Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:43]1([CH2:49][CH:50]=O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(O)(=O)C>ClC(Cl)C>[C:43]1([CH2:49][CH2:50][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH:2]2[CH2:11][NH:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3[C:25]([O:27][CH3:28])=[O:26])=[O:14])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3)cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3CCc3ccccc3)cccc21
Yield: 79.1 %

Procedure:
The product from Example 22B (0.2486 g, 0.50 mmol) and sodium triacetoxy borohydride (0.2235 g, 1.05 mmol) were suspended in dichloroethane (10 mL). The reaction flask was equipped with stir bar and spetum, then flushed with N2. Phenylacetaldehyde (0.10 mL, 0.85 mmol) was added followed by glacial acetic acid (0.2 mL, 3.4 mmol). After 1 hour of stirring at ambient temperature, the reaction mixture was quenched with water (20 mL) then partitioned between ethyl acetate/water. The aqueous phase was extracted with ethyl acetate (2×15 mL). The combined organic fractions were washed sequentially with aqueous saturated NaHCO3 (1×25 mL), water (1×25 mL), and brine (1×25 mL), dried (MgSO4), filtered and concentrated in vaco. The crude material was purified via column chromatography (2% to 5% methanol/dichloromethane) to afford the titled compound (0.1913 g, 79%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.99 (s, 1 H) 8.43 (s, 1 H) 7.80 (d, J=7.80 Hz, 1 H) 7.69 (d, J=8.48 Hz, 1 H) 7.48 (t, J=8.14 Hz, 1 H) 7.25 (m, 5 H) 7.04 (m, 1 H) 6.95 (d, J=7.46 Hz, 1 H) 6.71 (d, J=8.14 Hz, 1 H) 6.51 (t, J=6.95 Hz, 2 H) 4.03 (s, 3 H) 3.72 (m, 1 H) 3.37 (m, 3 H) 3.13 (m, 1 H) 2.82 (m, 3 H) 2.59 (m, 1 H) 1.89 (m, 1 H) 1.55 (m, 1 H). MS (ESI) m/z 484 (M+H)+, 482 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]1[O:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:19][C:20]2[O:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)o1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (5.0 g, 24 mmol) in 1,2-dimethoxyethane (40 ml) was added sodium hydride (60% in oil, 576 mg, 24 mmol) under ice-cooling and the mixture was stirred at room temperature for 1 hr. To the reaction solution was dropwise added a solution of. 2-(bromomethyl)-5-(trifluoromethyl)furan (6 g, 26 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate (4.5 g, 52%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:24]([CH3:26])[CH3:25]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH:24]([CH3:26])[CH3:25])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(Br)cc1OCc1ccccc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(Br)cc(OCc2ccccc2)c1=O
Reaction time: 8 h
Yield: 25.2 %

