Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C([Mg]Br)C.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[N:15]=[CH:14]2.CN([CH:24]=[O:25])C>C1(C)C=CC=CC=1.C1COCC1>[CH3:20][N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH:24]=[O:25])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: Cn1ncc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: CC[Mg]Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1ncc2cc(C=O)ccc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A suspension of n-BuLi (7.33 mL, 11.73 mmol) and ethylmagnesium bromide (5.76 mL, 5.76 mmol) in 30 mL toluene was stirred at −30° C. for 30 min, then 5-bromo-1-methyl-1H-indazole (2.25 g, 10.66 mmol) in 5 mL THF was added. After stirring at −10° C. for 1 hour, anhydrous DMF (4.95 mL, 64.0 mmol) was added at −10° C. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with 1N HCl and concentrated in vacuo. The residue was diluted with water, extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexane:EtOAc=10:1) to give the title compound as a white solid (1.37 g, 76%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.02 (s, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.78 (d, 1H), 4.09 (s, 3H). LCMS (method A): [MH]+=161, tR=4.00 min.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@@H:13]2[C@@H:17]3[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH2:40][CH2:41][C:42]([NH:44][NH2:45])=[O:43])[CH:33]=4)[N:16]3[C:15](=[O:46])[O:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)(O)[O-].[Na+].O.[N:55]#[C:56]Br>O1CCOCC1>[NH2:55][C:56]1[O:43][C:42]([CH2:41][CH2:40][C:34]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:32]([C:23]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:22]=3[C@H:21]3[N:16]4[C:15](=[O:46])[O:14][C@H:13]([C:5]5[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:48])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=5)[C@@H:17]4[CH2:18][CH2:19][CH2:20]3)[CH:33]=2)=[N:44][N:45]=1
Reactant: N#CBr
Reactant: COc1ccc(CCC(=O)NN)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CCC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CCc2nnc(N)o2)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CCC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Reaction time: 0.08 h
Yield: 65333.3 %

Procedure:
To 3-[2′-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanehydrazide (10 mg, 0.015 mmol) in dioxane (1 mL) was added sodium bicarbonate (2.4 mg, 0.029 mmol) followed by water (0.2 mL). The system was sealed and cyanogen bromide (5.8 mL, 0.029 mmol) was added at room temperature. The reaction was complete in 5 minutes and the solvent was removed before the crude material was purified by HPLC to yield (1R,5S,8aS)-5-{5′-[2-(5-amino-1,3,4-oxadiazol-2-yl)ethyl]-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl}-1-[3,5-bis(trifluoromethyl)phenyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (7 mg, 9.80 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1:1 ratio. 1H NMR (500 MHz, CDCl3) δ8.45 (br s, 1H), 8.3 (br s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.75 (m, 5H), 7.38 (t, J=8.5 Hz) 7.2 (m, 2H), 7.0 (m, 2H), 5.55 (d, J=8.9 Hz, 1H), 5.40 (d, J=8.9 Hz, 1H), 5.38 (m, 1H), 5.25 (m, 1H), 4.2 (m, 1H), 3.95 (m, 1H), 3.82 (s, 3H), 3.8 (s, 3H), 3.2-3.1 (br s, 4H), 2.2 (m, 1H), 2.12 (m, 1H), 1.80 (m, 4H). MS ESI calc'd. for C33H28F9N4O4 [M+H]+ 715.2. found 715.3. RTA (95% HS): 1319 nM
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:51])=[CH:43][CH:42]=1.Cl>ClCCl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C:21]([NH:20][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][CH2:49][C:50]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:51])=[CH:45][CH:46]=2)=[O:16])=[CH:13][CH:12]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(CCCc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCCC(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoic acid (2.96 g) in dichloromethane (20.0 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.80 g), benzyl 4-(4-hydroxyphenyl)butanoate (2.00 g), and N,N-dimethyl-4-aminopyridine (286 mg), followed by stirring at room temperature overnight. To a reaction solution was added 1 M hydrochloric acid, followed by concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-[4-(benzyloxy)-4-oxobutyl]phenyl 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoate (3.98 g).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ncn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)pyrimidin-4-yl)propanoate (233 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (2.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered through silica gel and the solvent was evaporated under reduced pressure to give the title compound (214 mg) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:16][CH:15]=1)[C:8]([OH:10])=[O:9])=[O:5].[OH-].[Na+:36]>CO>[Na+:36].[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]2[N:22]=[CH:23][CH:24]=[CH:25][N:26]=2)=[CH:18][CH:19]=1)[C:8]([O-:10])=[O:9])=[O:5]
