Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([O:18][CH3:19])=[C:7]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O>[Fe].CO>[NH2:15][C:13]1[CH:14]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:18][CH3:19])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(N)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Yield: 100 %

Procedure:
Methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate (10.42 g, 39.0 mmol), iron powder (325 mesh, 10.89 g, 195 mmol), ammonium chloride (3.13 g, 58.5 mmol), water (30 mL), and methanol (150 mL) were added together. The resultant mixture was then refluxed for 1 h. The mixture was then cooled to room temperature, filtered through celite, and the celite washed with methanol. The filtrate was then concentrated under vacuum and dissolved in ethyl acetate (600 mL). The resultant solution was then washed with water and brine. The organic extract was then dried, filtered and concentrated under vacuum to yield the title compound as an oil (9.25 g, 100%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][C@@H:28]([CH3:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[C@@H:28]([O:27][CH3:26])[CH3:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CO[C@@H](C)C(=O)O
Agent: Cl
Product: CO[C@@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (14.2 mg, 48.7%), MS (ISP) m/z=417.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and (S)-2-methoxypropanoic acid
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=2)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: Cc1nn(C)cc1N
Solvent: c1ccncc1
Product: Cc1nn(C)cc1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 81.8 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54 mmol) and 4-amino-1,3-dimethyl-1H-pyrazole (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a pale pink solid (501 mg, 1.26 mmol, 82%). δH (CDCl3, 300K) 7.65 (2H, s), 7.31 (1H, s), 6.77 (1H, s), 3.78 (3H, s), 2.04 (3H, s). m/z (ES+, 70V) 399.9 (MH+).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([CH3:21])[C:8]=2[C:9]#[N:10])[CH2:3]1.N.S(=O)(=O)(O)[OH:24]>>[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:12]=[C:11]([CH3:21])[C:8]=2[C:9]([NH2:10])=[O:24])[CH2:3]1
Reactant: Cc1cc(N2CCOCC2)cc(N2CC[C@@H](F)C2)c1C#N
Reactant: O=S(=O)(O)O
Agent: N
Product: Cc1cc(N2CCOCC2)cc(N2CC[C@@H](F)C2)c1C(N)=O
Yield: 68 %

Procedure:
A solution of 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrile (0.18 g, 0.62 mmol) in sulphuric acid (8 ml) is heated at 100° C. for 1 h. After completion of the reaction (monitored by TLC), the mixture is poured onto ice water. The aqueous layer is basified with aqueous ammonia to pH 10 and extracted with ethyl acetate (3×20 ml). The combined organic layers are washed with water (10 ml), dried over sodium sulfate and concentrated in vacuo yielding 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzamide (0.13 g, 0.423 mmol, 68%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22]Br>CN(C=O)C.O>[CH3:1][C:2]1[N:11]([CH2:20][O:21][CH3:22])[C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1ccc2ccc3nc(C)[nH]c(=O)c3c2c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1c(C)nc2ccc3ccc(C)cc3c2c1=O
Reaction time: 0.58 h

Procedure:
To a suspension of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (1.0 g, 4.5 mmol) in DMF (25 ml) was added 80% NaH (0.15 g, 5.0 mmol) (Aldrich) portion wise and the mixture was stirred 35 minutes. Bromomethyl methyl ether (0.39 ml, 4.8 mmol) (Aldrich) was added in one portion and the solution was stirred at room temperature overnight. The solution was then diluted with water (100 ml) and extracted twice with methylene chloride (100, 40 ml). The combined methylene chloride extracts were washed with a small volume of water, dried (K2CO3), and concentrated in vacuo. The residue was purified by silica gel (40 g) chromatography eluting with ethyl acetate:methylene chloride (0 to 1:19) to give 3,9-dimethyl-2-methoxymethylbenzo[f]-quinazolin-1(2H)-one and the corresponding O-alkylated material in a 4:1 ratio as determined by NMR (0.79 g). 1H NMR (DMSO-d6, 300 MHz) for major isomer δ: 2.57 (s, 3H, C9 -CH3), 2.68 (s, 3H, C3 -CH3), 3.38 (s, 3H, OCH3), 5.62 (s, 2H, NCH2O), 7.51 (dd, J=8,2 Hz, 1H, Ar), 7.56 (d, J=9 Hz, 1H, Ar), 7.96 (d, J=8 Hz, 1H, Ar), 8.24 (d, J=9 Hz, 1H, Ar), 9.63 (s, 1H, Ar). Anal. Calculated for C16H16N2O2 :C, 71.62; H, 6.01; H, 10.44. Found: C, 71.55; H, 6.03; H, 10.43.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]1[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]1.CN(C)C=O.[Li][N:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].O>CCOCC>[C:32]1([N:24]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[C:25](=[O:26])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2ccccc2CBr)OC1(C)C
Reactant: [Li]N(C(=O)OC(C)(C)C)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reaction time: 2 h

