].[OH-].[K+]>CO>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]([OH:17])=[O:18])=[CH:8][CH:9]=1
Reactant: O
Reactant: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](CC(=O)O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
2.91 g (12.0 mmol) of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone produced in Example 6 was dissolved in methanol (15 mL) and further mixed with water (10 mL) and potassium hydroxide (1.34 g, 23.9 mmol). The resulting solution was stirred at room temperature for 14 hours. On completion of the reaction, methanol was removed by distillation and toluene (10 mL) and water (5 mL) were added to separate the solution. The separated organic layer was further mixed with water (15.2 mL) and a 30 wt % aqueous solution of potassiumhydroxide (1.02 g) to separate the solution again. The separated aqueous layers were collected together and adjusted to be pH=1.5 by concentrated hydrochloric acid and extraction with toluene (20 mL) was repeated three times. The residue obtained by concentrating the organic layer was crystallized from toluene (9 mL)/hexane (35 mL) to obtain (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid as awhite crystal (2.38 g, isolated yield: 76%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.90 (3H, t), 1.5-1.8 (2H, m), 2.4-2.5 (2H, m), 3.7-3.9 (1H, m), 6.65 (2H, d), 7.39 (2H, d)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc(OCCO)cc1C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(OCCO)ccc1N
Reaction time: 1 h
Yield: 81.5 %

Procedure:
2-Amino-5-(2-hydroxyethoxy)benzoic acid hydrochloride (0.209 g, 895 μmol; CAS 78299-60-2) was suspended in dichloromethane (10 ml) at r.t under an argon atmosphere. The reaction mixture was diluted with MeOH (3 ml). Then trimethylsilyldiazomethane solution (1.45 ml, 2.9 mmol; 2M in hexane) was added dropwise. The reaction mixture was stirred at r.t for 1 hr. The solvents were evaporated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient to give the title compound (154 mg, 82%) as light yellow, waxy solid.
Reaction SMILES: O=[C:2]1[CH2:22][CH2:21][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH:4]=[CH:3]1.[ClH:23].[C:24]([NH:28][NH2:29])([CH3:27])([CH3:26])[CH3:25]>C(O)C>[ClH:23].[C:24]([NH:28]/[N:29]=[C:2]1/[CH:3]=[CH:4][C:5]2([CH2:21][CH2:22]/1)[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH2:6]2)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)NN
Reactant: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Agent: Cl
Solvent: CCO
Product: CC(C)(C)N/N=C1/C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 60 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
Benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (4.89 g, 16.3 mmol) was dissolved in ethanol (60 mL) and tert-butylhydrazine hydrochloride (2.44 g, 19.6 mmol) was added. The mixture was heated at reflux for 4 hours and then stirred at 60° C. for 48 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a tan oil which solidified upon standing to yield 6.60 g (99%) of the title compound as a tan solid. +ESI (M+H) 370.3; 1H NMR (400 MHz, CDCl3, δ): 7.26-7.42 (m, 5 H), 6.46 (d, J=10.0 Hz, 1 H), 6.26 (br. s., 1 H), 5.08-5.16 (m, 2 H), 3.43-3.58 (m, 4 H), 3.19 (s, 2 H), 1.78 (s, 2 H), 1.44-1.63 (m, 4 H), 1.17-1.30 (m, 9 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:68][C:69]1[CH:74]=[CH:73][C:72]([C@@H:75]([NH2:77])[CH3:76])=[CH:71][CH:70]=1>CN(C=O)C>[Br:68][C:69]1[CH:74]=[CH:73][C:72]([C@@H:75]([NH:77][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=2)[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:76])=[CH:71][CH:70]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
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: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(Br)cc3)cc12
Reaction time: 0.08 h

Procedure:
To a mixture of 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (46 mg, 0.1 mmol) in DMF (1 mL) was added DIEA (26 mg, 0.2 mmol) and HATU (46 mg, 0.12 mmol). The mixture was stirred for 5 min, and then (S)-1-(4-bromophenyl)ethanamine (20 mg, 0.13 mmol) was added. The reaction mixture was stirred at rt for 30 min. The completion of the reaction was monitored by anal. HPLC. The solvent was removed in vacuo to obtain the crude which was purified by flash chromatography (AcOEt/Hex 10→100%) to obtain the title compound. ESI-MS (m/z): 637/639 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:21]=[CH:22][C:23]2[N:28]([CH3:29])[N:27]=[CH:26][C:24]=2[N:25]=1.CN(C(C)C)C(C)C>C(O)CCC>[CH3:29][N:28]1[C:23]2[CH:22]=[N:21][C:20]([NH:18][C@H:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH3:17])=[N:25][C:24]=2[CH:26]=[N:27]1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Cn1ncc2nc(Cl)ncc21
Agent: CC(C)N(C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc2c(cnn2C)n1)c1nc2ccccc2n1-c1ccccc1
Yield: 35.9 %