Procedure:
3-(Benzyloxy)-5-bromopyridin-2(1H)-one (200 mg, 0.714 mmol), Cs2CO3 (302 mg, 0.928 mmol), and 2-iodopropane (0.086 mL, 0.857 mmol) were combined in DMF (3 mL) at RT. After stirring overnight the mixture was concentrated. The residue was taken up in CH2Cl2, filtered through a pad of Celite®, and concentrated. Flash column (Biotage-SNAP-10 g, 0-30% EtOAc/hexanes) gave the title compound as a clear oil (58 mg, 25%) which solidified under vacuum. 1H NMR (400 MHz, CDCl3): δ 7.46-7.29 (m, 5 H); 7.05 (d, J=2.4 Hz, 1 H); 6.66 (d, J=2.4 Hz, 1 H); 5.34-5.25 (m, 1 H); 5.09 (s, 2 H); 1.35 (d, J=6.8 Hz, 6 H). LC/MS (M+H)+ 322/324.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 115 °C
Yield: 47 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride was dissolved in dimethyl sulfoxide (1.0 mL). 2-Chloro-5-(trifluoromethyl)pyridine (36.0 mg, 0.198 mmol, 1.9 equivalents) and sodium carbonate (82.0 mg, 0.774 mmol, 7.5 equivalents) were added, and the resulting suspension was heated to 115° C. for 14 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, and then dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified via silica chromatography on 2 sequentially linked 4 g silica cartridges, eluted with 25:75 to 0:100 heptanes:ethyl acetate to give the titled compound (26 mg, 0.055 mmol, 47% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.66 (dd, J=9.0, 2.2 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 5.56-5.20 (m, 1H), 4.63 (d, J=14.4 Hz, 1H), 4.34 (d, J=15.2 Hz, 1H), 4.03 (td, J=9.3, 3.7 Hz, 1H), 3.90 (d, J=12.0 Hz, 1H), 3.83 (dd, J=16.0, 8.0 Hz, 1H), 3.56-3.41 (m, 1H), 3.36 (dd, J=14.4, 9.7 Hz, 1H), 2.72 (dd, J=12.1, 7.3 Hz, 2H), 2.66 (ddd, J=14.2, 9.1, 5.1 Hz, 1H), 2.15 (d, J=14.0 Hz, 1H), 2.06-1.91 (m, 1H), 1.04-0.88 (m, 4H); 1H NMR (400 MHz, pyridine-d5) δ ppm 8.64 (s, 1H), 8.25 (d, J=1.2 Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.79 (dd, J=9.1, 2.4 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 5.53-5.38 (m, 1H), 4.67 (d, J=14.3 Hz, 1H), 4.46 (d, J=15.4 Hz, 1H), 4.14 (d, J=13.2 Hz, 1H), 4.04 (ddd, J=18.1, 11.2, 4.4 Hz, 2H), 3.57-3.40 (m, 2H), 2.96-2.80 (m, 2H), 2.62 (ddd, J=14.1, 9.0, 5.3 Hz, 1H), 2.16 (dd, J=14.0, 3.3 Hz, 1H), 2.04 (td, J=8.2, 4.1 Hz, 1H), 1.15-1.04 (m, 2H), 1.04-0.83 (m, 2H); MS (ESI+) m/z 434.1 (M+H)+; [α]D24.6=37.3 (c=0.85, CH3OH).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CO)OC
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OC
Yield: 109 %

Procedure:
A 100 mL, round bottom flask equipped with a magnetic stirrer and a nitrogen inlet is added N-benzyloxycarbonyl-L-valine (3.6 g), dichloromethane (25 mL), and 2,2-dimethoxyethanol (1.85 g) and the mixture is cooled using an ice bath (0-5° C.). DMAP (0.089 g) is added to the reaction mixture followed by the addition of DCC (3.6 g) over a period of 2 minutes. The suspended solid is filtered, the filter cake is washed with 3×10 mL of heptanes, and the filtrate is concentrated. The crude product is purified by silica gel chromatography (4:1, heptanes/ethyl acetate eluent) to provide 5.3 g of 2,2-dimethoxyethyl N-benzyloxycarbonyl-L-valinate.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.[CH2:40]([N:42]=[C:43]=[O:44])[CH3:41]>C(Cl)Cl>[CH2:40]([NH:42][C:43]([N:21]1[CH2:22][CH2:23][C:17]2[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])=[N:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=3)=[N:19][C:18]=2[CH2:20]1)=[O:44])[CH3:41]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)NCC)C3)cc1
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (example 13 as a hydrochloride salt) (99 mg, 0.25 mmol) in DCM (3 mL) at room temperature (20° C.) was added DIPEA (44 uL, 0.26 mmol) followed by ethyl isocyanate (22 uL, 0.27 mmol). The reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) to afford a brown solid (55 mg, 47%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[O:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:23][CH2:24][CH:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(Oc3ccccc3)CC2)cc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (0.15 g, 1.063 mmol) and 4-phenoxypiperidine hydrochloride (0.250 g, 1.169 mmol) in dimethylformamide (2.126 ml) was treated with potassium carbonate (0.367 g, 2.66 mmol). The suspension was stirred at ambient temperature 2 hours, at 55° C. for 4 hours and at ambient temperature for 16 hours. The reaction was poured into water and the suspension was filtered and vacuum dried to provide the title compound.
Reaction SMILES: [CH2:1]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[CH2:1]([CH:7]([NH2:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC(=O)CCCCCC
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC(N)CCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 116.1 %

