Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccn(-c2ccc(F)cc2)n1
Temperature: 50 °C
Yield: 51.3 %

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)pyrazole-3-carboxylate (0.92 g, 3.9 mmol, 1 eq) in 18 mL of EtOH/H2O (1.5:1) was added NaOH (0.47 g, 11.8 mmol, 3 eq). The reaction mixture was heated at 50° C. for 1 h then quenched with H2O and extracted with ethyl acetate. The combined organic layers were concentrated and purified by silica gel column chromatography (EtoAc:MeOH 3:1) to provide 1-(4-fluorophenyl)pyrazole-3-carboxylic acid (0.42 g, 2.0 mmol, 52%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1>>[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[CH:16][CH:15]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CNc1ccc(-c2ccc3ncccc3c2)cc1

Procedure:
N-Methyl-4-(quinolin-6-yl)aniline T514 was prepared using general procedure A from 6-bromoquinoline (41 mg, 0.2 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (46 mg, 0.2 mmol). The product T514 was obtained as a black solid (20 mg, 43%). 1H NMR (400 MHz, CDCl3): δ 8.86 (dd, J=4.4, 1.6 Hz, 1H), 8.18 9m, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.96 (dd, J=8.8, 2.4 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.59 (m, 2H), 7.40 (dd, J=8.4, 4.4 Hz, 1H), 6.74 (m, 2H), 2.91 (s, 3H); MS (ESI): 235 (M+H+).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[O:22][B:23](OC)[O:24]C.Cl>C1COCC1.O>[CH2:6]([C:14]1[CH:19]=[CH:18][C:17]([B:23]([OH:24])[OH:22])=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCc1ccc(I)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
n-Butyllithium (BuLi, 1.6 M in hexanes, 2.4 mL, 3.8 mmol) was added dropwise to a stirred solution of p-n-octyliodobenzene (1.0 g, 3.2 mmol) in dry THF (15 mL) at −78° C. under nitrogen. After stirring for 30 minutes and maintaining the temperature at −78° C., trimethylborate (0.4 g, 3.8 mmol) was added dropwise. The system was allowed to return to room temperature after 1 hour and was left stirring under nitrogen overnight. Concentrated HCl (8 mL) and water (15 mL) were then added and stirring was continued for 2 hours. The mixture was extracted with ether (15 3 mL). The ethereal phase was combined and was washed with brine and water (20 2 mL), dried with MgSO4, and the solvent removed in vacuo to give p-n-octylphenylboronic acid as a white solid (0.63 g, 84% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The reaction sequence is shown in FIG. 5. Nε -(tert-butoxycarbonyl)-L-lysine (2 g, 8.12 mmol) was dissolved in methanol (40 ml) and water (40 ml), and the pH was adjusted to 8 with triethylamine. A solution of N-(benzyloxycarbonyl-oxy)succinimide in dioxane (2.4 g, 9.7 mmol in 20 ml) was added to the above mixture and the pH was maintained at 8-9 with triethylamine. The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation to obtain crude Nα -CBZ-Nε -(tert-butoxycarbonyl)-L-lysine. Nα -CBZ-Nε -(tert-butoxycarbonyl)-L-lysine was treated with 0.2M calcium carbonate (4 ml) and the aqueous layer was removed to obtain a white solid. The solid was resuspended in N,N-dimethylformamide(40 ml) and benzyl bromide (1.16 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was worked up with ethyl acetate and water, and the organic layer was dried over magnesium sulphate. The solvent was removed to obtain crude Nα -CBZ-Nε -(tert-butoxycarbonyl)-L-lysine benzyl ester which was purified by silica gel chromatography using 25% hexane in ethyl acetate as a solvent. To Nα -CBZ-Nε -(tert-butoxycarbonyl)-L-lysine benzyl ester (1 g, 2.2 mmol) in methylene chloride (10 ml) was added trifloroacetic acid at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for further 2.5 hr at room temperature. The solvent was removed and the crude product was obtained. Pure Nα -CBZ-L-lysine benzyl ester was obtained by silica gel chromatography.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([NH:17][NH2:18])=O)=[N:12][CH:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+]>C1COCC1>[CH3:23][C:22]1[NH:18][N:17]=[C:15]([C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)=[CH:11][N:12]=2)[N:24]=1
Reactant: CC(=N)N
Reactant: NNC(=O)c1ncc(-c2ccc(OC(F)(F)F)cc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)n[nH]1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 5-(4-(trifluoromethoxy)phenyl)oxazole-2-carbohydrazide (4.6 g, 16 mmol), acetimidamide hydrochloride (2.27 g, 24 mmol) and NaOH (1.1 g, 27.2 mmol) in dry THF (100 mL) was stirred at reflux for 16 h. The mixture was then cooled to RT, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1 to 1:1) to afford the title compound as a yellow solid (4.0 g, 80%). MS (ES+) C13H9F3N4O2 requires: 310. found: 311 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J=9.0 Hz, 2H), 7.51 (s, 1H), 7.28 (d, J=9.0 Hz, 2H), 3.79 (s, 1H), 2.65 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])[CH2:5][CH2:4]1.C(N(CC)CC)C.O>CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[C:17]([F:20])([F:18])[F:19])[CH2:5][CH2:4]1)=[O:1]
Reactant: N#Cc1ccc(N2CCC(CO)CC2)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCC(C=O)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 4-[4-(hydroxymethyl)piperidin-1-yl]-3-(trifluoromethyl)benzonitrile (3.55 g) in DMSO (50 mL) were added triethylamine (10.6 mL) and sulfur trioxide pyridine complex (6.63 g). The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.06 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:14][NH:13][C:12](=[O:21])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[N:14][N:13]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[N:31][CH:30]=4)[C:12](=[O:21])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: CN(C)C(=O)c1n[nH]c(=O)c2c1c1ccc(F)cc1n2C
Reactant: COc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N(C)C)c3c4ccc(F)cc4n(C)c3c2=O)cn1