Procedure:
A solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (200 mg, 0.83 mmol, 1.00 equiv, 98%), 5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (180 mg, 1.07 mmol, 1.29 equiv) and methylbis(propan-2-yl)amine (0.3 mL, 98%) in n-butanol (8 mL) was stirred at 130° C. for 96 h. The resulting mixture was concentrated under vacuum and the residue was purified on a C18 column eluted with water/acetonitrile to give 110 mg (31%) of 159 as a light yellow solid. LC-MS: (ES, m/z) 370 [M+H]+, 221, 115. H-NMR: (CD3OD, 300 Hz, ppm) δ 8.86 (s, 1H), 7.70 (s, 1H), 7.65-7.54 (m, 6H), 7.61 (d, 2H), 7.09 (s, 1H), 5.30 (m, 1H), 4.04 (s, 3H), 1.64 (d, 3H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]([NH2:28])[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([NH:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:27]
Reactant: CCN
Reactant: BrCCCCOC1=C(c2ccccc2)CCCC1=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCNCCCCOC1=C(c2ccccc2)CCCC1=Cc1ccccc1
Reaction time: 24 h

Procedure:
1-Bromo-4-[[2-phenyl-6-(phenylmethylene)-1-cyclohexen-1-yl]oxy]butane is dissolved in toluene, treated with two equivalents of ethyl amine and allowed to stand at room temperature for 1 day, and washed with potassium carbonate solution. Evaporation of the toluene yields the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH2:35]([NH2:37])[CH3:36]>>[CH2:35]([NH:37][C:30](=[O:32])[C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:34])[CH3:36]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: CCN
Product: CCNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 62 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with ethylamine to give the title compound as a beige solid (160 mg, 62%), except that the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum 1.04 (t, 3H), 1.65 (d, 3H), 3.17 (m, 2H), 5.15 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.01 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.44 (br t, 1H), 8.53 (m, 3H), 10.70 (br s, 1H); Mass spectrum MH+ 468.
Reaction SMILES: CC[O-].[Na+].Cl.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](=[NH:11])[NH2:10].[C:17]([OH:25])(=[O:24])/[C:18](=[C:20](\[CH:22]=O)/[Br:21])/Br>CCO>[Br:21][C:20]1[C:18]([C:17]([OH:25])=[O:24])=[N:11][C:9]([C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[N:10][CH:22]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: N=C(N)c1c(F)cccc1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1nc(-c2c(F)cccc2F)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.68 M NaOEt in EtOH solution (3 eq) was added to an ice-bath cooled mixture of 2,6-difluorobenzimidamide hydrochloride (2 eq) in EtOH (0.1 M). The resulting mixture was allowed to warm to rt and stirred under N2 for 30 min. To the reaction mixture was added drop wise a solution of mucobromic acid (1 eq) in EtOH and the reaction was heated in a 50° C. oil bath for 2.5 hr. After cooling to rt the reaction mixture was concentrated in vacuo. H2O and 1.0 N NaOH were added and the aqueous mixture was washed with EtOAc. The aqueous phase was acidified to pH=4 with 1.0 N HCl then extracted with EtOAc. Combined organic extracts were washed once with brine, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-bromo-2-(2,6-difluorophenyl)pyrimidine-4-carboxylic acid. The crude product was used for the next step without further purification. LC/MS (m/z): 316.9 (MH+). LC: Rt: 2.426 min.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]1([OH:51])[CH2:42][CH:41]2[CH2:43][CH2:44][CH:38]1[CH:39]=[C:40]2[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[N:34]([CH2:35][CH2:36][C@:37]1([OH:51])[CH2:42][C@H:41]2[CH2:43][CH2:44][C@@H:38]1[CH:39]=[C:40]2[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH3:33])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CNCCC1(O)CC2CCC1C=C2c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1)C(=O)CCNC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
