Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1
Reactant: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Yield: 73.7 %

Procedure:
To a solution of 4-chloro-2-(2-methoxyphenyl)quinazoline (1.0 g, 3.7 mmol) in 40 mL CH2Cl2 at −78° C. was added 5 equivalents of 1 M BBr3 dropwise. After complete addition the cooling bath was removed and the reaction was quenched with NaHCO3 after 90 minutes. The product was extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 60:40 CH2Cl2: hexanes gave 2-(4-chloroquinazolin-2-yl)phenol (700 mg, 74%). LC/MS: m/z 257.1 (M+H)+ at 3.75 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (m, 1H), 8.24 (m, 3H), 7.89 (m, 1H), 7.49 (m, 1H), 7.05 (m, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19]Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=[O:23])C.[K+].O.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][OH:23])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In N,N-dimethylformamide (10 ml), 4-tert-butoxycarbonyl-1-[(3-chloro-1-propyl)sulfonyl]piperazine (1.18 g) was dissolved, followed by the addition of potassium acetate (1.06 g). After stirring at room temperature for 2 hours, the reaction mixture was stirred under heat at 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, followed by the addition of water and a saturated aqueous solution of sodium bicarbonate. After stirring, the organic layer so separated was washed with a 5% aqueous citric acid solution, water and saturated saline. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran (20 ml). To the resulting solution, water and lithium hydroxide monohydrate (221 mg) were added, followed by stirring at room temperature for 18 hours. Ethyl acetate and saturated saline were added to the reaction mixture to separated an organic layer. From the water layer, another organic layer was extracted with ethyl acetate. The organic layers were combined together, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate an hexane, whereby the title compound (944 mg, 84%) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[CH3:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH2:39]Cl>CN(C=O)C.CCOCC.Cl>[CH3:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH2:39][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:23])[C:4]([OH:3])=[O:32])=[CH:12][CH:11]=2)[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: Cc1ccc(CCl)cc1C
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccc(F)cc4)C(=O)O)cc3)N(C)C2=O)cc1C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.07 mL of 3,4-dimethylbenzyl chloride is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 54 mg (56%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.18 (d, 2H, J=8.4 Hz), 7.06 (d, 1H, J=7.6 Hz), 7.00 (s, 1H), 6.97-6.85 (m, 5H), 6.75 (d, 2H, J=8.4 Hz), 4.34, 4.25 (ABq, 2H, J=15.0 Hz), 4.31 (bs, 1H), 3.98-3.90 (m, 2H), 3.69-3.61 (m, 1H), 3.39 (t, 1H, J=8.7 Hz), 3.25, 3.11 (ABq, 2H, J=14.0 Hz), 3.00 (t, 1H, J=8.7 Hz), 2.84 (s, 3H), 2.29-2.17 (m, 1H), 2.22 (s, 6H), 1.94-1.87 (m, 1H), 1.37 (s, 3H). HRMS (ES+) m/z exact mass calcd for C31H36N2O5F (m+1) 535.2608, found 535.2614.
