Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:9]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][CH2:11]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:31]([O:38]CC)([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34]>>[C:1]([C@H:9]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][CH2:11][P:31]([O:35][CH2:36][CH3:37])(=[O:38])[O:32][CH2:33][CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CCBr)C(=O)c1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCCCCCCCCCCCCCCCOC[C@H](CCP(=O)(OCC)OCC)C(=O)c1ccccc1
Yield: 81.5 %

Procedure:
A solution of 4.98 g (10.0 mmol) of bromide 4 in 25 mL (150 mmol) of triethyl phosphite [(EtO)3P] was heated at 150° C. (oil bath temperature) overnight. After the excess of (EtO)3P was removed by using a stream of air, the residue was purified by column chromatography on silica gel (elution with CHCl3/MeOH 25:1) to give 4.39 g (79%) of benzoyl phosphonate 5 as a colorless oil; [α]25D −6.88° (c 5.8, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=6.7 Hz), 1.26 (br s, 26H), 1.28-1.33 (m, 6H), 1.70-2.00 (m, 2H), 3.43-3.62 (m, 4H), 4.06-4.12 (m, 4H), 5.23-5.27 (m, 1H), 7.42-7.46 (m, 2H), 7.54-7.59 (m, 1H), 8.04 (d, 2H, J=7.0 Hz); 13C NMR (CDCl3) δ 14.1, 16.4 (d, J=5.8 Hz), 22.2 (d, J=143.2 Hz), 22.6, 24.3 (d, J=4.0 Hz), 29.3, 29.4, 29.6, 29.7, 31.9, 61.6, 71.3, 71.7, 72.8 (d, J=18.1 Hz), 127.7, 128.3, 129.6, 130.1, 133.0, 166.0; MS (electrospray) MH+m/z calcd for C31H56O6P 555.39, found 555.3.
Reaction SMILES: FC(F)(F)C1ON=C(C2SC(C(O)=O)=CC=2)C=1C.ClC1C=CN=CC=1NC(C1SC(C2C(C)=C(C(F)(F)F)ON=2)=CC=1)=O.[CH3:44][NH:45][C:46]([C@@H:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:54]([C:56]2[S:57][C:58]([C:61]3[C:65]([CH3:66])=[C:64]([C:67]([F:70])([F:69])[F:68])[O:63][N:62]=3)=[CH:59][CH:60]=2)=[O:55])[CH2:49]1)=[O:47]>>[CH3:44][NH:45][C:46]([C@H:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:54]([C:56]2[S:57][C:58]([C:61]3[C:65]([CH3:66])=[C:64]([C:67]([F:69])([F:70])[F:68])[O:63][N:62]=3)=[CH:59][CH:60]=2)=[O:55])[CH2:49]1)=[O:47]
Reactant: CNC(=O)[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Agent: Cc1c(-c2ccc(C(=O)Nc3cnccc3Cl)s2)noc1C(F)(F)F
Agent: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: CNC(=O)[C@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Yield: 81 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3S)-N-methylpiperidine-3-carboxamide (Preparative Example 32) in the same manner as the 3R isomer (Example 89) to afford product as a colorless solid (303 mg, 81%). LC/MS 5.88 min, [M+1]+ 402.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.CS[C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32].C(N(CC)CC)C>CO>[CH3:32][N:31]1[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[S:28](=[C:6]2[C:5](=[O:7])[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:3][CH:2]2[CH3:1])[CH2:27]1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1NN(c2ccccc2)C(=O)C1=S1CN(C)c2ccccc21
Reaction time: 1 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01 mol) was mixed with 3.68 g (0.01 mol) 2-methylthio-3-methylbenzothiazolium tosylate in 25 ml methanol. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for one hour, then filtered and washed with methanol. After drying the yield was 2.46 g (78%), mp 159°-162° C., λmax=375 (ε=25,000).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21](O)[CH2:22][C:23](=[O:29])[CH2:24][C:25]([O:27]C)=[O:26].Cl>C(O)C.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21]1[O:27][C:25](=[O:26])[CH2:24][CH:23]([OH:29])[CH2:22]1
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CC(O)CC(/C=C/c2c(Cl)cc(Cl)cc2OCc2ccccc2)O1
Yield: 107.5 %