To a solution of 159 mg of BOC-beta-alanine in 4 mL DCM were added 0.36 mL DIPEA and 113 mg of HOBt. After stirring for 15 min, 300 mg of rac-(1R*,2R*,4R*)-2-(2-methylamino-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 4 mL DCM were added followed by 161 mg of EDCI. The resulting suspension was stirred for 2 h at rt, then quenched with water. The water phase was reextracted with DCM, the combined organic phases were washed with sat. aq. NaHCO3, dried and concentrated in vacuo. The residue was purified by preparative TLC with EtOAc to give 168 mg of rac-(2-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-carbamoyl}-ethyl)-carbamic acid tert.-butyl ester as white foam.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].CN(C=O)C.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CCOC(C)=O>[Si:27]([O:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
(R)-tert-butyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (21) (4.4 g, 17.5 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by DMF (35 mL) and cooled to 0° C. via an ice bath. Next, TBDMSCl (2.9 g, 19.3 mmol, 1.1 equiv.) and imidazole (2.4 g, 35.1 mmol, 2.0 equiv.) were added to the reaction flask. The solution was stirred at 0° C. for 1 h and then allowed to warm to rt, stirring an additional 2 h. The reaction solution was transferred to a 500 mL separatory funnel with EtOAc (150 mL). The mixture was washed with 1% HCl (3×40 mL), sat. NaHCO3 (1×40 mL), and sat. NaCl (2×40 mL). The organic layer was separated and dried over Na2SO4. The solution was concentrated on a rotary evaporator and dried under vacuum to give 5.9 g (93%) of 22 as a colorless oil. Rf=0.54 (50% EtOAc/hexanes); [α]D23.5=+3.55 (c 1.22, MeOH); IR (film) 3437, 3324, 2953, 2929, 2884, 2856, 1715, 1666, 1496, 1471, 1365, 1253, 1171, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.34 (br d, J=8.5 Hz, 1H, carbamate-NH), 4.73 (br s, 1H, Boc-NH—CH), 3.83 (m, 1H, CH—CH2), 3.77 (m, 1H, CH—CH2), 3.73 (s, 3H, N—OCH3), 3.19 (s, 3H, NCH3), 1.41 (s, 9H, Boc-t-butyl-CH3), 0.84 (s, 9H, Si-t-butyl-CH3), 0.00 (s, 6H, Si—(CH3)2); 13C NMR (125 MHz, CDCl3) δ 170.9, 155.5, 79.7, 63.6, 61.6, 52.6, 32.3, 28.5, 25.9, 18.4, −5.4; LRMS (ESI-MS m/z): Mass calcd for C16H34N2O5Si [M]+, 362.54. Found 363. Anal. calcd for C16H34N2O5Si: C, 53.01; H, 9.45; N, 7.73. Found: C, 53.26; H, 9.63; N, 7.68.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11](C(OC)=O)[C:12]([O:14][CH3:15])=[O:13].[Na+].[Cl-]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a stirred solution of dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (5.0 g, 18.5 mmol, 1.0 eq) in DMSO (30 mL) was added NaCl (1.07 g, 18.5 mmol, 1.0 eq) and water (0.5 mL) and stirred at 120° C. for 3 h. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (50 mL×2), washed with brine, dried over Na2SO4 and the solvent evaporated. The crude residue was purified by CC using PE/EtOAc (19:1) to get methyl 2-(2-fluoro-4-nitrophenyl)acetate (2.5 g, 64%) as a viscous oil (TLC system: EtOAc/PE (1:4), Rf: 0.55).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH2:14][C:7]1=2>>[CH3:5][O:4][N:3]([CH3:2])[C:16]([NH:15][CH:11]1[C:8]2[CH:9]=[CH:10][S:6][C:7]=2[CH2:14][CH2:13][CH2:12]1)=[O:17]
Reactant: O=C=NC1CCCc2sccc21
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)NC1CCCc2sccc21

Procedure:
Following the procedure described in Example 6, N,O-dimethyl hydroxylamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate are allowed to react to give 1-methoxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is crystallized from acetone-hexane-ether to give product melting at 60° C. to 62.5° C.
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:14]
Reactant: CC1=NC(C)(C)SC1=NO
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNC(=O)ON=C1SC(C)(C)N=C1C
Reaction time: 16 h

Procedure:
20.0 g (0.126 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are dissolved in 100 ml of chloroform. To the solution are added 15 ml (0.252 mol) of freshly distilled methyl isocyanate as well as 3 drops of triethylamine. The mixture, which warms slightly after a short time, is left to stand at room temperature for 16 hours. Subsequently, the slightly turbid solution is filtered, and the solvent and excess methyl isocyanate are distilled off in vacuo. The oily residue is purified chromatographically on 250 g of silica gel using ethyl acetate/n-hexane (1:1) for the elution. The solvent is removed by evaporation, and the resulting residue is recrystallized from methyl chloride/n-hexane/diethyl ether to yield 5-oxo-2,2,4-trimethyl-3-thiazoline O-(methylcarbamoyl)oxime as white crystals, m.p. 90°-92° C.