Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C@@:30]21[CH2:48][C:40]1=[N:41][CH:42]=[C:43]([C:45]([OH:47])=O)[CH:44]=[C:39]1[CH2:38]2.Cl.[NH2:50][C@H:51]1[CH2:56][C@@H:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:54]([CH3:63])[N:53]([CH2:64][C:65]([F:68])([F:67])[F:66])[C:52]1=[O:69].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:63][C@H:54]1[N:53]([CH2:64][C:65]([F:68])([F:66])[F:67])[C:52](=[O:69])[C@@H:51]([NH:50][C:45]([C:43]2[CH:44]=[C:39]3[CH2:38][C@@:30]4([C:31]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:37][C:29]4=[O:28])[CH2:48][C:40]3=[N:41][CH:42]=2)=[O:47])[CH2:56][C@H:55]1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 23 °C
Reaction time: 3 h

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.89 g, 4.28 mmol) was added to a solution of (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 1) (1.10 g, 3.92 mmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 4) (1.15 g, 3.56 mmol), and N,N-diisopropylethylamine (3.11 mL, 17.8 mmol) in DMF (40 mL), and the resulting mixture was stirred at 23° C. for 3 h. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl actetate (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with hexanes initially, then grading to 100% EtOAc before stepping to 5% MeOH in EtOAc to afford the title compound as an amorphous solid, which was further purified by the following crystallization procedure. A solution of the amorphous product in a minimal amount of methanol required for dissolution was diluted with 10 volumes water, and the resulting slurry was seeded with crystalline product and stirred at 23° C. for 4 h. The solids were filtered, washed with water, and dried under a stream of nitrogen to give the title compound as a crystalline solid. HRMS: m/z=550.2068, calculated m/z=550.2061 for C29H27F3N5O3. 1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.70 (s, 1H), 8.17 (dd, 1H, J=5.4, 1.5 Hz), 8.04 (s, 1H), 7.37 (m, 3H), 7.29 (t, 1H, J=7.3 Hz), 7.21 (d, 2H, J=7.3 Hz), 7.13 (dd, 1H, J=7.3, 1.2 Hz), 6.89 (dd, 1H, J=7.3, 5.4 Hz), 4.99-4.90 (m, 1H), 4.53 (dt, 1H, J=10.7, 6.6 Hz), 3.94 (p, 1H, J=5.9 Hz), 3.78 (d, 1H, J=17.1 Hz), 3.67 (d, 1H, J=16.4 Hz), 3.65 (m, 1H), 3.34-3.26 (m, 1H), 3.28 (d, 1H, J=17.1 Hz), 3.17 (d, 1H, J=16.6 Hz), 2.79 (m, 1H), 2.58 (q, 1H, J=12.7 Hz), 1.07 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CO.[Zn]>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1

