Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:44][C@H:43]1[CH2:67][CH:68]1[NH:72][C:71](=[O:73])[NH:70][C:69]1=[O:74])=[O:41])[CH:37]=[CH2:38]>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1[CH2:67][CH:68]1[NH:72][C:71](=[O:73])[NH:70][C:69]1=[O:74])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1NC(=O)NC1=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3NC(=O)NC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 31 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (220 mg, 0.440 mmol) and (2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)-4-tritylthiopyrrolidine diastereomer B (220 mg, 0.406 mmol, compound of Reference Example 29) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer B (70 mg, yield: 31%).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4](N)[CH2:3]1.[CH2:20]=O.[C:22]([BH3-])#[N:23].[Na+]>CO.C1COCC1>[F:1][C:2]1([F:19])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([N:23]([CH3:22])[CH3:20])[CH2:3]1
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(N)CC(F)(F)C1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2c([N+](=O)[O-])cnn2C)CC(F)(F)C1
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.96 g, 2.56 mmol) in MeOH (3 mL) was added HCl in 1,4-dioxane (4 M, 12.8 mL, 51.2 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in DCM (30 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (30 mL), dried over Na2SO4 and the solvent removed under reduced pressure to give 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was dissolved in MeOH/THF (1:1, 50 mL) and treated with formaldehyde (38% in water, 0.45 mL, 6.21 mmol). After 5 min, sodium cyanoborohydride (0.39 g, 6.21 mmol) was added portionwise and the resulting mixture stirred for 5 hr. Additional formaldehyde (38% in water, 0.45 mL, 6.21 mmol) and sodium cyanoborohydride (0.39 g, 6.21 mmol) were added and the resulting mixture was stirred for 60 hr. The solvents were removed under reduced pressure and the crude was purified via silica gel column chromatography (0-10% MeOH/DCM) to give 6,6-difluoro-N,N-dimethyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine as a yellow oil (0.64 g, 82% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (m, 1H), 3.82 (s, 3H), 3.70-3.57 (m, 2H), 3.42-3.29 (m, 1H), 3.24-3.05 (m, 1H), 3.04-2.98 (m, 1H), 2.51-2.40 (m, 1H), 2.35-2.29 (m, 6H), 2.20-2.01 (m, 2H), 1.97-1.82 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][Br:12])[C:4]=2[O:3]1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br-:12].[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][P+:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[O:3]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)Cc2cccc(CBr)c2O1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2cccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2O1
Product: [Br-]

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 2, using 11.8 grams (0.049 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl bromide and 13.0 grams (0.050 mole) of triphenylphosphine in about 100 mL of toluene, yielding (2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)triphenylphosphonium bromide.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:4][S:5][CH:6]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[C:2]([Br:1])=[CH:6][S:5][N:4]=1)=[O:15]
Reactant: NCCSCc1nscc1Br
Reactant: CN=C=O
Product: CNC(=O)NCCSCc1nscc1Br

Procedure:
Reacting 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole with methyl isocyanate by the procedure of Example 24 gives the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI.CN([CH:26]=[O:27])C>>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)[C:5]([O:27][CH3:26])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1cc(O)cc(C(=O)O)c1
Agent: [Cs+]
Solvent: CI
Product: COC(=O)c1cc(OC)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Hydroxy-5-methylsulfonylbenzoic acid (D13) was dissolved in DMF (42 ml) and treated with caesium carbonate (14.1 g) and methyl iodide (8.6 ml) The mixture was sonicated under argon for 45 min. and stirred for 3 h at room temperature. The DMF was evaporated in vacuo and the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The aqueous layer was re-extracted twice with ethyl acetate and the combined extracts were washed with sodium bicarbonate solution, sodium thiosulfate solution, water and brine, dried (Mg SO4) and evaporated to a semi solid. Trituration with ether gave D14 (2 crops, 2.94 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:37]1C=CC(O)=CC=1C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]2)=[C:15]([CH3:37])[CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Reactant: Cc1cc(O)ccc1Br
Product: Cc1cc(OCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC2CCCC2)ccc1B1OC(C)(C)C(C)(C)O1