Procedure:
In a 250 mL round bottom flask, 5.00 g (25.5 mmol) dihexylketone, 19.7 g (255 mmol) ammonium acetate, and 1.10 g (17.8 mmol) sodium cyanoborohydride (NaBH3CN) were dissolved in 75 mL absolute MeOH and stirred at room temperature for 48 hours, until no significant amount of the starting material could be detected by NMR. The mixture was quenched by adding concentrated hydrochloric acid (HCl) dropwise (˜3 mL), then concentrated in vacuo. The resulting white solid was taken up in 500 mL water, basified to pH 10 with solid potassium hydroxide (KOH), and extracted with chloroform (CHCl3) twice (200 mL each). The CHCl3 fractions were combined and concentrated to give 4.12 g (81%) of 1-hexylheptylamine 1 as a pale yellow oil. 1H NMR (D2O, 500 MHz): δ 0.73 (t, 6H), 1.15-1.23 (m, 16H), 1.55 (m, 4H), 3.13 (m, 1H).
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:24])[CH2:4][CH2:3]2.[CH3:25]I>>[CH3:25][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:24]
Reactant: CI
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3cccc(Cl)c3)ccc12
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4cccc(Cl)c4)cc3CC[C@@H]12

Procedure:
A 612 mg portion of (4aR)-(10bR)-10b-methyl-8-(3-chlorophenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one was methylated with methyl iodide substantially as shown in Example 95. Attempts at crystallization of the product were unsuccessful, so it was characterized as an opaque colorless oil, 525 mg. FDMS: m/e=371. α[D]589 =+72.9, α[D]365 =+265.2 (chloroform).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:32])=[CH:29][C:28]=3[O:43][CH3:44])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)cc1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Nc4ccc(C(=O)NC5CCN(C)CC5)cc4OC)nc32)cc1
Yield: 99.2 %

Procedure:
A mixture of 0.11 g (0.30 mmole) of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-291), 0.088 g (0.22 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.062 g (0.33 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.13 g of 4-[7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-291) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[C:5]([Br:17])=[CH:4][N:3]=1.[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]1[CH:41]([NH2:43])[CH3:42])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:30][CH:29]1[CH:41]([NH:43][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[C:5]([Br:17])=[CH:4][N:3]=1)[CH3:42])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1ncc(Br)c(-n2cnc3ccccc32)n1
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(Nc1ncc(Br)c(-n2cnc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reaction time: 14 h