Procedure:
Pentane (350 mL) was added to tert-butyl phenylcarbamate (20.81 g, 107.7 mmol) to form a suspension. BuLi (67.3 mL, 107.7 mmol) in hexanes was added dropwise over 1 hour. During the addition a clear solution formed briefly then a white precipitate formed. After the addition was complete the mixture was stirred for 1 hour then the solid was collected on a glass frit, washed with pentane (2×20 mL), and dried under reduced pressure to afford LiN(Boc)Ph (16.6 g, 77.4%). 2-Bromomethylphenyl boronic acid pinacol ester (compound 9) (4.66 g, 15.7 mmol) and N,N-dimethylformamide (DMF) (35 mL) were combined to form a clear colorless solution. Then solid LiN(Boc)Ph (3.13 g, 15.7 mmol) was added in small portions over three minutes. The mixture was stirred for 2 hours then the white suspension was poured into water (250 mL). Et2O (150 mL) was added and the organics were separated, dried with brine then magnesium sulfate. Filtration followed by evaporation afforded the product as a white solid. 1H NMR (CDCl3, 250 MHz): 7.77 (d, 1H), 7.0-7.5 (m, 8H), 5.19 (s, 2H), 1.39 (s, 9H), 1.27 (s, 12H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H-].[Na+].CC1C=CC(C)=CC=1>O.C(O)(=O)C>[CH2:10]([O:25][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCC/C=C\CCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccc(C)cc1
Product: CCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1

Procedure:
A mixture of 57.2 (0.300 mole) of 5-bromo-2-furoic acid, 121.0 g (0.45 mole) of cis-9-pentadecenol, 18.0 g (0.750 mole) of sodium hydride and 2 liters of p-xylene are heated to reflux for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with 2 liters of water. The organic layer is separated, dried, evaporated to dryness, and the residue recrystallized from hexane to give 5-(cis-9-pentadecenyloxy)-2-furoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:18])=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1)#[CH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:19]#[C:20][C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:18])=[N:6][CH:7]=2)[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Nc1ncc(Br)cn1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1cc(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)cc(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 5-bromo-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (573 mg, 3.0 mmol), 1-ethynyl-3,5-dimethoxybenzene (483 mg, 3.0 mmol), triphenylphosphine (157 mg, 0.60 mmol), bis(triphenylphosphine)palladium(II) chloride (210 mg, 0.30 mmol), copper(I) iodide (57 mg, 0.30 mmol) and diethylamine (1.50 ml, 15.0 mmol) in N,N-dimethylformamide (10 mL) was degassed with nitrogen three times, and then stirred at 80° C. for 2 hrs. LCMS showed the reaction was completed. The mixture was cooled to RT, quenched with water (20 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were separated, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=4:1) to afford the title compound as a yellow solid (460 mg, 39%). MS (ES+) C21H8N4O4 requires: 390. found: 391 [M+H]+.
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>CCCCCC.CCOCC>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:7]1[O:6][CH:10]=[CH:9][N:8]=1
Reactant: c1cocn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)c1ncco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
n-Butyllithium (28.5 ml of a 2.54M solution in hexane) was added to a -78° solution of oxazole (5.0 g) in ether (150 ml). The resulting solution was stirred at -78° for 30 min, followed by the addition of trimethylsilyl chloride (7.86 g), and the mixture allowed to warm to room temperature. The reaction mixture was distilled and the fraction with a boiling point of about 130° was collected to afford 2-trimethylsilyl oxazole (5.12 g); MS, m/e=142(M+1), 91, 73.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[N:27]([CH3:28])[C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:20]([C:23]2[N:27]([CH3:28])[C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)n1C

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with methyl 5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.37 (dd, J=1.8 & 10.5 Hz, 1H), 7.29 (m, 2H), 7.12-6.94 (m, 4H), 5.87 (dt, J=1.8, 8.4 & 17.4 Hz, 1H), 5.56 (br s, 1H), 3.65 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCN1CCCCCC1=O
Yield: 85.4 %

