Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:11]([CH3:12])=[CH:10][C:8]([NH2:9])=[C:7]([CH3:13])[C:6]=1[Cl:14].[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([N:30]=[C:31]=[O:32])=[O:29]>C1(C)C=CC=CC=1.CCCCCC>[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([NH:30][C:31]([NH:9][C:8]1[CH:10]=[C:11]([CH3:12])[C:5]([O:4][C:3]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:18][C:2]=2[Cl:1])=[C:6]([Cl:14])[C:7]=1[CH3:13])=[O:32])=[O:29]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(-c2ccccc2)cc1Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)c(C)c(Cl)c1Oc1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C

Procedure:
To a solution containing 1.61 grams (0.004 moles) of 4-(2-chloro-4-phenylphenoxy)-2,5-dimethyl-3-chloroaniline prepared in Part B and 3 milliliters of toluene, which solution was warmed to 40° C.-50° C. and placed under an atmosphere of nitrogen, was added a solution containing 0.98 grams (0.005 moles) of 2-chlorobenzoyl isocyanate and 0.05 milliliters of toluene. The resulting mixture was then heated to a temperature of 60° C.-70° C, for a period of 0.5-1.0 hours. After cooling to ambient temperature, the reaction mixture was diluted with 4 milliliters of toluene and 2 milliliters of hexane. This mixture was then filtred to give a solid material. The solid material was washed once with a toluene-hexane mixture (1:2 volume ratio) and finally once with hexane and then dried overnight in a vaccum oven at 50° C. This afforded a tan powder material having a melting point of 198° C.-199° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1.[CH2:15](Br)[CH:16]=[CH2:17]>CN(C)C=O.[Cl-].[Na+].O>[CH2:17]([N:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:11]1=[O:12])[CH:16]=[CH2:15]
Reactant: COc1ccc2c(c1)C(=O)NCCC2
Reactant: C=CCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCCc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (10.0 g, 0.052 mol) in N,N-dimethylformamide (30 mL) and allylbromide (23 mL, 0.260 mL) was treated with Nail (60% by wt. dispersion in oil, 2.50 g, 0.063 mol) and the resulting grey suspension stirred at room temperature under an atmosphere of argon. Gas evolution was noted. After 15 minutes, the solution was diluted with brine and partitioned between ethyl acetate and brine. The combined organic layers were concentrated in vacuo and purified by chromatography over silica gel eluting with a gradient of hexane to 1:1 ethyl acetate/hexane to yield 8 g (83%) of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil:
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CS(C)=O>[CH3:22][CH:23]1[N:24]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25][CH2:26][O:27][CH2:28]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CC1COCCN1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), and 3-methylmorpholine (443 mg, 4.39 mmol, 10.00 equiv) in DMSO (1 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 46 mg (29%) of methyl 3-(3-methylmorpholino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [O-]CC.[Na+].C(O[C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])C.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([C:23](=[O:25])C)[CH:20]=[CH:21][CH:22]=1>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:23](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=1)[CH3:13]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A mixture of 1.96 g (0.0275 mol) sodium ethoxide (95%) and 22 ml ethanol was stirred 20 minutes at room temperature and was then cooled with an ice bath. 3.65 g (0.025 mol) diethyloxalate followed by 4.7 g (0.025 mol) 1-(3-trifluoromethyl-phenyl)-ethanone were added slowly. The mixture was stirred for 30 min. at 0-5° C., then allowed to warm to room temperature and additional 25 ml ethanol were added. After 1 d at room temperature the solvent was evaporated. Water and diethylether were added to the residue. The organic phase was separated and the aqueous