Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:28][CH2:27][C:22]3(OCC[O:23]3)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.Cl.CCOC(C)=O>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzamide (120 mg, 0.289 mmol) in dioxane (1 mL) and water (0.25 mL) was treated with 12 N HCl (0.25 mL). After 1.5 h, the mixture was poured into EtOAc and water. The organic layer was washed with satd sodium bicarbonate (2×), brine, dried with sodium sulfate, and concentrated yielding 100 mg of the title compound; which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16](C(OC(C)(C)C)=O)[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:16][C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)nc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cc(C)c(Cl)nc2[nH]1

Procedure:
A solution of 0.53 g (1.56 mmol) 6-chloro-5-methyl-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 8 mL dichloromethane was cooled to 0° C., 1.44 mL (2.14 g, 18.8 mmol) trifluoroacetic acid was added and the cooling bath removed. After 2 h the volatile components were removed and the residue was poured into saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The resulting off-white solid (91.1%) was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]3[NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:7]([C:32]#[N:33])=[C:6]([CH3:34])[NH:5][C:4]=1[CH3:35])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:7]([C:32]#[N:33])=[C:6]([CH3:34])[NH:5][C:4]=1[CH3:35])#[N:2]
Reactant: CCCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
57.8 mg (0.12 mmol) tert-butyl 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-3-[(propyl-sulfonyl)amino]-1H-indazole-1-carboxylate (Example 20A) were dissolved in dichloromethane (4 ml) and treated with 0.1 ml (1.28 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 13 mg (29% of th.) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][Cl:10].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:10][CH:9]1[CH2:8][NH:4][CH2:3][CH2:2][N:1]1[CH2:6][CH3:5]
Reactant: C1CNCCN1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCNCC1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
The piperazine Example 2 (500 mg, 1.36 mmol), BrCH2CH2Cl (0.7 mL), and K2CO3 (320 mg, 2.3 mmol) were taken up in CH3CN (2 mL) and stirred at 25° C. for 18 h. The solution was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4), Filtration and concentration gave a yellow oil. The residue was purified via gradient flash chromatography (0-15% EtOAc in CH2Cl2, SiO2) which gave 357 mg (61%) of the chloro-ethyl piperazine as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:6]2[CH:29]=[CH:28][C:27]([Cl:30])=[N:26][C:7]=2[N:8]2[C:13]=1[CH2:12][CH2:11][CH:10]([N:14]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:15])[CH2:9]2.O.[Li+].[OH-].CC(O)=O>C1COCC1.[Cl-].[Na+].O>[Cl:30][C:27]1[CH:28]=[CH:29][C:6]2[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:13]3[N:8]([C:7]=2[N:26]=1)[CH2:9][CH:10]([N:14]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:15])[CH2:11][CH2:12]3
Reactant: COC(=O)Cc1c2n(c3nc(Cl)ccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C1CCc2c(CC(=O)O)c3ccc(Cl)nc3n2C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 20 mg of (±)-{2-chloro-8-[(4-fluoro-benzenesulfonyl)-methyl-amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indolizin-5-yl}-acetic acid methyl ester in 1.2 mL of THF was added 1.5 mL of water, followed by 0.2 mL of 1 N aqueous LiOH solution. The mixture was stirred for 1 h at room temperature and 0.1 mL of AcOH was added, followed by 3 mL of brine. The mixture was extracted with 2×10 mL of EtOAc and the combined extracts was dried over Na2SO4 and concentrated to give 18 mg of the desired product as a white solid.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Li]CCCC.[CH:37]([C:40]1[CH:41]=[C:42]([CH:46]([CH3:50])[CH2:47][CH:48]=O)[CH:43]=[CH:44][CH:45]=1)([CH3:39])[CH3:38].O>C1COCC1>[CH:37]([C:40]1[CH:41]=[C:42]([CH:46]([CH3:50])[CH2:47][CH:48]=[CH:12][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH:43]=[CH:44][CH:45]=1)([CH3:39])[CH3:38]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C=CCC(C)c2cccc(C(C)C)c2)cc1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