Reaction SMILES: Cl.NO.[C:4]([SiH2:8][O:9][C:10]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:12]=[C:13]([CH:17]=O)[O:14][C:15]=1[CH3:16])([CH3:7])([CH3:6])[CH3:5].CC1OC=CC=1CCO.[Cl-].ClC1N(C)C=C[N+:43]=1C>ClCCl.O.C(N(CC)CC)C>[C:4]([SiH2:8][O:9][C:10]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:12]=[C:13]([C:17]#[N:43])[O:14][C:15]=1[CH3:16])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1oc(C=O)cc1C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: Cn1cc[n+](C)c1Cl
Agent: Cc1occc1CCO
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1oc(C#N)cc1C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Hydroxylamine hydrochloride (1.11 g, 16.0 mmoles) and triethylamine (2.22 ml) were added to a solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbaldehyde from (i)(6.3 g, 16.0 mmoles) in dichloromethane (125 ml) and the mixture was stirred at room temperature for 17 hours. After cooling to 0° C., 2-Chloro-1,3-dimethylimidazolium chloride (2.81 g, 16.6 mmoles) and triethylamine (4.6 ml) were added and the yellow suspension was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with dichloromethane. The combined extracts were washed with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and water, and finally dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (silica, cyclohexane/diethyl ether 99:1 v/v as eluent) to afford 4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbonitrile as a viscous oil, (3.75 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1C(=O)C2=CC=CC=C2C1=O.[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1.C1(C2N=CN(CCCN)C=2)C=CC=CC=1.CC1N(CCCN)C=CN=1.C(C1N(CCCN)C=CN=1)C.N1C=CN=C1>>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])[CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1c[nH]cn1
Agent: CCc1nccn1CCCN
Agent: Cc1nccn1CCCN
Agent: NCCCn1cnc(-c2ccccc2)c1
Product: Cc1cn(CCCCN)cn1

Procedure:
The procedure of Example 2 was repeated using N-(4-bromobutyl)phthalimide and 4-methyl-1H-imidazole giving the desired intermediate. Preparation of 4-phenyl-1H-imidazole-1-propanamine, 2-methyl-1H-imidazole-1-propanamine and 2-ethyl-1H-imidazole-1-propanamine was accomplished by the procedure of Example 4 using the appropriate imidazole starting materials.
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N(CC)CC)C.ClC(OCC(C)C)=[O:37].NCCO>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:37])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: NCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 166.9 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.215 g, 0.58 mmol, 1.0 eq), and triethylamine (96 uL, 70 mg, 0.64 mmol, 1.20 eq), in acetonitrile (10 mL) was treated with isobutyl chloroformate (83 uL, 86 mg, 0.63 mmol, 1.1 eq) followed by 2-aminoethanol (69 uL, 70 mg, 1.15 mmol, 2.0 eq). Workup as above provided 127 mg (53%) of L-isoleucine, N-[1-(2-(2-hydroxyethylamine)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6](F)[CH:5]=[CH:4][N:3]=1.BrC1C=NC=C(Cl)C=1[CH2:24][O:25]C1CCCCO1.C([O-])([O-])=O.[Cs+].[Cs+]>CO>[Cl:1][C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([O:25][CH3:24])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccnc(Cl)c1COC1CCCCO1
Reactant: Clc1cncc(Br)c1COC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1ccnc(Cl)c1COC1CCCCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-chloro-4-fluoro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (0.20 g. 0.81 mmol) which was prepared according to the synthesis of 3-bromo-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine in anhydrous MeOH (4 mL) was added Cs2CO3 (0.54 g. 1.6 mmol). After vigorous stirring for 20 h at room temperature acedic acid (92 μL. 1.6 mmol) was added the solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and water (4 mL). The organic layer was dried over Na2SO4 filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 257.9 [M+H+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]3[CH2:14][C:13](=[CH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=4[Cl:25])[CH2:12]3)[CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[C:35]([O:39][C:40](=[O:49])[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH2:48])([CH3:38])([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]3[CH2:14][C:13](=[CH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([NH:48][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[NH:41][C:40](=[O:49])[O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:21])=[CH:18][C:17]=4[Cl:25])[CH2:12]3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzoic acid (0.26 g, 0.74 mmol) in DCM (25 mL) was added DIPEA (0.29 g, 2.22 mmol), tert-butyl-2-aminophenylcarbamate (0.27 g, 1.18 mmol) and HATU (0.37 g, 0.96 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the mixture was washed with saturated sodium bicarbonate (2×20 mL) and brine (1×15 mL). It was dried (Na2SO4), filtered and evaporated to give the crude product which was purified by column chromatography (10% MeOH: 90% DCM). After evaporation of pooled fractions of pure product, tert-butyl (2-(4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzamido)phenyl)carbamate (0.2 g) was isolated as an off-white solid. ES+(M+H)+ 543.