Reactant: CC(C)N(c1ccc(/C=C/C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(c1ccc(/C=C/C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)[O-])cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (390.4 mg) in methanol (15 ml), 1N aqueous sodium hydroxide solution (0.782 ml) was added, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated to dryness to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid sodium salt (388.8 mg). IR(KBr)cm−1: 3386, 2974, 1585, 1549, 1509, 1455, 1292, 1122, 968, 798, 780.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 78 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-chloroaniline provided the title compound (78% yield). 1H NMR (DMSO-d6) δ 2.34 (s, 3H, CH3), 6.10 (s, 1H, Ar), 6.45 (s, 2H, NH2), 7.30-7.33 (m, 3H, Ar), 7.37 (dd, 1H, J=8.1 Hz, J=2.3 Hz, Ar), 7.41 (d, 1H, J=2.2 Hz, Ar), 7.80-7.83 (m, 2H, Ar), 9.35 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][C@@H:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C@H:13]([CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: C[C@@H](NC(=O)Nc1ccc([N+](=O)[O-])cc1O)c1ccccc1
Yield: 70.9 %

Procedure:
(R)-N-(2-Hydroxy4-nitrophenyl)-N′-(methylbenzyl)urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2.0 mmol) and (R)-methyl benzyl isocyanate (2 mmol) according to the procedure in General Method A. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (427 mg, 71%). EI-MS m/z 300(M−H)−
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:3]1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][N:4]1[CH2:3][CH:2]([OH:1])[C:6]2([CH2:7][CH2:8]2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: OCCCN1CC(O)C2(CC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propanol (1.14 g, 6.67 mmol) and Et3N (1.35 g, 13.34 mmol) in CH2Cl2 (20 mL) was added methanesulfonyl chloride (1.15 g, 10 mmol) dropwise at 0° C. The reaction was then stirred at 0° C. for 3 hrs. The reaction mixture was washed with cold water (10 mL) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound as orange oil. The crude product was used for the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[OH-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>C1COCC1>[C:33]([O:32][C:30](=[O:31])[CH2:29][O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([C:18]4[CH:25]=[CH:24][CH:23]=[C:20]([C:21]#[N:22])[CH:19]=4)[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:4][CH2:3]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: N#Cc1cccc(-c2nc(N3CCC(O)CC3)cc3cccnc23)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC1CCN(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[6-(4-Hydroxy-piperidin-1-yl)-[1,7]naphthyridin-8-yl]-benzonitrile (570 mg, 1.73 mmol) THF (5 ml) is added to NaOH (60% dispersion in mineral oil) (166 mg, 6.9 mmol) suspended in THF (20 ml) at 0° C. Stirred at 0° C. for 30 minutes. tert-Butyl bromoacetate (0.51 ml, 3.45 mmol) is added and the reaction mixture is stirred at 0° C. for 5 minutes then at room temperature for 18 hours. Further tert-butyl bromoacetate (0.25 ml, 1.73 mmol) and NaOH (80 mg, 3.3 mmol) are added and the reaction mixture is stirred at room temperature for 2 hours. After cooling to 0° C. water (20 ml) is added and the mixture is extracted with ethyl acetate (×1). The ethyl acetate extract is dried (MgSO4), filtered and concentrated. Purification by chromatography on silica gel, eluting with 10-20% ethyl acetate in isohexane, gives the product. MS (ES+) Observed [M+H]+ 445.12
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]([NH2:12])=[O:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N:9]1[C:10](=[O:11])[N:12]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=12
Reactant: O=C1CCCCC1Br
Reactant: NC(N)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1N=C2CCCCC2=N1
Temperature: 25 °C

Procedure:
A mixture of 2-bromocyclohexanone (6.23 g, 0.035 mol) and urea (2.1 g, 0.035 mol) is refluxed in a solution of ammonium acetate (10 g), acetic acid (15 mL) and water (50 mL) for 4 h. Upon cooling slowly to room temp, white crystals form in the reaction vessel. The solid is collected by suction filtration, washed thoroughly with water and ether, and dried in vacuo to afford 4,5,6,7-tetrahydro-2-benzimidazolone (Compound 7).