Procedure:
Following example 10, from 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 33 g (0.2 M) of 1-bromohexane on 19 hr. reflux was obtained 29.8 g (85.3%) of colorless product; b.p 122-128°/0.4 mm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:18][C:19]([CH3:21])=[CH2:20])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:20][C:19](=[O:18])[CH3:21])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C=C(C)OC(C)=O
Reactant: Clc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 68.3 %

Procedure:
To a stirred solution of 4-bromo-4'-chlorobiphenyl (16 g; F. R. Shaw and E. E. Turner. J. Chem. Soc., 285 (1932) ), isopropenyl acetate (9 g) and dichlorobis(tri-o-tolylphosphine)palladium (0.47 g) in dry toluene (30 ml), under nitrogen, was added tributyltin methoxide (25.9 ml; Aldrich). The mixture was stirred and heated at 100° for 5 hr, cooled and the solvent evaporated in vacuo. The residue was chromatographed on silica gel, eluting with cyclohexane then ether. The resultant solid was recrystallised from cyclohexane to afford the title compound (10 g), m.p. 79°-81°.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([N:17]1[CH2:34][CH2:33][C:20]2([C:24](=[O:25])[N:23]([C:26]3[CH2:27][O:28][C:29](=[O:32])[C:30]=3[CH3:31])[CH2:22][CH2:21]2)[CH:19](O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([N:17]1[CH2:34][CH2:33][C:20]2([C:24](=[O:25])[N:23]([C:26]3[CH2:27][O:28][C:29](=[O:32])[C:30]=3[CH3:31])[CH2:22][CH2:21]2)[CH:19]([F:7])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1=C(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)COC1=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(Cc4ccccc4)CC3F)C2=O)COC1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a flask charged with DCM (5 mL) and a stir bar was added DAST (0.092 mL, 0.69 mmol) at −78° C., which was followed by addition of 8-benzyl-6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-35, Step C) (165 mg, 0.46 mmol) in DCM. The mixture was stirred at −78° C. for 15 minutes, and then allowed to warm up to RT slowly. The reaction was quenched with aq NaHCO3 and after 3 hours at RT it was extracted with DCM, dried over sodium sulfate, and purified by MPLC with hexane and EtOAc. Two spots were collected with the desired molecule weight in the ratio of 1:4. The less polar compound, which is the minor isomer, was designated as Isomer A, and the more polar major isomer was designated as Isomer B. LCMS: m/z 359 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([CH2:11][P:12]([O:16]C)([O:14]C)=[O:13])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].C[Si](I)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([CH2:11][P:12]([OH:16])([OH:14])=[O:13])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](CP(=O)(OC)OC)CCN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](CP(=O)(O)O)CCN1C(=O)OCc1ccccc1

Procedure:
A mixture of 600 mg of cis-1-benzyloxycarbonyl-4-dimethylphosphonomethyl-2-piperidinecarboxylic acid methyl ester in 10 ml of methylene chloride is treated with 538 mg of trimethylsilyl iodide at room temperature to yield cis 1-benzyloxycarbonyl-4-phosphonomethyl-2-piperidinecarboxylic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:32]=[CH:31][C:20]([CH2:21][NH:22][CH2:23][CH:24]4[CH2:28][O:27]C(C)(C)[O:25]4)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:32]=[CH:31][C:20]([CH2:21][NH:22][CH2:23][CH:24]([OH:25])[CH2:28][OH:27])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(CNCC4COC(C)(C)O4)cc3)n2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CNCC(O)CO)cc3)n2)cc1Cl
Temperature: 65 °C
Yield: 32.1 %

Procedure:
To a solution of N-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (108 mg, 0.236 mmol) in THF (4 mL) was added 1N aqueous HCl (0.778 mL, 0.778 mmol) The reaction was heated to 65° C. under nitrogen for 90 minutes. Heating was stopped and the reaction was neutralized by addition of 1N aqueous NaOH (0.778 mL, 0.778 mmol). THF was removed under reduced pressure and the remaining aqueous solution was basified (pH approx 9) by the addition of 0.1N NaOH, at which point white precipitate formed. Solid was collected by vacuum filtration, and washed with 0.1N NaOH (3×10 mL). Solid was dried in a vacuum oven overnight to give 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzylamino)propane-1,2-diol (31.7 mg, 32%) as an off-white solid. LCMS (Table 1, Method c) Rt=1.90 min, m/z 418.47 (M+H)+; 1H NMR (400 MHz, methanol) δ ppm 7.22 (d, J=8.68 Hz, 1H), 7.60 (d, 2H), 8.01 (dd, 1H), 8.10 (d, 1H), 8.16 (d, 2H), 4.78 (sept, 1H), 2.76 (dd, 1H), 2.63 (dd, 1H), 3.52 (d, 2H), 3.90 (d, 2H), 3.78 (m, 1H), 1.40 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([C:35]3([NH:39]C(OC(C)(C)C)=O)[CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:7][CH:6]=1.Cl.O1CCOCC1>CO>[NH2:39][C:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:28]3[N:14]4[C:15]5[CH:27]=[CH:26][CH:25]=[N:24][C:16]=5[NH:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:13]4=[N:12][C:11]=3[C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:3](=[O:47])[O:2][CH3:1])=[CH:10][CH:9]=3)=[CH:30][CH:31]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 132.4 %