Procedure:
Sodium tetrahydridoborate (1.55 g, 41.1 mmole) was added with stirring to a cooled solution (5° C.) of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-5-hydroxy-3-oxo-6-heptenoate (34.8 g, 82.3 mmole) in ethanol (200 ml) at a rate sufficient to maintain the internal temperature at 15°-20° C. The resulting solution was stirred with ice-bath cooling for 15 min. and then acidified with 6N hydrochloric acid. The resulting mixture was diluted with water (500 ml) and extracted with ether (3×250 ml). The organic extracts were combined, washed with brine (4×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as a yellow oil (34.8 g, 99.5%): pmr CDCl3) δ2.45 (2H, d), 3.65 (3H, s), 4.18 (H, m), 4.45 (H, m), 4.98 (2H, s), 7.28 (5H, s).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][CH:14]([CH2:16][O:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([OH:37])[CH:12]1[F:38].[C:39](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40]>N1C=CC=CC=1>[C:39]([NH:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][CH:14]([CH2:16][O:17][C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]([O:37][C:18](=[O:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]1[F:38])(=[O:40])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1ncn2C1OC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O)C1F
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2C1OC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(OC(=O)c2ccccc2)C1F)c1ccccc1
Reaction time: 8 h
Yield: 198.5 %

Procedure:
Compound 55.2 (18.2 mmol) in pyridine (180 mL) was treated with BzCl (6.33 mL, 54.6 mmol) and stirred overnight. The solvent was removed in vacuo and the solid was dissolved in EtOAc (100 mL) and washed with H2O (2×50 mL). The solution was dried over MgSO4, filtered, and subjected to Combiflash purification (SiO2, 330 g, 0-100% EtOAc-hexanes gradient) which afforded 55.3 as a white solid (13.0 g, 96%, two steps).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Se](=O)=[O:22]>>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:22])[CH:8]=[CH:7]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: BrCc1ccccc1
Reactant: O=[Se]=O
Product: O=Cc1ccc2cccc(OCc3ccccc3)c2n1
Yield: 35 %

Procedure:
The title compound was prepared from 8-hydroxy-2-methylquinoline (6d), benzyl bromide, and selenium dioxide using methods as described in the literature for similar compounds (Buchi et al., 1956) in 35% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21](O)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(Br)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Product: NS(=O)(=O)CC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Br)c1

Procedure:
In anology to the procedure of Example XVI, the title compound is prepared from 2.8 g (7.5 mmol) of the compound from Example XXI, 0.71 g (7.5 mmol) of dried methanesulphonamide, 1.44 g (7.5 mmol) of N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 0.92 g (7.5 mmol) of dimethylaminopyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]([NH2:36])[CH2:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]([NH:36][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:23]([C:18]3[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=3)(=[O:25])=[O:24])[N:9]=2)[CH2:28]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NC1COc2ccccc21
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: O=S(=O)(Nc1cccc2nc(NC3COc4ccccc43)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=454.3 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonyl chloride and rac-2,3-dihydro-benzofuran-3-ylamine (CAS 109926-35-4).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([OH:18])=[O:17].[N+:19]([O-])([OH:21])=[O:20]>>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([N+:19]([O-:21])=[O:20])[C:8]=1[C:16]([OH:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Br)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Br)c(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a 3-L 4-neck round-bottomed flask equipped with a mechanical stirrer, thermometer, 250-mL addition funnel and charged with concentrated H2SO4 (577 mL), was added 4-bromoisophthalic acid (75.0 g, 306 mmol). The white suspension was cooled to ice-bath temperature and a nitrating reagent (pre-prepared by the careful addition of H2SO4 (169 mL) to HNO3 (107 mL)) was slowly added while maintaining an internal reaction temperature of less than 15° C. When addition was complete, the ice-bath was removed and the suspension stirred overnight at room temperature. After approximately 14 hours, the flask was placed in an ice-bath and crushed ice was added to quench the excess nitrating reagent while maintaining an internal temperature less than 40° C. The cream-colored suspension was filtered, and the solids were collected by filtration and washed with a small volume of ice-cold water. The solids were dissolved in methanol and the volatile components were evaporated. The resulting solids were dried at 60° C. in a vacuum oven overnight to afford Intermediate 39(a) (79.6 g) in 87% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](=[N:11][OH:12])[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[NH2:1][C:2]1[C:3]([C:9](=[NH:10])[NH:11][O:12][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=NO)c1nc(Br)cnc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N=C(NOC(=O)c1ccccc1)c1nc(Br)cnc1N
Reaction time: 1 h
Yield: 69.1 %