phase was extracted one more time with diethyl ether. The aqueous phase was acidified with 2M HCl to pH2 and extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulfate, the solvent was evaporated and the residue triturated with petrol ether to give 5.35 g (0.0185 mol) 3-oxo-3-(3-trifluoromethyl-phenyl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]2[N:19]=[CH:20][N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:22]=2)=[O:11])=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O>[NH:21]1[CH:22]=[C:18]([C:14]2[S:15][CH:16]=[CH:17][C:13]=2[NH:12][C:10](=[O:11])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:19]=[CH:20]1
Reactant: COc1ccc(CC(=O)Nc2ccsc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(=O)Nc2ccsc2-c2c[nH]cn2)cc1

Procedure:
2-(4-Methoxyphenyl)-N-(2-(1-trityl-1H-imidazol-4-yl)thiophen-3-yl)acetamide (561 mg, 1.01 mmol) in TFA (10 ml) was stirred for 1 h. The solution was concentrated under reduced pressure and the residue was directly purified by HPLC to yield N-(2-(1H-imidazol-4-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide. Method [8] Retention time 3.37 min by HPLC (MH+ 314). 1H NMR (300 MHz, DMSO) δ 10.28 (s, 1H), 8.60 (s, 1H), 7.59 (s, 1H), 7.53 (d, J=5.7 Hz, 1H), 7.49 (d, J=5.7 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 3.73 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].FC(F)(F)C(O)=O.[F:26][C:27]([F:40])([F:39])[C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][N:29]=1>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:36]1[CH2:35][CH2:34][N:33]([C:31]2[S:32][C:28]([C:27]([F:39])([F:26])[F:40])=[N:29][N:30]=2)[CH2:38][CH2:37]1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, dichloromethane/methanol 98:2) to yield the title compound as a colorless solid. MS (m/e): 493.4 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([S:13][CH3:14])=[N:10][C:9]=2[C:15]([O:17]CC)=[O:16])=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([S:13][CH3:14])=[N:10][C:9]=2[C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(SC)sc1-c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of ethyl 5-(4-fluorophenyl)-2-(methylthio)thiazole-4-carboxylate 2 (2.6 g, 9.1 mmol) in dioxane (20 mL) was added lithium hydroxide (0.32 g, 13.7 mmol) and the resulting mixture was stirred at 50° C. for two hours. Reaction mixture was then gradually acidified with 1N HCl. The precipitates were filtered, washed with water and dried under high vacuum to give 2.4 g of product S-25 (95%). 1H-NMR (CD3OD, 250 MHz) δ 2.75 (s, 3H), 7.12 (t, 2H, J=8.75), 7.50 (dd, 2H, J=5.25, 8.75).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=2[CH3:16])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].CN(C=O)C.[H-].[Na+]>O>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=2[CH3:16])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1C#N
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A flask was charged with 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (27.77 g, 90.41 mmol), pyridine-2-thiol (10.55 g, 94.93 mmol), and DMF (300 mL). The reaction was cooled to 0° C. and 95% sodium hydride (2.741 g, 108.5 mmol) was added portionwise. The reaction was stirred at ambient temperature overnight, then carefully diluted with water (2 L) and extracted with ethyl acetate. The organic layer was washed with brine (4×500 mL), dried over sodium sulfate and concentrated to afford 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (29.50 g, 87.43 mmol, 96.70% yield) as yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>ClCCCl.ClC(Cl)C.[Cl-].[Zn+2].[Cl-]>[F:13][C:11]1[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=[C:7]([OH:6])[C:12]=1[C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1cc(F)cc(OC)c1