Procedure:
2-(4-Benzyloxyphenoxy)-5-nitropyridine (7.84 g, 24.32 mmol) and zinc (15.16 g, 231.8 mmol) were suspended in 300 ml of methanol. Under argon 5.2 ml of acetic acid were slowly added dropwise at room temperature. After 1 h the mixture was filtered and the filtrate was concentrated. The crude product obtained was further reacted without purification.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C:41]#[CH:42]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([NH:39][CH2:40][C:41]#[CH:42])=[O:35])(=[O:29])=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: C#CCN
Product: C#CCNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 70.5 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 40 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]+.
Reaction SMILES: C(Cl)Cl.Cl.[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:22]=[CH:21][C:20]3[N:19]=[CH:18][C:17]4[CH2:23][N:24]([CH3:34])[C:25](=[O:33])[N:26]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[C:16]=4[C:15]=3[N:14]=2)=[CH:9][CH:8]=1.[C:35](O)(=[O:39])[C@@H:36]([CH3:38])[OH:37].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CO.C(N(CC)CC)C>[OH:37][C@H:36]([CH3:38])[C:35]([N:30]1[CH2:31][CH2:32][CH:27]([N:26]2[C:16]3[C:15]4[N:14]=[C:13]([C:10]5[CH:11]=[N:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=5)[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[CH2:23][N:24]([CH3:34])[C:25]2=[O:33])[CH2:28][CH2:29]1)=[O:39]
Reactant: C[C@@H](O)C(=O)O
Reactant: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCNCC2)C(=O)N(C)C4)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)[C@@H](C)O)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To DCM (20 mL) were added 9-(6-methoxypyridin-3-yl)-3-methyl-1-(piperidin-4-yl)-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-2(1H)-one hydrochloride salt (Compound 1) (100 mg, 0.227 mmol) and triethylamine (0.177 mL). The mixture was stirred at ambient temperature for 0.5 h. Then to the mixture were sequentially added (R)-lactic acid (26.7 mg, 0.296 mmol), 1-hydroxybenzotriazole (37.8 mg, 0.280 mmol) and 1-ethyl-(3-dimethyllaminopropyl)carbodiimide hydrochloride (70.8 mg, 0.37 mmol). The reaction mixture was stirred at ambient temperature for 2 h, and the completion of the reaction was indicated by TLC (DCM/methanol=10/1). The reaction mixture was washed sequentially with saturated aqueous sodium carbonate, water and brine. The organic phase was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (DCM/methanol=10/1) to give a white solid (88 mg, 81.4% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:15]([CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([O-])=O>ClC1C=CC(CN)=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:13][C:12]=3[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:18]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Agent: NCc1ccc(Cl)cc1
Product: Clc1ccc(Cn2cc(-c3ccc(Cl)cc3)c3c2CCNC3)cc1
Yield: 52.4 %

Procedure:
The title compound (260.2 mg) was prepared from 0.55 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 340 μL of 4-chlorobenzylamine, and 0.51 g of (2-nitro-vinyl)-4-chlorobenzene. MS (ESI): exact mass calculated for C20H18Cl2N2, 356.08. found, m/z 357.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.31 (m, 6H), 7.17-7.13 (m, 3H), 5.15 (s, 2H), 4.35 (s, 2H), 3.51 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C1(C)C=CC=CC=1>N1C=CC=CC=1>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCCCN1CCOCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1NCCCN1CCOCC1
Temperature: 130 °C
Reaction time: 14 h