Procedure:
A solution of 0.3 g (1.04 mmol) of 7-fluoro-N,N,5-trimethyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-carboxamide (obtained in stage 3.2.), 0.120 g (0.63 mmol) of cuprous iodide, 0.20 g (1.45 mmol) of potassium carbonate and 0.60 g (3.19 mmol) of 3-bromo-6-methoxypyridine in 50 ml of N,N-dimethylformamide is heated at 150° C. for 20 h. The reaction mixture is cooled and concentrated under reduced pressure. Dichloromethane, water and a sodium hydroxide solution (1M) are added. The organic phase is separated by settling, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate: 100/0 to 0/100; then ethyl acetate/methanol: 95/5). The white solid obtained is recrystallized from a dichloromethane/ethyl acetate mixture and washed with diethyl ether. A white solid (0.26 g; 0.66 mmol) is isolated.
Reaction SMILES: [C:1]1([C@:7]23[CH2:12][C@H:11]2[CH2:10][O:9][C:8]3=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:18]([NH:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.C1COCC1>[CH2:18]([N:25]([CH3:26])[C:8]([C@@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][C@H:11]1[CH2:10][OH:9])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1OC[C@@H]2C[C@]12c1ccccc1
Reactant: CNCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)[C@@]1(c2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of (1S,5R)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one (10.5 g, 60.0 mmol) in CH2Cl2 (200 mL) was added AlCl3 (16.0 g, 120 mmol) and then the mixture was cooled to 0° C., and then benzyl methyl amine (240 mmol, as a 2.0M solution of benzyl methyl amine in THF) was added slowly. The mixture was stirred at room temperature for 24 h, and then the reaction was quenched with saturated aqueous NH4Cl. After addition of CH2Cl2 and H2O, the resulting mixture was partitioned. The organic layer was washed with 1N HCl and brine, dried (Na2SO4), evaporated, and purified by column chromatography (silica gel; AcOEt/hexane, 1:4) to give (1S,2R)-2-Hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid benzyl-methyl-amide.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])[N:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])[N:3]=1
Reactant: Cc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 4-{1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (2.86 g; compound B2) in DCM (100 ml) is added a solution of hydrogen chloride in 1,4-dioxane (10 ml, 4.0 M). The reaction mixture is stirred for 1 d at RT. The precipitate is filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1
Reactant: CC(C)CCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(CCC(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(3-piperidinylmethyl)-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:30])([F:29])[F:28])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.C([N:34]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH2:34])=[O:23])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:28])([F:29])[F:30])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 4-{4-[3-(4-Fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (90 mg, 0.22 mmol) in THF (4 mL), was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl (50.7 mg, 0.26 mmol) and N-hydroxybenzotriazole (40.5 mg, 0.0.6 mmol), followed by adding ammonium chloride (40.6 mg, 0.76 mmol) and N,N-diisopropylethylamine (199.2 μL, 1.1 mmol) and the reaction mixture was stirred at room temperature overnight. Then 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl (50.7 mg, 0.26 mmol) and N-hydroxybenzotriazole (40.5 mg, 0.0.6 mmol), followed by adding ammonium chloride (40.6 mg, 0.76 mmol) and N,N-diisopropylethylamine (199.2 μL, 1.1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was then extracted with ethyl acetate and the combined organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:3 to 0:100) afforded the title compound (38 mg, 42%) which was obtained as a white solid. MS: m/e=417.4 [M+H]+.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C@H:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH3:8])[C:3]1=[O:16].[F:17][C:18]1([F:31])[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][NH:20][CH2:19]1.C(N(CC)CC)C>>[F:31][C:18]1([F:17])[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]([CH:2]2[CH2:6][CH2:5][N:4]([C@H:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH3:8])[C:3]2=[O:16])[CH2:19]1
Reactant: Oc1ccc(C2CCNCC2(F)F)cc1
Reactant: C[C@@H](c1ccc(F)cc1)N1CCC(Br)C1=O
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(F)cc1)N1CCC(N2CCC(c3ccc(O)cc3)C(F)(F)C2)C1=O
Temperature: 120 °C