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(CC(=O)c2c(O)cc(OC)cc2F)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To 1,2-dichloroethane (40 mL) were added anhydrous aluminum chloride (4.27 g) and zinc chloride (436 mg), followed by stirring 15 min. Under ice-cooling, a solution of 1,3-dimethoxy-5-fluorobenzene (5 g) in 1,2-dichloroethane (15 mL) was added. The mixture was cooled to −10° C. and 4-methoxyphenylacetyl chloride (4.9 mL) in dichloroethane (10 mL) was added drop-wise. The mixture was stirred 30 min at −10° C., and 1 h at room temperature and then heated to reflux for 2 h. The mixture was cooled at 0° C., poured carefully into ice-water and extracted twice with dichloromethane. The dichloromethane layer was dried over MgSO4 and evaporated in vacuo to give the title compound (9.1 g); 1H NMR (CDCl3): 13.23 (s, 1H), 7.17 (d, 2H, J=8.4 Hz), 6.88 (d, 2H, J=8.4 Hz), 6.24 (d, 1H, J=2.1 Hz), 6.18 (dd, 1H, J=13.8 Hz, J′=2.1 Hz), 4.20 (d, 2H, J=3.9 Hz), 3.82 (s, 3H), 3.80 (s, 3H); MS: 291 (MH+); containing 1-(4-fluoro-2-hydroxy-6-methoxyphenyl)-2-(4-methoxyphenyl)ethanone as a by-product. 1H NMR (CDCl3): 13.62 (s, 1H), 7.2–6.0 (6H), 4.29 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH3:18]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1OC

Procedure:
A flask containing vanillin (20 g, 0.13 mol), ethyl bromoacetate (28.4 g, 0.17 mol) and potassium carbonate (32.7 g, 0.24 mol) and acetone 200 mL were heated to reflux for 3 hours. The reaction was allowed to come to rt. The acetone was stripped off and the residue partitioned between water and ethyl acetate. The ethyl acetate was washed with brine and dried over magnesium sulfate. The organic layer was concentrated and the solid triturated with hexanes to yield 28.4 grams of example No. 169.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[O:7]1[C:9]([CH3:11])([CH3:10])[CH2:8]1.[NH:12]1[CH2:15][CH:14]([C:16]2[CH:17]=[CH:18][C:19]3[O:28][CH2:27][CH2:26][C:25]4[S:24][C:23]([C:29]5[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=5)=[N:22][C:21]=4[C:20]=3[CH:37]=2)[CH2:13]1>C1COCC1>[CH:34]([N:30]1[C:29]([C:23]2[S:24][C:25]3[CH2:26][CH2:27][O:28][C:19]4[CH:18]=[CH:17][C:16]([CH:14]5[CH2:13][N:12]([CH2:8][C:9]([CH3:11])([OH:7])[CH3:10])[CH2:15]5)=[CH:37][C:20]=4[C:21]=3[N:22]=2)=[N:33][CH:32]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: CC1(C)CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CC(C)(C)O)C3)cc1-2
Reaction time: 0.21 h
Yield: 35.7 %

Procedure:
Lithium perchlorate (52 mg, 0.49 mmol) was added to THF (5 mL) followed by 1,2-epoxy-2-methylpropane (0.43 mL, 4.9 mmol) and the mixture was stirred for 10-15 minutes giving a clear solution. 9-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol) was added and the reaction mixture was stirred for 72 hours then concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-10% MeOH in EtOAc) and the resulting solid extracted several times with ether. The ether extracts were concentrated in vacuo to give 377 (77 mg, 97%). LCMS: RT=7.45 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.28 (1H, d, J=2.34 Hz), 7.90 (1H, s), 7.16 (1H, dd, J=8.29, 2.35 Hz), 7.02 (1H, d, J=8.27 Hz), 5.93-5.83 (1H, m), 4.40-4.34 (2H, m), 4.04-3.95 (2H, m), 3.89-3.79 (1H, m), 3.46-3.36 (4H, m), 2.55 (2H, s), 1.63 (6H, d, J=6.64 Hz), 1.15 (6H, s). 1 Exchangeable proton not seen
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:18])[C@H:6]([CH2:15][S:16][CH3:17])[NH:7]C(OCCCC)=O)[CH3:3]>C(OCC)(=O)C>[ClH:1].[CH2:2]([NH:4][C:5](=[O:18])[C@H:6]([CH2:15][S:16][CH3:17])[NH2:7])[CH3:3]
Reactant: CCCCOC(=O)N[C@@H](CSC)C(=O)NCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@@H](N)CSC
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To 60 ml of ice-cooled 16% solution of hydrogen chloride in ethyl acetate was added dropwise a solution of 3.93 g (15 mmole) of S-methyl-N-butyloxycarbonyl-L-cysteine ethylamide in 60 ml of ethyl acetate over 20 minutes. After stirring for 2 hours, the reaction mixture was concentrated in vacuo and the residual oil was treated with ethyl ether to give 2.8 g (94% yield) of S-methyl-L-cysteine ethylamide hydrochloride as powder.