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CN(C=O)C.[H-].[Na+].Cl[CH2:20][S:21][C:22]#[N:23]>O>[NH2:6][C:5]1[CH:7]=[C:8]([S:11][CH2:20][S:21][C:22]#[N:23])[CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Reactant: N#CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CSCSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of 3.4 g. of 2-nitro-5-mercaptoaniline in 20 ml. of DMF is treated with 0.5 g. of 100% sodium hydride, and 2.2 g. of chloromethylthiocyanate is added to the solution. After 30 minutes at 20°-25° C., the solution is diluted with water and extracted with chloroform. Removal of the chloroform leaves 1-amino- 2-nitro-5-(thiocyanatomethylthio)benzene.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.C1([NH3+])CCCCC1.[C:44]1([S-:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[P:51](=[S:54])([O-])[O-:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1([NH3+])CCCCC1.C1([NH3+])CCCCC1.O>N1C=CC=CC=1>[C:44]1([SH:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[P:51]([O:13][CH2:12][C@H:11]2[O:14][C@@H:7]([N:6]3[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]3=[O:16])[CH2:8][C@@H:9]2[OH:10])(=[S:54])[OH:52])[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: [O-]P([O-])(=S)[S-](c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: [NH3+]C1CCCCC1
Solvent: c1ccncc1
Solvent: O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COP(O)(=S)[SH](c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A solution of 500 mg (2.03 mmol) of 2'-deoxy-5-fluorouridine in 5 ml of pyridine was cooled to -10° C. to 0° C. in an ice-water bath. To this solution was added dropwise a mixture of 1.00 g (3.30 mmol) of 2,4,6-triisopropylbenzenesulfonylchloride, 1.36 g (3.56 mmol) of S,S-diphenylphosphorodithioate monocyclohexylammonium and 5 ml of pyridine over the period of 10 minutes. After the completion of the dropwise addition, the mixture was stirred at room temperature overnight. To this reaction mixture was added 100 ml of water. The mixture was extracted with 10 ml of chloroform repeatedly three times. The extract was washed with an aqueous solution of dilute hydrochloric acid and water in order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure The obtained residue was subjected to silica gel column chromatography with the use of a mixture of chloroform and methanol (9:1 v/v) as the eluent to give 599 mg of 2'-deoxy-5-fluorouridine 5'-(S,S-diphenylphosphorodithioate) in a glassy form (Yield 55%).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:17]2[CH:16]=[C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2>C(O)C>[OH:3][CH:4]1[C:17]2[CH:16]=[C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CCOC(=O)Cc1ccc2oc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc2c(c1)C(O)c1ccccc1O2
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
5.67 g (150 mmol) of sodium borohydride are added in portions to a solution of 14.2 g (50 mmol) of ethyl 9-oxo-9H-xanthene-2-acetate (Example 10d) in 130 ml of ethanol. The suspension is stirred at room temperature for 15 hours, subsequently diluted with 80 ml of ethanol and poured onto water. The product is extracted with ethyl acetate. The organic phases are washed with an aqueous saturated sodium chloride solution, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. The solid residue is suspended in ethanol, the suspension is filtered and the product is dried under a high vacuum. 6.1 g (43%) of ethyl 9-hydroxy-9H-xanthene-2-acetate, melting point 214°-219° C., results as a white powder.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])=[N+]=[N-]>O1CCOCC1.[Ni]>[NH2:1][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:12][CH:13]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)Nc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: NCC(=O)Nc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