Procedure:
Methyl{4-[3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl]phenyl}carbamate (41 mg, 0.050 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 24 hours. The mixture was concentrated to afford the desired product (35 mg, 83%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 9.79 (s, 1H), 8.79-8.73 (m, 3H), 8.14 (dd, J=4.0 Hz and 1.7 Hz, 1H), 7.96 (dd, J=8.0 Hz and 1.1 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.44-7.40 (m, 4H), 7.34-7.30 (m, 3H), 7.17 (t, J=7.2 Hz, 1H), 6.91 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.78 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.66 (s, 3H), 2.57 (t, J=7.7 Hz, 4H), 2.24-2.16 (m, 1H), 1.85-1.78 (m, 1H). LCMS: 529 [M+H].
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: COC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COC(=O)C1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (400 mg, 0.98 mmol) was added to a solution of methyl piperidine-4-carboxylate (703 mg, 4.90 mmol) and DMAP (600 mg, 4.90 mmol) in MeCN (50 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC using 50-90% EtOAc/Heptane on silica gel to provide the title compound as colorless oil. Yield: 182 mg (38%); 1H NMR (400 MHz, CDCl3) δ 1.48-1.57 (m, 4 H), 1.59 (s, 9 H), 1.76-1.89 (m, 2 H), 1.91-2.00 (m, 2 H), 2.17-2.34 (m, 2 H), 2.48 (td, J=11.28, 2.83 Hz, 2 H), 3.27-3.39 (m, 2 H), 3.64 (s, 3 H), 3.65-3.70 (m, 1 H), 3.95-4.04 (m, 2 H), 4.25 (d, J=7.42 Hz, 2 H), 7.42 (dd, J=8.59, 0.59 Hz, 1 H), 7.64 (dd, J=8.40, 1.76 Hz, 1 H), 8.17 (dd, J=1.66, 0.49 Hz, 1 H); MS (ESI) (M+H)+=478.0.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[OH-].[Na+].CS(C)=O.Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]>C1(C)C=CC=CC=1>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])=[CH:2][CH:1]=1
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CO[Si](CCCOc1ccc(N)cc1)(OC)OC
Temperature: 85 °C

Procedure:
A glass reactor was charged with 60 g (0.55 mole) p-aminophenol, 43.28 g of a 50% aqueous solution of sodium hydroxide (0.54 mole NaOH), 112 cc dimethylsulfoxide and 120 cc toluene. The resultant mixture was heated to the boiling point for six hours under a nitrogen atmosphere to remove all of the water present by azeotropic distillation. The reaction mixture was then allowed to cool to about 75° C., at which time 109 g (0.55 mole) of 3-chloropropyl trimethoxysilane was added dropwise while the reaction mixture was stirred. The temperature of the reaction mixture increased spontaneously to 85° C. during this addition. The temperature of the reaction mixture was maintained at from 75° to 85° C. by heating and control of the addition rate. Following completion of the addition, the reaction mixture was heated at 115° C. for 16 hours, following which the mixture was allowed to cool and was filtered to remove any solid material. The solvents were then removed under a pressure of about 15 mm of mercury at a temperature of about 60° C. The pressure was then reduced to from 3 to 4 mm of mercury and the material boiling from 170° to 180° C. was recovered. This fraction, which weighed 70 g, was distilled using a fractionating column and a 50 g portion boiling from 175° to 177° C. under a pressure of 3 mm of mercury, was collected. The colorless liquid was found to contain 10.19% silicon and 5.20% nitrogen. The calculated values for 3(p-aminophenoxy)propyl trimethoxy silane are 10.33% silicon and 5.17% nitrogen. The infrared and nuclear magnetic resonance spectra of the product were in agreement with the proposed structure.