Procedure:
N-(3-Aminopropyl)morpholine (1.04 ml) was added to a solution containing 2-chloronitrobenzene (1.005 g) in pyridine (0.78 ml), and stirred for 14 hours at 130° C. Toluene was added to the reaction mixture and concentrated. The residue, with ethyl acetate added thereto, was extracted with 1N hydrochloric acid aqueous solution. The extract was alkalified with 1N sodium hydroxide aqueous solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (1.217 g) as orange oil.
Reaction SMILES: [O:1]([CH3:13])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>N1C=CC=CC=1>[Br:34][CH:11]([OH:12])[C@H:9]1[O:10][C@H:2]([O:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](C(O)Br)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
To a 0° C. solution of methyl α-D-glucopyranoside (3.9 g, 20 mmol) in 125 mL of anhydrous pyridine was added triphenylphosphine (10.5 g, 40 mmol) followed by carbon tetrabromide (9.9 g, 30 mmol). The reaction was stirred at 0° C. for 10 minutes then warmed to 65° C. for 4 hours. The reaction was quenched with 20 mL of methanol and concentrated to a crude residue, a portion of which was purified by column chromatography eluting from silica gel with a gradient of 0 to 15% methanol in dichloromethane to give 1.1 g of an off-white solid (64%). 1H NMR (400 MHz, d6-DMSO) δ 3.00-3.06 (m, 1H), 3.16-3.23 (m, 1H), 3.30 (s, 3H), 3.30-3.41 (m, H), 3.47-3.57 (m, 2H), 3.73-3.76 (dd, J=1.6, 10.3 Hz, 1H), 4.56-4.57 (d, J=3.6 Hz, 1H), 4.82-4.83 (d, J=6.4 Hz, 1H), 4.90-4.91 (d, J=5.0 Hz, 1H), 5.21-5.23 (d, J=5.9 Hz, 1H). 13C NMR (100 MHz, d6-DMSO) δ 35.2, 55.0, 71.0, 71.9, 72.3, 73.0, 99.9.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1C=CC([CH2:35][C:36]#[N:37])=CC=1.Cl>CN(C=O)C>[CH2:7]([O:14][C:15]1[C:16]([C:24]([F:25])([F:26])[F:27])=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:35][C:36]#[N:37])[CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: N#CCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cc(OCc2ccccc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Potassium tert-butoxide (3.94 g, 35.4 mmol) was dissolved in anhydrous DMF (15 ml) and a mixture of 2-benzyloxy-5-nitro-trifluoromethylbenzene (3.5 g, 16.1 mmol) and 4-chlorophenylacetonitrile (2.96 g, 17.7 mmol) in DMF (20 ml) was added over 30 minutes keeping the temperature at −15C. The mixture was stirred at −10° C. for 1 hour, then poured into 1M hydrochloric acid (150 ml) and the product extracted with dichloromethane (2×100 ml). The organic extracts were dried (MgSO4) and purified by silica column chromatography eluting with dichloromethane/hexane (1/1) to give 5-benzyloxy-2-nitro-4-(trifluoromethyl)phenylacetonitrile (5.2 g, 77%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]([CH:19]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:20](OCC)=[O:21])=[C:17]=[O:18]>>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([N:14]3[C:20](=[O:21])[CH:19]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:16][C:17]3=[O:18])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: CCOC(=O)C(CC(C)C)N=C=O
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(C)C)C2=O)cn1
Yield: 50 %

Procedure:
Prepared as in Example 10-41 from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 10-41a) and ethyl 2-isocyanato-4-methylpentanoate. Yield: 50%. 1H NMR (CDCl3, 400 MHz): δ 1.01-0.98 (m, 8H), 1.87-1.82 (m, 1H), 2.19 (s, 3H), 2.41 (s, 3H), 4.13-4.12 (t, 1H), (5.05 (s, 2H), 5.70 (bs, 1H), 7.90 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.0 μM.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C)c(Oc2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A suspension of 1-methyl-4-(methyloxy)-2-[(4-nitrophenyl)oxy]benzene (Intermediate 13, 2.5 g) and Pd/C (10%, 1 g) in MeOH (100 mL) was stirred under H2 atmosphere for overnight at room temperature and filtered through a pad of celite. The filtrate was evaporated to afford the title compound as a solid (2.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][C:11]#[N:12])[C:3]=1[N+:13]([O-])=O.O.C(O)(=O)C>C(O)C.[Zn]>[NH2:13][C:3]1[C:4]([NH:8][CH2:9][CH2:10][C:11]#[N:12])=[N:5][CH:6]=[N:7][C:2]=1[Cl:1]
Reactant: N#CCCNc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#CCCNc1ncnc(Cl)c1N
Reaction time: 0.5 h