A solution of (3,4-dimethoxyphenyl)methyltriphenylphosphonium bromide (4.93 g, 10.0 mmol, 1.0 equiv.) in THF (10 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 6.3 mL, 10.0 mmol, 1.0 equiv.) at 0° C., the red suspension was stirred at 0° C. for 20 min. 3-(3-Isopropylphenyl)butanal (2.09 g, 11.0 mmol, 1.1 equiv.) in THF (11 mL) was added, and the mixture was stirred at 0° C.→25° C. for 16 h. After addition of H2O at 25° C., the aqueous layer was extracted with hexanes (2×), the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexanes/EtOAc 99:1→4:1) to yield 2.67 g (82%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[CH2:18][O:19][CH3:20].CO.O.O.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[CH2:18][O:19][CH3:20]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1Cl
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of methyl 2′-chloro-2-(methoxymethyl)biphenyl-4-carboxylate (11 g, 37.8 mmol) in a mixture of THF (50 ml), MeOH (50 ml) and water (25 ml) was added lithium hydroxide monohydrate (4.76 g, 113.5 mmol) in portions. After 12 hours at RT, the reaction mixture was concentrated and the aqueous residual layer was acidified with a concentrated aqueous solution of HCl, and then extracted with EtOAc (2×100 mL). The organic layers were washed with water and brine, combined, dried (Na2SO4) and concentrated under reduced pressure to afford of the title compound as a white solid (7.5 g, 72%). LC/MS, M−(ESI): 275.0. 1H NMR (DMSO-d6, 400 MHz) δ 13.0 (1H, brs), 8.08 (1H, s), 7.92 (1H, d), 7.58 (1H, d), 7.44 (2H, m), 7.29 (2H, m), 4.21 (1H, dd), 4.13 (1H, dd), 3.16 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: BrCCOCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of 21.43 g (0.1 mol) of tert-butyl N-(trans-4-aminocyclohexyl)carbamate in 250 mL of N,N-dimethylformamide were added 16.76 mL (0.12 mol) of bis(2-bromoethyl)ether and 34.85 mL (0.25 mol) of triethylamine, and the mixture was stirred for 6 hours at 70° C. Then solvent was removed under reduced pressure and the residue was treated with ethyl acetate. The organic layer was washed with sodium carbonate aqueous solution and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: chloroform alone to chloroform/methanol=30/1) to give 19.92 g (70%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.C(N1CC[CH:22]([C:25]([N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=O)[CH3:37])[CH:31]=2)[CH2:28][CH3:29])=[O:26])CC1)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].C(O[Ti+](OC(C)C)OC(C)C)(C)C.O.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][CH:36]([C:32]2[CH:31]=[C:30]([N:27]3[CH2:28][CH2:29][CH2:22][C:25]3=[O:26])[CH:35]=[CH:34][CH:33]=2)[CH3:37])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: CCN(C(=O)C1CCN(C(C)=O)CC1)c1cccc(C(C)=O)c1
Agent: CC(C)O[Ti+](OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(Nc1ccccc1Oc1ccc(Cl)cc1)c1cccc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Chlorophenoxy)aniline (245 mg, 1.118 mmol, 1 eq) and 1-acetyl-N-(3-acetylphenyl)-N-ethylpiperidine-4-carboxamide (250 mg, 1.230 mmol, 1.1 eq) were stirred in dry dichloromethane (DCM) (2 mL) at room temperature for 10 min. Tri-isopropoxytitanium chloride (534 μL, 2.236 mmol, 2 eq) was added to the reaction mixture which was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (947 mg, 4.472 mmol, 4 eq) was then added to the reaction mixture and was stirred at room temperature for a further 24 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (120 mL). The organic layer was washed with brine (120 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (437 mg, 91%) as a pale yellow oil. 1H NMR (270 MHz, CDCl3) δ 1.45 (3H, d, J=8.1 Hz, CH3), 2.02-2.18 (2H, m, CH2), 2.58 (2H, t, J=10.8 Hz, CH2), 3.77 (2H, t, J=9.7 Hz, CH2), 4.50 (2H, m, NH and CH), 6.47-6.62 (2H, m, Ar) 6.77-6.96 (4H, m, Ar), 7.09 (1H, d, J=8.1 Hz, Ar), 7.22-7.32 (3H, m, Ar), 7.48 (1H, dd, J=2.4, 8.1 Hz, Ar), 7.59 (1H, m, Ar). LCMS (90% MeOH and 10% H2O; Symmetry C18 reverse phase column) tr=2.73 min; (ES+), m/z 407.2. HPLC 98.56% purity.