Procedure:
To a mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (0.134 g, 0.47 mmol, from Example 50, step B) and 4-(3,3-difluoropiperidin-4-yl)phenol (0.05 g, 0.23 mmol, E-1a from Example 56, step D) was added triethylamine (0.16 mL, 1.2 mmol) and the resulting mixture was heated at 120° C. for 1 h. After cooling, the reaction was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with water and brine, then dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified via preparative HPLC (method B) to yield the homochiral Examples 56 P-3 and P-4 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one diastereomers. The relative and absolute configurations of Examples 56 P-3 and P-4 were not determined and are arbitrarily named P-3 and P-4 based on the order of elution during the HPLC purification. Data for P-3: 11.5 mg pale yellow solid, LCMS (method O) RT 1.23 min (99.8% AP), m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.55 (d, J=7.2, 3H), 1.83 (m, 1H), 1.91-1.99 (m, 1H), 2.10-2.30 (m, 2H), 2.57-2.64 (q, 1H), 2.82-3.95 (m, 3H), 3.07-3.20, (m, 1H), 3.33-3.42 (m, 2H), 3.67 (t, J=9, 1H), 5.40 (d, J=7.2, 1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H), 7.37-7.41 (m, 2H); 19F NMR δ ppm-102.515, -103.158, -114.576, -115.216, -117.070. Data for P-4: 13.7 mg pale yellow solid; LCMS (method O) RT 1.215 min (100% AP), m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.59 (d, J=6.4, 3H), 1.80-1.90 (m, 1H), 2.01-2.29 (m, 3H), 2.53 (t, 1H), 2.81-2.97 (m, 3H), 3.01-3.25 (m, 3H), 3.34-3.43 (m, 1H), 3.64 (t, J=8.8, 1H), 5.42 (d, J=7.2, 1H), 6.74-6.77 (m, 2H), 7.09-7.16 (m, 4H), 7.35-7.38 (m, 2H); 19F NMR δ ppm-102.632, -103.271, -115.162, -115.801, -116.989.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][N:10]([CH2:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[C:13]([Cl:22])[CH:12]=1.[ClH:33]>ClCCl>[ClH:22].[ClH:33].[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][N:10]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[C:13]([Cl:22])[CH:12]=1
Reactant: COC(=O)CCCNCCN(CCC(=O)OC(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CCCNCCN(CCC(=O)O)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 220.1 %