Procedure:
2-[(6-Chloro-5-nitro-4-pyrimidinyl)amino]ethyl cyanide (18.7 g, 82.2 mmol) was dissolved in 180 ml ethanol, 180 ml water and 18 ml acetic acid, and zinc powder was added slowly thereto at 0° C. The reaction solution was returned to room temperature and stirred for 30 minutes. Then, the insoluble matters were filtered off, and the filtrate was evaporated. The residue was diluted with ethyl acetate and washed with water and brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was suspended in diethyl ether, and the precipitated solid was collected by filtration to give the title compound which was then washed with diethyl ether to give the title compound (44.6 g, 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[CH3:21]C#N>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]([CH3:21])[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)ccc21
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (4.0 g, 12.8 mmol), iodomethane (2.74 g, 9.2 mmol), and K2CO3in CH3CN (60 mL) was stirred at room temperature under a blanket of nitrogen overnight. Upon completion of the reaction, ethyl acetate (200 mL) was added and the organic layer was washed with H2O (200 mL), dried over Na2SO4, and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 5-bromo-3-methyl-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as a white solid: mp 98-99° C.; 1H-NMR (CDCl3) δ7.7 (d, 1H, J=8,5 Hz), 7.27 (bs, 2H), 7.09 (d, 1H, J=2 Hz), 3.4 (s, 3H), 1.7 (s, 9H); MS (ES) m/z 349([M+Na]+, 20%), 351([M+Na]+, 20%); Anal. Calc. For C13H15BrN2O3: C, 47.73; H, 4.62; N, 8.56. Found: C, 47.46; H, 4.5; N, 8.29.
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9](=[O:18])[C:10]([CH3:17])([CH3:16])[CH2:11][C:12](=[O:15])[CH2:13]Br)[CH3:7].[CH3:19][C:20]([SH:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CCCCCC>[CH2:6]([O:8][C:9](=[O:18])[C:10]([CH3:17])([CH3:16])[CH2:11][C:12](=[O:15])[CH2:13][S:23][C:20]([CH3:22])([CH3:21])[CH3:19])[CH3:7]
Reactant: CCOC(=O)C(C)(C)CC(=O)CBr
Reactant: CC(C)(C)S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Temperature: -2.5 °C
Reaction time: 25 h

Procedure:
To a reaction flask containing THF (5.0-fold, V/W of starting material) was added 5-bromo-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester (1.0 eq) under N2. The mixture was cooled to a temperature of −5-0° C., and a solution of 2-methyl-2-propanethiol (1.2 eq) and triethylamine (1.25 eq) was added while maintaining the temperature below 0° C. The reaction was stirred at room temperature for 25 hours, and then hexane (3.0-fold, V/W of starting material) was slowly added. After agitating for 30 minutes, the solid material was removed by filtration and washed with 50% EtOAc/hexane solution. The filtrate was concentrated under reduced pressure to give the desired product, which was taken on to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:36])[NH:24][C@@H:25]([CH2:29][C@H:30]3[CH2:35][CH2:34][CH2:33][O:32][CH2:31]3)[CH2:26][NH:27][CH3:28])[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:37]([OH:46])(=[O:45])[C@@H:38]([C@H:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]>C(O)C>[C:42]([C@@H:40]([C@H:38]([C:37]([O-:46])=[O:45])[OH:39])[OH:41])([O-:44])=[O:43].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:36])[NH:24][C@@H:25]([CH2:29][C@H:30]3[CH2:35][CH2:34][CH2:33][O:32][CH2:31]3)[CH2:26][NH:27][CH3:28])[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CNC[C@H](C[C@H]1CCCOC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Solvent: CCO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 35 °C
Reaction time: 2 h