Procedure:
3-amino-6-bromo-N′-hydroxypyrazine-2-carboximidamide (890 mg, 3.836 mmol) was suspended in dichloromethane (11.56 mL) and treated with triethylamine (427.0 mg, 588.2 μL, 4.220 mmol) followed by benzoyl chloride (593.2 mg, 489.8 μL, 4.220 mmol) The reaction mixture was allowed to stir for 1 hour and concentrated in vacuo. The resultant residue was triturated with methanol to give the desired product as a pale beige solid (891 mg, 69% Yield). 1H NMR (400.0 MHz, DMSO) d 7.55 (2H, m), 7.65 (1H, m), 7.90 (2H, br s), 8.28 (2H, m), 8.33 (1H, s); MS (ES+) 337.87
Reaction SMILES: [Cl-].[CH2:2]([NH+:9]([CH3:41])[CH2:10][CH2:11][O:12][C@H:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([OH:36])=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:42](Cl)(=O)C>CO>[CH2:2]([N:9]([CH3:41])[CH2:10][CH2:11][O:12][C@H:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([O:36][CH3:42])=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[NH+](CCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Reactant: CC(=O)Cl
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)Cc1ccccc1)COc1ccccc1-3

Procedure:
A solution (0.014 M) of N-benzyl-2-{[(7S)-11-carboxy-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl]oxy}-N-methylethanaminium chloride in anhydrous MeOH was treated with acetyl chloride (1.1 eq.). The mixture was heated at reflux overnight. All the volatiles were removed in vacuo to afford the title compound. The product was used in the next step without further purification. (ES+) m/z 553 (M+H)+.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].CO[CH:7](OC)[CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH3:25]>C(O)C>[CH3:3][O:2][N:4]=[CH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH3:25]
Reactant: COC(CCCn1c(C)nc2c(N)nc3ccccc3c21)OC
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=CCCCn1c(C)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methoxylamine hydrochloride (22.8 g, 272 mmol) was added to a solution of 1-(4,4-dimethoxybutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (36.6 g, 136 mmol) in ethanol (200 mL). The reaction mixture was stirred at room temperature for two hours, then was concentrated under reduced pressure. The residue was diluted with water and brought to pH 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with 5% methanol/dichloromethane. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 5% methanol in dichloromethane) followed by recrystallization from ethyl acetate to yield 4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butanal O-methyloxime as an off-white powder, mp 153-155° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([NH:11][C:12]1[C:13]([S:22][CH2:23][CH3:24])=[N:14][C:15]([CH3:21])=[CH:16][C:17]=1[S:18][CH2:19][CH3:20])=[O:10].[SH:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1>C(#N)C>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[S:25][CH2:8][C:9]([NH:11][C:12]1[C:13]([S:22][CH2:23][CH3:24])=[N:14][C:15]([CH3:21])=[CH:16][C:17]=1[S:18][CH2:19][CH3:20])=[O:10]
Reactant: CCSc1cc(C)nc(SCC)c1NC(=O)CBr
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSc1cc(C)nc(SCC)c1NC(=O)CSc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
This nitropyridine (775 mg, 3 mmol) was dissolved in a mixed solvent of acetic acid (30 ml) and conc. hydrochloric acid (1.5 ml), and zinc (4 g, 60 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 10 minutes, the reaction mixture was filtered, and the filtrate was neutralized with a sodium hydroxide aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 590 mg (yield 86%) of 3-amino-2,6-bis(ethylthio)-6-methylpyridine as a yellow oil. Triethylamine (304 mg, 3 mmol) was added to a THF (10 ml) solution of this aminopyridine (590 mg, 2.6 mmol), and bromoacetyl bromide (606 mg, 3 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. Then, the residue was purified through silica gel chromatography (silica gel 60 g, eluent—hexane:acetone=10:1→5:1) to obtain 410 mg (yield 45%) of 2-bromo-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide as a light brown needle crystal. Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (3 ml) solution of this amide (105 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:ethyl acetate=3:1) to obtain 70 mg (yield 56%) of the desired compound as a colorless needle crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)(=[O:21])[CH:18]([CH3:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:25]2[CH2:26][CH2:27][N:22]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)C(=O)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-isobutyrylpiperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-2-methylpropan-1-one (129 mg, 78%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.18 min, m/z 389.48 (36), 387.46 (M++H, 100). HPLC tr=3.65 min 97.72%) 1H NMR (270 MHz, CDCl3) δ 1.079 (3H, d, J=6.7 Hz, CH3), δ 1.082 (3H, d, J=6.7 Hz, CH3), 1.23 (2H, m, CH2), 1.45 (br s, NH), 1.83 (2H, m, CH2), 2.70 (2H, m, H2), 2.77 (1H, hept, J=6.7 Hz, CHMe2), 3.01 (1H, m, CHNH), 3.80 (2H, m, CH2), 3.83 (1H, m, ½CH2), 4.41 (1H, br d, J=13.4 Hz, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.87 (1H, m, ArH), 7.12 (1H, td, ArH), 7.24 (1H, m, ArH), 7.25 (2H, AA′BB′, ArH) and 7.39 (1H, dd, J=7.4, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 19.46, 19.65 (CH2), 30.13 (CH), 32.39, 33.30, 40.43, 43.95, 45.67 (CH2), 53.97 (CH), 118.94, 119.61, 124.54, 127.96, 128.72, 129.84, 130.58, 131.80, 154.35, 156.37 (ArC), and 175.30 (C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[CH:15]=[C:11]2[O:12][C:13]=1[CH3:14].F[B-](F)(F)F.[O:24]=[N+:25]=[O:26].CCOCC>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([N+:25]([O-:26])=[O:24])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: Cc1cc2oc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (Intermediate HE) (768 mg, 2.73 mmol) in MeCN (13 ml) is added nitronium tetrafluoroborate (0.5M solution in sulfolane, 6.6 ml, 3.3 mmol, 1.2 eq.). The dark orange reaction mixture is stirred at RT for 3 h then diluted into Et2O (150 ml) and washed successively with Na2CO3 1M in water (100 ml), water (100 ml) and brine (50 ml). The organic layer is dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME 95:5→7:3) to yield the title compound as a greenish solid. TLC: RF=0.27 (heptane/TBME 3:1); HPLC: AtRet=2.73; MS: m/z 325.8 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 2.49 (s, 3H), 2.66 (s, 3H), 7.47 (dd, J 8.3, 2.0, 1H), 7.52 (d, J 8.3, 1H), 7.64 (d, J 2.0, 1H).
Reaction SMILES: C([NH:8][C@@H:9]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])(OC(C)(C)C)=O.[ClH:22]>O1CCOCC1>[ClH:22].[NH2:8][C@@H:9]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)[C@H](N)CCSC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 16.0 g of methyl Boc-D-methionyl-glycinate in 50 ml of dioxane is added 50 ml of a solution of 5.6 M hydrogen chloride in dioxane. The reaction mixture is stirred for 30 minutes at room temperature and the solvent is removed under reduced pressure. The residue is stirred with diethyl ether to give a gum. The ether is decanted and the product dried under high vacuum to give methyl D-methionyl-glycinate hydrochloride which is represented by the following formula
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[OH-].[Na+].Br[CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:1]([NH:4][CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:2][CH3:3]
Reactant: CCOC(CBr)OCC
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Product: CCCNCC(OCC)OCC