Procedure:
Synthesised by analogous methods to Intermediate 2b, using 4-bromo-3-methyl-phenol at Stage 6 of Scheme 2. m/z 504 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:20])[N:3]=1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([C@:29]23[CH2:34][C@H:33]2[CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CC(O)=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:31]3[CH2:32][C@H:33]4[C@:29]([C:26]5[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:35])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1ccc(-c2cn(CCC=O)c(=O)[nH]c2=O)c(Cl)n1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)c(Cl)n1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
A solution of 3-[5-(2-chloro-6-methylpyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep109, 78 mg, 0.26 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 60 mg, 0.26 mmol), and AcOH (19 μl) in dichloroethane (4 ml) was cooled to 0° C. NaBH(AcO)3 (58 mg, 0.26 mmol) was added portionwise. The mixture was stirred at 0° C. for further 2 hours and then basified with 1N NaOH. The product extracted with DCM, the organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred overnight in presence of PS-isocyanate. The mixture was filtered and the solvent was evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) and then was passed over a SCX cartridge to give 20 mg of the free base of title compound (15% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].CCN(C(C)C)C(C)C.[CH2:23]([O:26][C:27](Cl)=[O:28])[CH:24]=[CH2:25].Cl>C(Cl)Cl.O>[CH:7]1([NH:6][C:4](=[O:5])[CH:3]([OH:10])[CH:2]([NH:1][C:27](=[O:28])[O:26][CH2:23][CH:24]=[CH2:25])[CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9]1
Reactant: C=CCOC(=O)Cl
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)NC(CCC)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (10 g, 53.7 mmol), DIEA (28 mL, 161 mmol, 3 eq.) in methylene chloride (250 mL) was added dropwise at 0° C. to a solution of allylchloroformate (6.8 mL, 64.4 mmol, 1.2 eq.) in DCM (50 mL). The reaction solution was warmed to room temperature and stirred for 4 hours. Water (300 mL) was then slowly added followed by aqueous HCl (1.0 N, 300 mL). The phases were separated and the organics washed with saturated aqueous NaHCO3 (300 mL), brine (300 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting off-white solid was recrystallized from 30% hexanes in EtOAc (120 mL) to yield the title compound M1A as a white solid. The mother liquor was concentrated, in vacuo, and recrystallized from 50% hexanes in EtOAc to yield another 4.04 g of MIA. The mother liquor from the second recrystallization was concentrated in vacuo on Celite®, and the resulting Celite® plug was purified by flash chromatography (Isco Companion®, SiO2, DCM to 70% EtOAc in DCM) to give 1.46 g of MIA. The total amount of compound MIA was 13.4 g (yield 93%). (Rf˜0.40 in 1:1 DCM:EtOAc, CAM detection).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[C:10]=1[CH:15]([CH3:17])[CH3:16].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:14][C:11]1[C:10]([CH:15]([CH3:17])[CH3:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[O:13][N:12]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)c1c(O)noc1-c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(F)cc1F
Yield: 78.2 %

Procedure:
5-(2,4-Difluorophenyl)-3-hydroxy-4-isopropylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.16 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.25 g, 78%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[C:32]([O:34]C)[C:31]([F:36])=[C:30]([F:37])[CH:29]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[C:32]([OH:34])[C:31]([F:36])=[C:30]([F:37])[CH:29]=1
Reactant: COc1cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)c(F)c(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
(S)-2-(1-((6-Amino-5-(3,4-difluoro-5-methoxyphenyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (87 mg, 0.17 mmol) was dissolved in 3 mL dichloromethane. A solution of boron tribromide (1M, 520 μl, 0.52 mmol) was added dropwise and the reaction was stirred at room temperature overnight. Further tribromide (1M in dichloromethane, 260 μl, 0.26 mmol) was added dropwise and stirred for 2 h more. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1® Purification System to give 25 mg (44% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][CH:5]([CH3:13])[C:6](=O)[CH:7]=[CH:8][N:9](C)[CH3:10].[NH2:19][C:20]1N=C[NH:22][N:21]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][CH:5]([C:6]1[N:22]2[N:21]=[CH:20][N:19]=[C:10]2[N:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)C=CN(C)C
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: CC(Oc1ccc(Cl)cc1Cl)c1ccnc2ncnn12
Temperature: 25 °C