Procedure:
The free base of methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-(methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (0.28 g, 0.53 mmol) and L-tartaric acid (84.4 mg, 0.56 mmol, 99.5%) were dissolved in ethanol (5 mL) to give a clear solution. The solvent was removed in vacuo to dryness, and the residue was redissolved in 95% ethanol:MeCN (3:97 v/v) (10.5 mL) at 35° C. A seed crystal was added and the resulting solution was stirred at 35° C. for 2 hr, then cooled to rt slowly, and stirred for 48 hr. The resulting white crystal was filtered and washed with MeCN (2×5 mL) to give 1:1 L-tartrate of methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-(methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (0.31 g, 84%). Selected 1H NMR (CD3OD, 400 MHz), δ: 7.36 (m, 3H), 7.22 (d, 1H), 4.40 (s, 2H), 4.18-4.00 (m, 3H), 3.86 (m, 3H), 3.62 (s, 3H), 3.40 (m, 1H), 3.24 (m, 3H), 3.18-2.84 (m, 5H), 2.72 (s, 3H), 1.90-1.08 (m, 12H); mp=122-127° C. MS ESI +ve m/z 525 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:21]=[C:20](Cl)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=4)[N:13]=3)[CH2:9][CH2:8][CH2:7][C:6]=2[CH:24]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:21]=[C:20]([NH:27][CH2:26][CH2:25][NH2:28])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=4)[N:13]=3)[CH2:9][CH2:8][CH2:7][C:6]=2[CH:24]=1
Reactant: NCCN
Reactant: Clc1ccc2nc(N3CCCc4cc(Br)ccc4C3)cc(Cl)c2c1
Product: NCCNc1cc(N2CCCc3cc(Br)ccc3C2)nc2ccc(Cl)cc12
Temperature: 160 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
The mixture of 7-bromo-2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (200 mg, 0.47 mmol) and ethane-1,2-diamine (0.5 mL) was heated with stirring in a 5 mL microwave process vial for 2 hours at 160° C. under microwave irradiation. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give 38 mg of product (yield was 18%). MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (d, J=2.4 Hz, 1 H), 7.49 (d, J=8.8 Hz, 1 H), 7.41 (m, 1 H), 7.35 (m, 1 H), 7.31 (m, 2 H), 5.99 (s, 1 H), 4.80 (s, 2 H), 4.13 (m, 2 H), 3.40 (m, 2 H), 3.00 (m, 4 H), 1.90 (m, 2 H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16]>CO>[C:1]1([N:7]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: ON=C1CCN(c2ccccc2)CC1
Yield: 91.9 %

Procedure:
A mixture of 1-phenyl-piperidin-4-one (180 mg, 1.03 mmol) and hydroxylamine hydrochloride (142 mg, 2.06 mmol) in methanol (10 mL) was heated at reflux for 6 h. The solvent was evaporated and the residue diluted with water. The mixture was extracted with ethyl acetate then the organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to afford 1-phenyl-piperidin-4-one oxime (0.18 g, 92%) as a liquid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C:27]=2[CH2:28]C)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:8].[NH2:36][C:37]([NH2:39])=[O:38].C(Cl)(Cl)Cl>O>[CH3:5][O:6][C:7]([CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:19]=1)[C:10]([NH:36][C:37]([NH2:39])=[O:38])=[O:12])=[O:8]
Reactant: CCc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(=O)O)C(=O)OC)cc1
Reactant: NC(N)=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)NC(N)=O
Temperature: 60 °C
Yield: 82.2 %

Procedure:
Thionyl chloride (4.0 ml) was added to 2-methoxycarbonyl-3-[4-(2-(5-ethyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (4.10 g, 10.0 mmol) obtained in Example 1 and the mixture was stirred with heating at 60° C. for 1 hr. Excess thionyl chloride was evaporated under reduced pressure and urea (900 mg, 15.0 mmol) was added to the residue obtained, which was followed by stirring with heating at 100° C. for 45 min. Chloroform (100 ml) and water (50 ml) were added for partition. The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:1) to give the title compound (3.71 g, yield 82%) as a white solid.
Reaction SMILES: C([CH2:5][C:6]([C@@H:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:12]([O:11][C:9](=[O:10])[C@@H:8]([C:6](=[O:7])[CH3:5])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)CC(=O)[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 105.3 %

Procedure:
The product from Example 94 (0.52 g, 1.47 mmol) was dissolved in a 1:1 (v:v) solution (6 mL). of trifluoroacetic acid and dichloromethane and stirred at room temperature for 1 h. The volatiles were removed in vacuo to provide the title compound (0.437 g, 100%) as an oil which crystallized on standing. The unpurified material was of sufficient purity to employ in subsequent steps. Mass spectrum: (M)+=298.