Procedure:
A solution of 0.30 g (0.6 mmol) of 4-{2-[(2-tert-butoxycarbonyl-ethyl)-(3-chloro-4-trifluoromethoxy-phenyl)-amino]-ethylamino}-butyric acid methyl ester in 2 ml of dichloromethane was cooled (0° C.), treated with 3.10 ml (12.4 mmol) of HCl solution (4 M in dioxane) and stirred at RT for 16 h. The solution was evaporated, suspended in acetonitrile and evaporated (3×) to yield 0.33 g (97%) of the title compound as light yellow oil. MS: 427.12 (MH+, Cl).
Reaction SMILES: [C:1]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)([O:3][CH3:4])=[O:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:15][S:16]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:1]([O:3][CH3:4])=[O:2])[NH:7][C:8]=2[CH:14]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Product: COC(=O)Nc1nc2ccc(S(=O)(=O)Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 2-carbomethoxyamino-benzimidazole (5.0 g, 0.026 mole) in chlorosulfonic acid (35.00 mL) was stirred at 0° C. for 30 minutes and at room temperature for 3 hours. The resulting dark colored reaction mixture was poured into an ice-water mixture (200 mL), and stirred at room temperature for 30 minutes. The resulting precipitate was filtered and washed with cold water (500 mL). The solid was dried overnight under high vacuum in a desiccator over NaOH pellets to give 5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole (5.9 g, 78%) as a grey powder. 1H NMR (DMSO-d6) d: 3.89 (S, 3H), 7.55 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.88 (s, 1H). (German Patent DE 3826036)
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[NH:28]1[CH2:32][CH2:31][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1.C(N(CC)CC)C>C(#N)C.CCOC(C)=O>[C:36]([O:35][C:34]([NH:33][C@@H:30]1[CH2:31][CH2:32][N:28]([C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)[CH2:29]1)=[O:40])([CH3:39])([CH3:37])[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(N)nc3c2CCCc2ccccc2-3)C1
Temperature: 25 °C

Procedure:
A solution of the product from Example 4C (1.5 g, 3.93 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (CAS #: 122536-77-0) (1.1 g, 5.9 mmol) and triethylamine (0.9 mL, 5.9 mmol) in acetonitrile (35 mL) was heated to 80° C. for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc, washed with H2O and brine, dried (MgSO4), concentrated and chromatographed on silica gel eluting with ethyl acetate to provide the title compound.
Reaction SMILES: C([O:3][P:4]([C:9]([CH3:25])([CH2:15][C:16]([CH3:24])([CH3:23])[CH2:17][C:18]([O:20]CC)=[O:19])[C:10]([O:12]CC)=[O:11])([O:6]CC)=[O:5])C>Br>[CH3:25][C:9]([P:4]([OH:5])([OH:6])=[O:3])([CH2:15][C:16]([CH3:23])([CH3:24])[CH2:17][C:18]([OH:20])=[O:19])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CC(C)(C)CC(C)(C(=O)OCC)P(=O)(OCC)OCC
Agent: Br
Product: CC(C)(CC(=O)O)CC(C)(C(=O)O)P(=O)(O)O

Procedure:
Hydrolysis of this ester in concentrated hydrobromic acid gave 2,4,4-trimethyl-2-phosphonoadipic acid as a hygroscopic solid having a 31P chemical shift of -25 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCn1ccc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(ccn4CCC(=O)O)c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
D6 MF105672-178A2 (38 mg) was dissolved in EtOH, treated with 12.5 M aqueous NaOH (2 ml) and stirred at RT for 4 hours. The reaction mixture was evaporated, re-dissolved in H2O and washed with diethyl ether. The aqueous solution was acidified then extracted with DCM. The DCM solutions were combined, dried over MgSO4, filtered and evaporated to give the title compound MF105672-181A1 (5 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.44 (6H, d), 2.94 (2H, t), 4.51 (2H, t), 4.73 (1H, septet), 6.61 (1H, d), 7.07 (1H, d), 7.22 (1H, d), 7.45 (1H, d), 7.94 (1H, d), 8.07 (1H, d), 8.27 (1H, s), 8.47 (1H, s). MS (ES): C22H20ClN3O4 requires 425; found 426 (MH+).
Reaction SMILES: [CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:19][C:20]([O:22]CC)=[O:21]>CN(C=O)C.O>[CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:19][C:20]([OH:22])=[O:21])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Sc2ccccc2NC1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1Sc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-butyl-2H-benzo[b][1,4]thiazin-3(4H)-one (6.3 mmol, 1400 mg) in DMF (5 ml) was added NaH (6.9 mmol, 167 mg) and the reaction mixture was stirred at room temperature for 1 h before the dropwise addition of ethyl bromoacetate (6.3 mmol, 1052 mg). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, Sat. NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude compound was dissolved in MeOH (10 ml) and 1 N NaOH (10 ml) and stirred at room temperature for 2 h. The MeOH was removed under reduced pressure and the resulting aqueous solution extracted with EtOAc. The aqueous layer was acidified to pH 2 with 1N HCl and extracted with EtOAc. The organic phase was dried over Na2SO4 and the solvent was evaporated to give the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=280.2; tR=3.01.