A 2.0 g portion of this azide was dissolved in 40 ml of p-dioxane and subjected to hydrogenation with Raney nickel catalyst for 1.5 hours. The mixture was filtered, the filtrate concentrated to a residue and recrystallized from ethanol giving 944 mg of the desired product as white crystals, mp 181°-184° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)[CH:18]([CH3:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=1>C(O)C.[OH-].[K+].O>[CH2:12]([N:5]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:18]([CH3:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[NH:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(NCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(NCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
Dissolve 2-[[4-[3-[(6-amino-1-propyl-1,2,3,4-tetrahydro-3-propyl-2,4-dioxo-5-pyrimidinyl)amino]-2-methyl-3-oxopropyl]phenyl]amino]-acetic acid, 1,1-dimethylethyl ester (1.59 g, 3.18 mmol) in a mixture of ethanol (30 mL) and 15% potassium hydroxide (30 mL). Heat at 55° C. and stir for 5 hours. Cool, acidify and dilute with water (200 mL). Filter the precipitate and dry to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.ClC1C=CC=C(C(OO)=[O:19])C=1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:19])=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Product: [O-][n+]1ccc(Br)c2cc[nH]c21
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (25 mmol) in diethyl ether (400 mL) under nitrogen at room temperature was added m-chloroperbenzoic acid (40 mmol). The reaction was stirred for 2.5 h. The resultant precipitate was filtered and washed with cold ether (50 mL) to give the title compound as an off-white solid (87%). ESMS[M+H]+: 213.2
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[F:27][CH:28]([F:37])[C:29]1[N:30]2[CH:36]=[N:35][CH:34]=[C:31]2[S:32][CH:33]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:35]3[CH:34]=[C:31]4[S:32][CH:33]=[C:29]([CH:28]([F:37])[F:27])[N+:30]4=[CH:36]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: FC(F)c1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C(F)F)[n+]4c3)[C@H](C)[C@H]12
Yield: 7.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 97 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 70 mg of 3-difluoromethylimidazo[5,1-b]thiazole were used, thereby obtaining 7.9 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Br:30]Br.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:30])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCC(c2ccccc2)CC1
Reactant: BrBr
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCC(c2ccc(Br)cc2)CC1
Yield: 70.8 %

Procedure:
10 g (45.8 mmol) of methyl-4-phenylcyclohexane carboxylate and 3.46 g (7.78 mmol) of thallium(III) nitrate were dissolved in chloroform. 120 mL of the resulting solution was cooled to 0° C. 1.87 mL (36.6 mmol) of Br2 was added dropwise to the resulting solution, and reacted at room temperature for 24 hours. Then, the reacted solution was neutralized by 10% NaOH aqueous solution, extracted by chloroform, dried by anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The resulting material was recrystallized from ethanol to obtain 7.7 g (57%) 4-(4-bromophenyl)cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [OH:1][CH:2]([PH:5](=[O:7])[OH:6])[CH2:3][Cl:4].[CH2:8](O)[CH2:9][CH2:10][CH3:11].O>C1C=CC=CC=1>[OH:1][CH:2]([PH:5](=[O:6])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][Cl:4]
Reactant: CCCCO
Reactant: O=[PH](O)C(O)CCl
Solvent: c1ccccc1
Solvent: O
Product: CCCCO[PH](=O)C(O)CCl
Yield: 64.6 %

Procedure:
A solution of α-hydroxy-β-chloroethylphosphinic acid (2.9 g) and 1-butanol (10.0 g) in benzene (30 ml) was heated for 3 hours with removal of water through a Dean-Stark apparatus. The same work-up as in Example 6 gave 2.60 g (64.8%) of n-butyl α-hydroxy-β-chloroethylphosphinate (Compound No. 82).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:39])=[CH:29][C:30]([CH2:35][CH2:36][CH2:37][OH:38])=[C:31]([CH:34]=1)[C:32]#[N:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:39][C:28]1[CH:29]=[C:30]([CH2:35][CH2:36][CH2:37][OH:38])[C:31]([C:32]#[N:33])=[CH:34][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: N#Cc1cc(N)c(Cl)cc1CCCO
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCO)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (211 mg, 0.595 mmol), 5-amino-4-chloro-2-(3-hydroxypropyl)benzonitrile (125 mg, 0.595 mmol), palladium (II) acetate (40.1 mg, 0.178 mmol), DPPF (33.0 mg, 0.059 mmol), Xantphos (34.4 mg, 0.059 mmol), and cesium carbonate (388 mg, 1.189 mmol) were combined in a 20 dram vial and dioxane (6 mL) was added. The vial was evacuated and backfilled with N2 3×, then heated at 100° C. for 30 min. The reaction was cooled to room temperature and the reaction mixture was filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo and the material was purified by ISCO Companion (0-3% MeOH/DCM; 12 g column). 2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (253 mg) was obtained as a yellow glass.