Procedure:
Propylamine (100 ml) and 1-bromo-2,2-diethoxyethane (50 ml) were charged into a glass reaction flask equipped with a stirrer, thermometer, heater and reflux condenser. The reaction mixture was then heated at reflux for a period of one hour with stirring. After this time the mixture is treated with 50% by weight aqueous sodium hydroxide and was then distilled under reduced pressure to yield the desired product N-propyl-N-(2,2-diethoxyethyl)amine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[CH2:29][OH:30]>O>[CH3:22][CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[N:8]([CH:9]=2)[CH2:7][CH2:6][O:5][C:4]2[C:13]3=[CH:14][N:15]=[C:2]([N:24]3[CH2:28][CH2:27][CH2:26][CH:25]3[CH2:29][OH:30])[CH:3]=2)=[N:17][CH:18]=[N:19]1)[CH3:23]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: OCC1CCCN1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3CO)cc1OCC2
Temperature: 160 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
A mixture of 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene from Example 135 (500 mg, 1.51 mmol) and pyrrolidin-2-yl-methanol (1.00 g, 9.89 mmol) was stirred at 160° C. for 4 hr. The resulting mixture was poured into water and extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and evaporated to give the crude product, which was purified by reverse phase combiflash eluting with 0-50% gradient of CH3CN in 0.5% NH4HCO3 to give (1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}pyrrolidin-2-yl)methanol as white solid (345 mg, 58% yield). LCMS (ESI) m/z: 396.2 [M+H+].