Procedure:
A solution of 2-chloro-4-(benzimidazol-1-yl)-5-bromopyrimidine (100 mg) and 1-benzyloxycarbonyl-2-(1-aminoethyl)-4-tert-butyloxycarbonylpiperazine, diastereomer 1 (EXAMPLE 14 Step D; 115 mg), in 10 mL of toluene was heated to 100° C. and stirred overnight (14 h) at this temperature. The mixture was then cooled and diluted with 20 mL of EtOAc and 30 mL of water. The phases were separated and the aqueous phase was extracted with 2×20 mL of EtOAc. The combined organics were dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 20:1 hexanes-acetone to provide 133 mg of the title compound. Mass spectrum (ESI) 638.4 (M+1).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11])[CH:2]=[CH2:3].[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1>CN(C)C=O>[CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[O:11][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:26])[F:25])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1CCCC[C@H]1O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@H]1CCCC[C@@H]1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
To 15 mL anhydrous DMF (dimethylformamide) was added trans 2-allyloxy-cyclohexanol (1.144 g, 7.323 mmol), then NaH (60% in oil, 0.4261 g, 10.65 mmol) was added and stirred at room temperature 15 min. Then 4-fluoro-2-trifluoromethyl benzonitrile (1.435 g, 7.59 mmol) was added, and the solution was stirred at room temperature overnight. The DMF solution was extracted twice with hexane. Then the reaction mixture was poured into 100 mL of water and extracted three times with ether. The combined ether layers were extracted three times with water, then once with brine, and dried over magnesium sulfate, filtered, and the solvent removed. The crude product was chromatographed with a hexane/methylene chloride mixture (100% hexane to 1:1 hexane/methylene chloride). The desired fractions were combined, and the solvent removed to give 0.6245 g product. HNMR (CDCl3, ppm) 7.70-7.68 (1H, d, J=8.8 Hz), 7.32 (1H, s), 7.19-7.16 (1H, d, J=8.8 Hz), 5.80-5.71 (1H, m), 5.20-5.0 (2H, m), 4.30-4.20 (1H, m), 4.10-4.00 (1H, m) 4.00-3.90 (1H, m), 3.50-3.39 (1H, m), 2.20-2.00 (2H, m), 1.80-1.70 (2H, m), 1.65-1.20 (5H, m). FNMR (CDCl3)-62.67 ppm. MS+326.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=2)[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:7][CH2:6]1.CCN(CC)CC.[CH3:44][OH:45].CN([CH:49]=[O:50])C>>[CH3:44][O:45][C:49](=[O:50])[C:32]1[CH:33]=[CH:34][C:29]([CH:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:36])[CH2:6][CH2:7]2)[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[CH:30][CH:31]=1
Reactant: CN(C)C=O
Reactant: CO
Reactant: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc2)CC1
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C(=O)OC)cc2)CC1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer were introduced {4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-bromo-phenyl)-ethyl]-piperazin-1-yl}-acetic acid methyl ester (compound 184 prepared at example 1.4.1 above; 0.5 g, 0.8 mmoles), Et3N (0.26 ml, 1.8 mmoles), MeOH (3 ml) and DMF (9 ml). The mixture was purged with N2 and a stream of CO was passed into the mixture for 10 min. A solution of Pd(OAc)2 (19.2 mg, 10% moles) and Diphenylphosphinopropane (Dppp) (33 mg, 10% moles) dissolved in MeOH/DMF 1/3 (0.65 ml), purged with N2, was then added to the mixture. The reaction mixture was heated at 70° C. and CO was bubbled through the reaction mixture overnight. The reaction mixture was purged with N2, quenched with NaHCO3 and extracted with AcOEt. The combined organic layers were dried over MgSO4 and concentrated to give an oil which was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/NH3: 99.5/0.5/0.1 v/v/v) to afford 4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-methoxycarbonylmethyl-piperazin-1-yl)-ethyl]-benzoic acid methyl ester (compound 316; 150 mg, 30%).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1)#N.Cl.[C:20](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:21].C[OH:36]>>[N:6]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][C@@H:3]([C:1]([O:21][CH3:20])=[O:36])[CH2:4][C@H:5]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-cyanopyrrolidine-1,2-dicarboxylate (9.0 g, 35.4 mmol) in MeOH (196 mL) was added HCl (4M in 1,4-dioxane, 100 mL, 403 mmol). The solution was stirred at room temperature for 16 h and concentrated in vacuo. The crude intermediate was dissolved in EtOAc (180 mL) and basified with aqueous bicarbonate (sat.). Di-tert-butyl dicarbonate (8.5 g, 38.9 mmol) was added and the biphasic solution was stirred at room temperature for 12 h. The layers were then separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude oil was purified by silica gel chromatography (15% to 40% to 100% EtOAc/Hexanes) to provide (2S,4S)-1-tert-butyl 2,4-dimethyl pyrrolidine-1,2,4-tricarboxylate (9.56 g, 94%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH:26]([OH:29])[CH2:27][NH2:28].O>C1C=CC=CC=1>[OH:3][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:28][CH2:27][CH:26]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=2)[OH:29])[CH3:15])=[CH:9][CH:8]=1
Reactant: NCC(O)c1cc2ccccc2o1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-carbomethoxymethoxyphenyl)-propan-2-one (1 g) and 2-(2-benzofuranyl)-2-hydroxyethanamine (0.8 g) in benzene (80 ml) was boiled under reflux for one hour, with azeotropic removal of water, using a Dean and Stark head. The solution was evaporated, the residue dissolved in methanol (80 ml), cooled in ice, and excess sodium borohydride added. The solution was stirred at ambient temperature for 1 hour, heated under reflux for one hour, the methanol evaporated and the residue partitioned between water and ethyl acetate. The dried organic extract was evaporated to give an oil which was chromatographed on silica gel in 4% methanol/dichloromethane. The resulting oil was treated with ethereal hydrogen chloride to give the title compound as the hydrochloride salt hemi-hydrate, isolated as a 50:50 mixture of diastereoisomers. (mpt 56°-65°) (Ethyl Acetate-Ether).