Reaction SMILES: [Cl:1]Cl.[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[Na]>C(Cl)Cl>[Cl:1][N:7]1[C:3](=[O:13])[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:5]2[C:6]1=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCl
Agent: [Na]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To 170 ml. of methylene chloride saturated with chlorine and maintained at 0° C. were added 8.3 grams (49 mmoles) of sodium phthalimide. The resulting mixture was warmed to 20° C. and was stirred for 1.5 hours. The resulting precipitated sodium chloride was removed by filtration, and the filtrate was evaporated to dryness to afford 8.0 grams (90% yield) of N-chlorophthalimide.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([CH2:26][CH2:27][CH3:28])=[CH:9][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][CH:2]1[O:7][C:6]2[C:8]([CH2:26][CH2:27][CH3:28])=[CH:9][C:10]([CH2:12][N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:29]
Reactant: CCCc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc2c1OC(C)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(CN2CCNCC2)cc2c1OC(C)C(=O)N2
Temperature: 23 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
In a 20 mL scintillation vial was added tert-butyl 4-((2-methyl-3-oxo-8-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)piperazine-1-carboxylate 358D (90 mg, 0.223 mmol) and TFA (2.0 mL, 26.0 mmol) in DCM (2.0 mL) and stirred at 23° C. for 1 h. The reaction was concentrated in vacuo, taken up in MeOH, and filtered through a PL-HCO3 MP resin column to give the free base. The MeOH filtrate was concentrated in vacuo to give the title compound as a yellow solid (68 mg, 0.224 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 3H) 1.38 (d, J=6.82 Hz, 3H) 1.53 (dt, 2H) 2.43-2.49 (m, 4H) 2.52 (br. s., 2H) 3.00 (d, J=4.29 Hz, 4H) 3.33 (br. s., 1H) 3.39 (s, 2H) 4.60 (q, J=6.74 Hz, 1H) 6.63-6.76 (m, 2H) 10.58 (s, 1H). ESI-MS: m/z 304.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][C@@H:27]1[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@H:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:18])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[Cl:17])[CH:3]=2)[CH2:28][C@@H:27]1[CH3:33])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Reactant: C[C@H]1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Yield: 46.1 %

Procedure:
Dissolve N-(3-amino-phenyl)-2-chloro-4-fluoro-benzamide (Preparation 1, 200 mg, 0.756 mmol) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (161 mg, 0.756 mmol) in tetrahydrofuran (5 mL). Add acetic acid (52 μL, 0.907 mmol) and sodium triacetoxyborohydride (192 mg, 0.907 mmol) and stir at room temperature for 18 hr. Heat the reaction to 45° C. for 4 hr. Cool the reaction to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (20%–75% ethyl acetate/hexane) to yield 161 mg (46%) of the title compound. Mass spectrum (ion spray): m/z 462.4 (M+1); 1H NMR: δ (CDCl3, ppm) 7.76 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.20 (m, 1H), 3.82 (m, 2H), 3.67 (bs, 1H), 3.20 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H), 1.47 (s, 9H), 1.27, (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[OH:29][C:26]([CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:28])[CH3:27]
Reactant: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Product: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 142.1) and pyrimidin-5-ylboronic acid to afford an off-white powder. HPLC (Condition 4) tR=4.88 min, UPLC-MS (Condition 7) m/z=474.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.94 (s, 6H) 2.50-2.58 (m, 1H) 3.63 (d, J=7.43 Hz, 4H) 4.39 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.49-7.68 (m, 1H) 7.79-7.91 (m, 2H) 8.06 (dd, J=2.15, 0.98 Hz, 1H) 8.73-8.81 (m, 1H) 8.85-8.96 (m, 1H) 9.20 (d, J=0.78 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.N12CCCN=C1CCCCC2.[C:67](OCC)(=[O:69])C>O1CCCC1.O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:67][OH:69])[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCOC(C)=O
Agent: C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy) phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 15l (100 mg, 0.13 mmol) in tetrahydrofuran (5 mL) were added formaldehyde (72.3 mg, 2.47 mmol, 37 wt % solution) and 1,8-diazabicyclo[5.4.0]undec-7-ene (16.3 mg, 0.11 mmol) in turn at room temperature. The mixture was stirred at room temperature for 48 hours, and then ethyl acetate (20 mL) and water (5 mL) were added. The resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 15m as yellow oil (108 mg, 100%). This material was not further purified.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1.[BH4-].[Na+].O>CCO.CC(=O)OCC>[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=1
Reactant: COCc1ccc(C=O)s1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCc1ccc(CO)s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(methoxymethyl)thiophene-2-carbaldehyde (782 mg, 5.01 mmol) in EtOH (10 mL) was treated at 0° C. with NaBH4 (379 mg, 10.0 mmol) and the resulting solution was stirred for 5 min at 0° C. and then allowed to warm to rt. Water (5 mL) and EA (5 mL) were added. The aq. layer was extracted with EA (2×15 mL) and the combined org. layers were washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.51 min.