Reaction SMILES: [CH2:1]([N:8]([C:12]1[C:13]2[CH2:34][NH:33][CH2:32][CH2:31][C:14]=2[N:15]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[N:17]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]([C:12]1[C:13]2[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][C:14]=2[N:15]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[N:17]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCO)Cc4ccccc4)n2)CNCC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCO)Cc4ccccc4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
2-(Benzyl(2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)ethanol (95 mg, 0.21 mmol) was dissolved in methanol (3 mL). Acetic acid (0.012 mL, 0.21 mmol) was added followed by formaldehyde (0.016 mL, 0.21 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (13.10 mg, 0.21 mmol) was added. The solvent was evaporated after 1 h and the crude purified by preparative HPLC yielding 2-(benzyl(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)ethanol (8.60 mg, 7.8%) as acetate salt. MS (ES+) m/z 470.3 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][CH2:29]C)=[O:27]>CC(C)=O>[CH3:29][O:28][C:26]([CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1)=[O:27]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
4.5 g (0.02 mol) of benzyl p-hydroxybenzoate were suspended in about 60 ml of acetone together with 9.7 g (0.03 mol) of cesium carbonate and treated with 2.3 ml (0.025 mol) of ethyl bromoacetate. The mixture was then refluxed until reaction was complete. For working-up, the reaction solution was filtered through a clarifying layer and the filtrate was concentrated to dryness. The residue was taken up in ethyl acetate and the mixture was washed three times each with 10% strength citric acid solution and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was recrystallized from diisopropyl ether/heptane. Yield: 5.5 g.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>[OH-].[Na+].C(O)C>[OH:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH:10][CH:11]([OH:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCCCCC(=O)C=CC1CCC(=O)C1CCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)C=CC1CCC(O)C1CCCCCC(=O)O
Temperature: 10 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
A solution of sodium borohydride (0.2 g., 0.005 mole) in 0.2N aqueous sodium hydroxide (2 ml.) was added dropwise to a solution of 6-[2-oxo-5-(3-oxo-1-octenyl)cyclopentyl]hexanoic acid (0.61 g., 0.0019 mole) in ethanol (15 ml.) and N aqueous sodium hydroxide (1.9 ml., 0.0019 mole). The resulting solution was stirred for 1 day and then the ethanol was removed in vacuo. A small quantity of water was added and the solution was extracted twice with diethyl ether (to remove non-acidic material). The aqueous solution was covered with a layer of diethyl ether and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid, cooling the solution to about 10°C. The ether layer was separated and the aqueous layer extracted twice more with diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated to give 6-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]-hexanoic acid (0.53 g., 86%) which required no further purification. N.M.R. (approximately 10% solution in deuterochloroform) 0.82 δ (triplet J=51/2c/s, terminal CH3), 1.32 δ (multiplet, chain CH2), 1.63 δ (multiplet CH--C=C), 2.30 δ (triplet J=61/2c/s, CH2CO), 3.6-4.3 δ (overlapping multiplets, HCOH), 4.90 δ (singlet OH and COOH), 5.41 δ (multiplet, CH=CH). (Found: C, 69.7: H, 10.5. C19H34O4 requires C, 69.9; H, 10.5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:29][CH:30]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: O=C(OCc1ccc(OC(F)(F)F)cc1)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 67.5 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (15 g, 68.93 mmol) and 4-trifluoromethoxybenzyl piperazine-1-carboxylate (25.17 g, 82.72 mmol) in DMF (75 ml) was stirred at 65-70° C. for 20 hours. The reaction mixture was allowed to return to room temperature and poured into water (475 ml), and extracted with ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) again. The organic phases were combined, washed with water (400 ml) 3 times and a saturated saline solution (100 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to afford 4-trifluoromethoxybenzyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate (29.98 g, yield 83%) as a yellow oil.
Reaction SMILES: [N+](C1C=CC=C[C:5]=1[C:6](Cl)=[O:7])([O-])=O.[C:13]([NH:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:6](=[O:7])[CH3:5])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: CC(=O)Nc1ccccc1C(=O)NC(C)(C)C

Procedure:
The method of Example 3 is repeated using 2-nitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2-nitrobenzamide (CPI1035).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:40]1[CH2:45][CH2:44][C:43]2([O:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]3[CH:55]=[CH:56][CH:57]=[C:46]23)[CH2:42][CH2:41]1.CCN(CC)CC>CN(C=O)C>[N:40]1([C:9]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)=[O:11])[CH2:41][CH2:42][C:43]2([O:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]3[CH:55]=[CH:56][CH:57]=[C:46]23)[CH2:44][CH2:45]1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cc1
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCC(F)(F)F)cc1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2,2,2-Trifluoroethoxy)benzoic acid (22 mg, 0.10 mmol), HATU (42 mg, 0.11 mmol), and DMF (0.8 mL) were combined and allowed to stir at room temperature for 10 minutes. The activated acid was then added to spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (28 mg, 0.10 mmol) followed by the addition of Et3N (84 μL, 0.60 mmol). The reaction mixture was stirred at room temperature for 17 h before it was filtered and purified by prep-HPLC (5 mM HCl/H2O and MeOH) to provide spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-(2,2,2-trifluoroethoxy)phenyl)methanone. ESI-MS m/z calc. 442.2, found 443.4 (M+1)+. Retention time: 2.05 minutes (4 min run).
Reaction SMILES: [NH2:1][CH:2]([CH3:12])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1.CS([C:16]1[N:21]=[C:20]([NH:22][C:23]2[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:24]=2)[CH:19]=[CH:18][N:17]=1)=O.CCOC(C)=O>CN1C(=O)CCC1>[OH:11][CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][CH:2]([NH:1][C:16]2[N:21]=[C:20]([NH:22][C:23]3[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:24]=3)[CH:19]=[CH:18][N:17]=2)[CH3:12])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)Cc1cccc(CO)c1
Reactant: Cn1c(Nc2ccnc(S(C)=O)n2)nc(-c2ccccc2)cc1=O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(Cc1cccc(CO)c1)Nc1nccc(Nc2nc(-c3ccccc3)cc(=O)n2C)n1
Temperature: 100 °C

Procedure:
A mixture of [3-(2-amino-propyl) -phenyl]-methanol (300 mg, 1.8 mmol) and 2-(2-methanesulfinyl-pyrimidin-4-ylamino) -3-methyl-6-phenyl-3H-pyrimidin-4-one (300 mg, 0.9 mmol) in NMP (8 mL) was heated to 100° C. for 16 h. The reaction was cooled to room temperature and EtOAc was added. The mixture was then washed with H2O three times, brine once, dried (MgSO4), filtered, concentrated under vacuum, and purified by preparative-scale TLC to give the product. M+1: 443.