Procedure:
A solution of 4-(2,4-dichlorophenoxy)-1-(dimethylamino)-1-penten-3-one (2.9 g) in glacial acetic acid (25 ml) was added to a stirred solution of 3-amino-1,2,4-triazole (0.93 g) also in glacial acetic acid (25 ml). The mixture was heated under reflux for 5 hours and then cooled to room temperature. The mixture was then poured into 200 ml of ice-water and extracted with toluene. The toluene extracts were washed with a 10% aqueous solution of sodium hydrogen carbonate followed by water, then dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was triturated with cold diethyl ether and the solid was collected by filtration, followed by recrystallisation from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60° C.) to give 7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.02 g, (mp 137°-138° C.).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].C(O)=[O:29]>>[CH2:23]([O:22][P:20]([CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:29])[NH:10][C:9]([NH2:11])=[N:8][C:7]1=2)([O:25][CH2:26][CH3:27])=[O:21])[CH3:24]
Reactant: O=CO
Reactant: CCOP(=O)(COCCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Product: CCOP(=O)(COCCCOn1cnc2c(=O)[nH]c(N)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
6-Chloro-9-[3-(diethoxyphosphorylmethoxy)propoxy]-2-formamidopurine (1.5 g, 3.56 mmol) was heated at 100° C. for 2 h in 80% formic acid (15 ml) then evaporated under reduced pressure. The residue was taken up in methanol (15 ml) and 0.88 ammonia (15 ml) and stirred at 25° C. for 1 h then evaporated to dryness. Precipitation from hot water afforded 9-[3-(diethoxyphosphorylmethoxy)propoxy]guanine (0.69 g, 52%) as a pale yellow solid; νmax 3335, 1694, 1475, 1390, 1249, 1026 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz, (CH3CH2O)2), 1.90(2H, m, CH2CH2CH2), 3.68(2H, t, J6 Hz, CH2OCH2P), 3.83(2H, d, J8.3 Hz, CH2P), 4.03(4 H, m, (CH3CH2O)2), 4.31(2H, t, J6.6 Hz, CH2ON), 6.60(2H, br.s, D2O exchangeable, NH2) 7.95(1H, s, H-8), 10.50(1H, br.s, D2O exchangeable, NH); Found C, 41.90; H, 5.94; N, 18.65%; C13H22N5O6P requires: C, 41.60; H, 5 91; N, 18.61%.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:7])=[O:6])=[O:3].[CH3:8][C:9]([CH2:11][C:12]([CH3:14])=[O:13])=[O:10].CC(CC(C)=O)=O.[Co:22].C1(C)C=CC=CC=1.C(NCCNCCCC)CCC>O>[CH3:7]/[C:5](/[OH:6])=[CH:4]\[C:2]([CH3:1])=[O:3].[CH3:14]/[C:12](/[OH:13])=[CH:11]/[C:9]([CH3:8])=[O:10].[Co:22]
Reactant: CC(=O)CC(C)=O
Agent: [Co]
Agent: CCCCNCCNCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)/C=C(/C)O
Product: CC(=O)/C=C(\C)O
Reaction time: 1 h