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]2[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=2[CH:60]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:48][C:44]1[CH:43]=[C:42]([CH:40]([OH:41])[CH:39]([NH:38][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH2:49][C:50]2[CH:51]=[CH:52][C:53]3[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=3[CH:60]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: CC1(C)COc2ccc(CC(N)C(O)c3cccc(Cl)c3)cc21
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)COc2ccc(CC(NC(=O)c3ccc(F)c4ccccc34)C(O)c3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of 4-fluoronaphthalene-1-carboxylic acid (242 mg, 1.27 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243 mg, 1.27 mmol) and 1-hydroxybenzotriazole monohydrate (195 mg, 1.27 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol (0.40 g, 1.21 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide (383 mg, 68%) as colorless crystals.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:37])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH3:45][O:46][C:47]([NH:49][C@H:50]([C:55](O)=[O:56])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:48].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:37][C:55](=[O:56])[C@H:50]([C@H:51]([CH2:53][CH3:54])[CH3:52])[NH:49][C:47]([O:46][CH3:45])=[O:48])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 0.6 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and 198 μl (1.8 mmol) of NMM in 5.8 ml of DMF are added to 136 mg (0.72 nmol) of N-methoxycarbonyl-(L)-iso-leucine and 179 mg (0.60 mmol) of TPTU in 3 ml of DMF and the mixture is stirred at room temperature for 14 hours and worked up analogously to Example 3, yielding the title compound: TLC: Rf =0.59 (methylene chloride/THF 3:1); HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH3:18][NH2:19].C[O-].[Na+].S(=O)(=O)(O)O>CN(C=O)C>[CH3:1][CH:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([NH:19][CH3:18])=[O:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CN
Reactant: CCC(C)Oc1ccc(OCC(=O)OC)cc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCC(=O)NC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 4-(1-methylpropoxy)phenoxyacetate (7.94 g, 33.3 mmol) in 65 ml of dry DMF at 0° and with stirring is added methylamine gas to saturation (ca. 25 min.). A trace of sodium methoxide (ca. 10 mg) is added and the mixture is allowed to warm to RT. After 20 hours at RT, the reaction mixture is poured into ice water and 10 ml of 3N sulfuric acid and extracted with ether. The combined organic phases are washed with water, with 10% sodium bicarbonate, with water and with brine, dried, filtered and the filtrate evaporated in vacuo to give 4-(1-methylpropoxy)phenoxy-N-methylacetamide.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[CH:13]([Br:16])[CH2:14][CH3:15])(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20].C(Cl)Cl>>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[CH:13]([Br:16])[CH2:14][CH3:15]
Reactant: CCC(Br)C(=O)NCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(Br)C(=O)NCCCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[3-(2-Bromobutyrylamino)propyl]carbamic acid tert-butyl ester (1.41 g, 4.36 mmol) was treated with TFA:DCM (1:1 (v/v), 20 mL) and the solution stirred at room temperature for 3 h. The volatiles were removed in vacuo and crude product, isolated as the trifluoroacetic acid salt, used directly in the next stage.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:20]>C(OCC)C>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][Br:20])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CO)c1OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1cccc(CBr)c1OCc1ccccc1
Temperature: 25 °C
Yield: 131.1 %

Procedure:
To a solution of 15.04 g (62 mmol) of 2-benzyloxy-3-hydroxymethyl-1-methoxybenzene, from Step 2, in 140 mL of diethyl ether at 0° C. was added slowly, with stirring, 2.9 mL (31 mmol) of phosphorous tribromide. The reaction mixture was stirred at 0° C. for 30 minutes and then allowed to warm to ambient temperature over a 4 h period. The solution phase was decanted and the reaction was quenched with aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 12.48 g (65% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30][CH2:29]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][CH:31]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30][CH2:29]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(CNC(=O)OC(C)(C)C)CC2)n1
Yield: 94 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and tert-butyl 4-piperidinylmethylcarbamate as in previous examples gave tert-butyl {1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methylcarbamate in 94% yield: mp (CH2Cl2/MeOH) 210-212° C.; 1H NMR (DMSO-d6) δ 7.88 (d, J=8.1 Hz, 1H), 7.68 (t, JHF=52.9 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 6.87 (t, J=5.5 Hz, 1H), 4.68-4.59 (m, 2H), 3.98 (s, 3H), 3.80-3.78 (m, 4H), 3.70-3.69 (m, 4H), 3.05-2.87 (m, 2H), 2.90 (t, J=5.9 Hz, 2H), 1.72 (br, 3H), 1.38 (s, 9H), 1.09 (br, 2H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.7; H, 6.3; N, 19.6%.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=O)=O.[NH2:38][CH2:39][CH2:40][OH:41]>CO>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@@:8]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)([CH2:7][CH2:6][NH:38][CH2:39][CH2:40][OH:41])[O:13][C:12]2=[O:14])[CH3:16])=[CH:18][CH:19]=1
Reactant: NCCO
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Solvent: CO
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNCCO)(c2ccc(F)cc2)OC1=O
Yield: 3.6 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobi-phenyl-4-yl)ethyl)-6-(4-fluorophenyl)2-oxo 1,3-oxazinan-6-yl)ethyl methanesulfonate (58 mg, 0.11 mmol) in anhydrous MeOH was added 2-amino-ethanol (54 mg, 0.88 mmol). Then the reaction mixture was refluxed overnight. When the reaction was over, solvent was removed in vacuo. The residue was purified by preparative HPLC to give (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(2-hydroxyethylamino)ethyl)-1,3-oxazinan-2-one (2 mg, 3%). 1H NMR (CDCl3): 1.53 (m, 3H), 2.25-2.36 (m, 4H), 2.51 (m, 1H), 2.87-3.24 (m, 5H), 3.75-4.02 (m, 2H), 5.60 (m, 1H), 6.85-6.96 (m, 2H), 6.96-7.10 (m, 4H), 7.22 (m, 2H), 7.38 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:25][CH:24]=1
Reactant: O=C1CCN(Cc2ccccc2Br)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CCN(Cc2ccccc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a 5 mL microwave vial equipped with a stir bar was added sodium carbonate (79 mg, 0.75 mmol). The vial was dried in an oven for 16 hours, then cooled to room temperature under nitrogen. 1-(2-Bromo-benzyl)-piperidin-4-one (100 mg, 0.37 mmol), 4-fluorophenyl boronic acid (52.2 mg, 0.37 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) were added, followed by dioxane (5 mL) water (1 mL). The resulting mixture was degassed thoroughly with nitrogen and then heated in a microwave to 100° C. for 10 minutes. The reaction was filtered and the filtrate was concentrated. The crude residue was purified via flash chromatography (heptanes/EtOAc gradient) to afford the desired product as a yellow solid (58 mg, 40% yield). MS (ESI) ink (M+H+): 283.3.