Procedure:
Several secondary diamine adducts of cobalt(II) acetylacetonate were prepared by adding 1.04 grams (4 millimoles) of cobalt acetylacetonate into a 50 ml two-necked flask. There was then added 30 ml of freshly distilled toluene along with a stir bar. The mixture was heated and residual water bound to the cobalt acetylacetonate was azotropically removed. When the distillation temperature reached 110° C., heating of the mixture was discontinued. There was then added 0.76 grams (4.4 millimoles) of N,N'-dibutylethylenediamine when the refluxing had subsided. The solution was stirred for one hour and allowed to cool. The product was crystallized from the solution after removal of some of the solvent by rotoevaporation. Recrystallization was effected from a hexane/methylenechloride mixture at -20° C. The same procedure was repeated except that in place of N,N'-di-t-butylethylenediamine there was added N,N'-t-N-butylethylenediamine. The following results were obtained:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(C(F)(F)F)c1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-trifluoromethylphenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 447 ([M+H]+); Anal. Calcd for C23H12F6N2O: C, 61.89; H, 2.71; N, 6.28. Found: C, 61.70; H, 2.66; N, 6.14.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[Cl:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:5]=[O:7]
Reactant: Nc1cccc(F)c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1cccc(F)c1Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
A solution of acetic anhydride (10 mL, 106 mmol) and formic acid (30 mL, 795 mmol) was stirred at room temperature for 10 mins. 2-Chloro-3-fluoroaniline (2.9 g, 20 mmol) was added and the reaction mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, the solvents were removed in vacuo and the residue was redissolved in DCM (100 mL) and was washed with sat aq. NaHCO3 until the aqueous phase had a measured pH of 8. The organic layer was further washed with water (2×100 mL), separated and dried over MgSO4. Filtration and concentration in vacuo gave N-(2-chloro-3-fluoro-phenyl)-formamide (3.3 g, 95%) as a colorless solid which did not require further purification. MS (M+H)+: 173.9, tR=2.04 min (method 1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](ON=C2CCCC2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21](S(O)(=O)=O)=CC=1.C(O)(=[O:31])C>>[N+:1]([C:4]1[C:5]2[O:31][C:21]3[CH2:28][CH2:18][CH2:23][C:22]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc(ON=C2CCCC2)cc1
Agent: Cl
Product: O=[N+]([O-])c1cccc2c3c(oc12)CCC3
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
The core molecule was synthesized following method A. Potassium t-butoxide (12 g, 110 mmol) was added in portions to a cooled (0° C.) solution of cyclopentanone oxime (9.9 g, 100 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-fluoro-4-nitrobenzene (14 g, 100 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water to provide cyclopentanone O-(4-nitro-phenyl)-oxime (17 g). Cyclopentanone O-(4-nitro-phenyl)-oxime (14 g, 62 mmol) was dissolved in glacial acetic acid (40 mL) and 1.9 N hydrochloric acid (40 mL) was added. The reaction mixture was stirred at room temperature for 50 minutes and then concentrated. The solid was mixed with water (250 mL) and allowed to stand for 1 hour. The crude mixture was extracted with ethyl acetate and the combined organic phases were dried (Na2SO4) and concentrated. The crude material was dissolved in toluene (350 mL) and p-toluenesulfonic acid (2.0 g, 10 mmol) was added. The reaction mixture was heated to reflux for 4 hours and water was removed with a Dean-Stark trap. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated to give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (10 g). A mixture of give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (5.4 g, 27 mmol) and Raney nickel (˜5 g wet weight) in ethanol (50 mL) was hydrogenated at 50 PSI on a Parr shaker for 2 hours. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by column chromatography to provide 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (4.0 g). Mp 86.5-88.5° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([OH:24])[CH:22]=2)[N:17]=[CH:16][N:15]=1.[CH3:27][N:28]1[CH2:32][CH2:31][CH:30](O)[CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([O:24][CH:30]3[CH2:31][CH2:32][N:28]([CH3:27])[CH2:29]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: CN1CCC(O)C1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OC1CCN(C)C1
Reaction time: 1 h
Yield: 29.6 %

Procedure:
Diethyl azodicarboxylate (793 mg, 4.56 mmol) was added portionwise at room temperature to a stirred suspension of 4-chloro-7-methoxyquinazolin-6-ol (800 mg, 3.80 mmol), 1-methylpyrrolidin-3-ol (422 mg, 4.18 mmol) and triphenylphosphine (1.3 g, 4.96 mmol) in dichloromethane (16 ml). The reaction mixture was stirred for 1 hour and then a further portion of diethyl azodicarboxylate (360 ul) and triphenylphosphine (0.65 mg) were added. The mixture was stirred for 1 hour and the resulting orange solution was purified directly by silica gel chromatography eluting with a 0-10% mixture of methanol in dichloromethane to 4-chloro-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]quinazoline (330 mg, 28% yield) as a tan coloured solid: