Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[CH:33][N:32]([CH3:35])[C:31](=[O:36])[CH:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[CH:33][N:32]([CH3:35])[C:31](=[O:36])[CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1ccc(Br)cc1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 2 tR=1.16, m/z=921.5; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.22 (t, 1H), 1.52 (m, 3H), 2.21 (s, 2H), 2.22-2.34 (m, 2H), 2.34-2.46 (m, 1H), 2.85 (m, 1H), 3.57 (s, 3H), 5.59 (m, 1H), 6.33 (d, 1H), 6.68 (s, 1H), 7.01 (d, 2H), 7.29-7.41 (m, 8H); 1H NMR (CD3OD) 0.98 (s, 3H), 1.29 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.22 (m, 1H), 2.50 (m, 2H), 3.08 (m, 1H), 3.59 (s, 3H), 5.59 (m, 1H), 6.61 (d, 1H), 6.66 (s, 1H), 7.08 (m, 2H), 7.30-7.40 (5H), 7.42 (d, 2H), 7.70 (d, 1H).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([N+]([O-])=O)[CH:14]=1.O>CN(C)C=O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:14]=1
Reactant: CC(C)=NO
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=NOc1cc(Cl)ccc1C#N
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
In 75 ml of dry N,N-dimethylformamide was dissolved acetone oxime (1.21 g), followed by potassium tertiary butoxide (1.85 g) and stirred under nitrogen. After 30 minutes, 4-chloro-2-nitro-benzonitrile (2.00 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of the product, m.p. 83-84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][C@@H:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@@H:9]([CH3:14])[C:10]([OH:12])=[O:11])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](C)OCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CO[C@@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of (S)-methyl 2-((4-methoxybenzyl)oxy)propanoate (1 g, 4.46 mmol) in THF (20 mL) and MeOH (6 mL) at 0° C. was added lithium hydroxide (0.225 g, 9.38 mmol) and stirred for 3 h. Then warmed to room temperature in 30 min. After completion of starting material (by TLC), reaction mixture was concentrated and the resultant residue was taken EtOAc (100 ml), acidified by 1.5N HCl (up to pH 1) and extracted into EtOAc (2×100 ml). Combined organic extracts were dried over anhydrous Na2SO4, concentrated to give (S)-2-((4-methoxybenzyl)oxy)propanoic acid (0.6 g) was obtained as a gummy liquid.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:25][CH3:26])=[CH:6][C:7]([O:23][CH3:24])=[C:8]([C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]=[CH2:22])[CH:18]=3)[CH2:13]2)=[O:11])[CH:9]=1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl.[OH-].[Na+]>[CH:1]([C:4]1[C:5]([O:25][CH3:26])=[CH:6][C:7]([O:23][CH3:24])=[C:8]([C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]4[CH2:22][O:35]4)[CH:18]=3)[CH2:13]2)=[O:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(OC)cc1OC)C2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(C3CO3)cc2C1
Temperature: 25 °C

Procedure:
To (5-isopropyl-2,4-dimethoxy-phenyl)-(5-vinyl-1,3-dihydro-isoindol-2-yl)-methanone (0.80 g, 2.28 mmol) in DCM (22 ml) was added mCPBA (0.61 g, 2.73 mmol) at 0° C. The reaction was stirred at room temperature for an hour. The reaction was diluted with NaOH (1M, aq.) and extracted the product with EtOAc. The EtOAc layer was washed with NaOH again. The organic layer was washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to yield crude (5-isopropyl-2,4-dimethoxy-phenyl)-(5-oxiranyl-1,3-dihydro-isoindol-2-yl)-methanone as a very pale yellow oil. MS: [M+H]+ 368.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.O1CCCC1>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6])=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of t-butyl N-{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (50 g) in tetrahydrofuran (700 mL) was gradually added dropwise at 0° C. to a 2.5M 4-fluorophenylmagnesium bromide/tetrahydrofuran solution (300 mL) which had been prepared previously. The mixture was stirred at room temperature for 14 hours, cooled to 0° C., and extracted twice with ether after addition of saturated aqueous sodium bicarbonate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated off in vacuo. The resulting residue was purified by column chromatography on silica gel (C-300; hexane:ethyl acetate=4:1) to give the title compound.
Reaction SMILES: [Na].[C:2](#[N:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[C:6]([O:7][CH3:8])[CH:5]=1.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18]>>[CH3:8][O:7][C:6]1[CH:5]=[C:4]([CH:3]([C:2]#[N:14])[C:15]([O:16][CH2:17][CH3:18])=[O:19])[CH:13]=[CH:12][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(CC#N)cc1OC
Agent: [Na]
Product: CCOC(=O)C(C#N)c1ccc(OC)c(OC)c1

Procedure:
25.7 g (1.1 mol eq.) of sodium in small pieces were added gradually to a solution of 198 g (1.1 mol) of homoveratronitrile in 500 ml of diethyl carbonate in such a manner that the temperature remained at approximately 100°. Thereafter, the reaction mixture was heated to reflux for 1 hour, evaporated under reduced pressure, treated with cooled water, acidified with 70 ml of glacial acetic acid and extracted with ether. The combined organic extracts were dried and evaporated. The residual oil Was distilled in a high vacuum, whereby ethyl 3,4-dimethoxyphenylcyanoacetate was obtained, b.p. 170°-172°/70 Pa. HPLC purity >99%.
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:48]1[CH:49]=[C:50]([C:55]#[N:56])[C:51]([F:54])=[CH:52][CH:53]=1.[CH2:57]([O:59]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:58]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:57]([C:48]1[CH:49]=[C:50]([C:55]#[N:56])[C:51]([F:54])=[CH:52][CH:53]=1)(=[O:59])[CH3:58]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(Br)ccc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(F)c(C#N)c1

Procedure:
Under an argon atmosphere, 449 mg (0.490 mmol) of tris(dibenzylideneacetone)dipalladium and 671 mg (1.078 mmol) of rac-1,1′-binaphthalene-2,2′diylbis(diphenylphosphane) are added to 4.90 g (24.5 mmol) of 3-bromo-6-fluorobenzenecarbonitrile in 180 ml of toluene. After the addition of 10.6 g (29.4 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 200 ml of THF. After the addition of an aqueous 2N hydrogen chloride solution (50 ml), the mixture is stirred at room temperature for 4 h. The reaction mixture is subsequently neutralized using a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1→3:1). 3.50 g (88% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[CH:22]2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:34]([C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[N+:34]([C:37]1[CH:38]=[CH:39][C:40]([C@@H:43]([NH:45][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=2)[CH:22]=[C:23]3[CH3:33])=[O:31])[CH3:44])=[CH:41][CH:42]=1)([O-:36])=[O:35]
Reactant: Cc1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Product: Cc1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc([N+](=O)[O-])cc3)cc12

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3-methyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the (S)-1-(4-nitrophenyl)ethanamine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.37 (s,6H), 1.44 (s,9H), 1.95 (m,1H), 2.46 (d,15 Hz,1H), 2.59 (d,15 Hz,1H), 2.6-3.0, (m,3H), 4.53 (m,1H), 5.30 (br s,1H), 6.72 (d,7 Hz,1H), 6.98 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.82 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,70%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[N:34]1([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]4[O:20][C:21]([C:24]5[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=5)=[CH:22][N:23]=4)=[O:18])=[CH:13][CH:14]=3)=[CH:7][CH:8]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCCCC5)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (19 mg, 0.043 mmol) and piperidine (0.007 mL, 0.07 mmol) were dissolved in dichloroethane (2 mL) and NaBH(OAc)3 (18 mg, 0.086 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 1 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 5% MeOH/EtOAc) to furnish methyl 6-(2-(3-(4′-(piperidin-1-ylmethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a clear pale yellow oil (14 mg, 64%): 1H NMR (CDCl3, 600 MHz) δ 8.11 (d, 1H, J=7.7 Hz), 8.02 (d, 2H, J=9.0 Hz), 7.97 (t, 1H, J=7.8 Hz), 7.52 (dd, 4H, J=7.9, 6.4 Hz), 7.37 (d, 2H, J=7.9 Hz), 7.33 (d, 2H, J=7.8 Hz), 4.03 (s, 3H), 3.52-3.50 (m, 4H), 3.15 (t, 2H, J=7.6 Hz), 2.42 (bs, 4H), 1.61-1.58 (m, 4H), 1.44 (bs, 2H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.5, 139.2, 139.1, 138.3, 129.7, 128.8, 128.0, 127.1, 126.7, 125.2, 123.3, 63.4, 54.4, 53.1, 40.6, 29.3, 25.9, 24.3; HR ESI-TOF m/z 510.2385 (M+H+, C31H31N3O4, requires 510.2387).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[C:15]([CH3:23])[C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].[Li]CCCC.[P:29](Cl)(=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>C1COCC1>[CH3:23][C:15]1[CH:16]=[C:17]([S:19]([CH2:22][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])(=[O:21])=[O:20])[CH:18]=[C:2]([CH3:1])[C:3]=1[O:4][Si:5]([CH:6]([CH3:7])[CH3:8])([CH:9]([CH3:10])[CH3:11])[CH:12]([CH3:14])[CH3:13]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1cc(S(C)(=O)=O)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)c1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a stirring solution of (2,6-dimethyl-4-methanesulfonylphenoxy)triisopropylsilane (0.47 g, 1.32 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.58 mL), the reaction mixture was stirred at −78° C. for 1 hr, then diethyl phosphorochloridate (0.25 mL, 1.72 mmol) was added at −78° C. The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford diethyl (3,5-dimethyl-4-triisopropylsilanyloxy-benzenesulfonyl)methylphosphonate as a colorless oil (0.1 g, 15%): 1H NMR (200 MHz, CDCl3-d6): δ 7.57 (s, 2 H), 4.17 (m, 4 H), 3.71 (d, J=17.2 Hz, 2H), 2.29 (s, 6 H), 1.33 (m, 9 H), 1.10 (d, J=7.2 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:1); Rf=0.45.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].O.[C-:21]#[N:22].[Na+]>CN(C)C=O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:21]#[N:22])=[C:4]([O:18][CH3:19])[CH:5]=1
Reactant: [C-]#N
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3ccccc3o2)ccc1CC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (318 mg, 1 mmol), dimethylformamide (7.5 mL) and deionzed water (2.5 mL) was stirred at rt. Sodium cyanide (150 mg, 3.0 mmol) was added to reaction. After 3 h, dimethylformamide (10 mL) was added to help dissolve solids in reaction mixture. Let reaction mixture stir overnight at rt. Workup was done by washing reaction with brine (3×30 mL), extraction with EtOAc, combined organic extracts, dried (Na2SO4), filtered and removed solvent in vacuo. Flash chromatography of resulting orange solid on silica gel using a gradient elution of 1:9 EtOAc:hexanes to 1:3 EtOAc:hexanes afforded the desired intermediate, [4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]acetonitrile as a yellow solid. 1H NMR(CDCl3, 300 MHz) δ 7.86–7.36 (m, 7H), 3.99 (s, 3H), 3.74 (s, 2H), 2.59–1.91 (m, 8H). MS (ESI) 265 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C@H:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)[C@H](C)CNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Yield: 93.8 %

Procedure:
To a solution of ethyl (4R)-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-α]indole-7-carboxylate (1.3 g, 4.8 mmol) in ethanol (60 mL) is added 1M NaOH solution (12 mL, 12 mmol). The reaction mixture is refluxed for 1.5 h. Then the reaction mixture is acidified with 1M HCl and ethanol is removed under vacuum. The resulting solid is filtered, washed with water, and dried to afford the title compound (1.1 g, 98%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:10]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=3[C:12]#[N:13])[C:4]=2[CH:3]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[C:15]([C:18]([F:20])([F:21])[F:19])[CH:16]=[CH:17][C:10]=1[N:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:22]=[C:23]([S:25]([Cl:24])(=[O:27])=[O:26])[C:2]([F:1])=[CH:3][C:4]1=2)#[N:13]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2ccc(F)cc21
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a vial charged with 2-(6-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)benzonitrile (1.85 g, 5.74 mmol) was added DCM (23 mL). The resulting solution was cooled in an ice water bath prior to the addition of chlorosulfonic acid (1.526 ml, 22.96 mmol), faster than dropwise. After 30 min of stirring LC-MS of the resulting yellow/brown solution indicated desired product mass as the main mass (M+23) with consumption of starting material. The solution was added to ice water, and extracted 2× with DCM. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 25 g SNAP column ramping EtOAc in heptane (0-25%, then isocratic at 25%, 10% DCM throughout) providing product as a white foam 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (1.80 g, 4.28 mmol, 74.5% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.87-3.94 (m, 2 H) 4.40-4.49 (m, 2 H) 6.37 (d, J=11.15 Hz, 1 H) 7.50 (d, J=6.46 Hz, 1 H) 7.64 (d, J=8.51 Hz, 1 H) 7.94-8.01 (m, 1 H) 8.09 (dd, J=1.57, 0.59 Hz, 1 H). m/z (ESI) 443.1 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:33])[C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:33])[C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])=[CH:13][CH:12]=1)[CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)[C@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)[C@H]2CCCN2C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
300 mg of the compound [52-1] was dissolved in a mixed solvent of 6 mL of tetrahydrofuran and 6 mL of methanol, then 100 mg of a carbon catalyst of 20% palladium hydroxide was added thereto, and the mixture was stirred for 2.5 hours at room temperature under hydrogen atmosphere. The catalyst was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 6 mL of tetrahydrofuran, then 147 μL of 37% formaldehyde solution and 420 mg of sodium triacetoxyborohydride were added thereto, and the mixture was stirred for 1.5 hours at room temperature. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, the solution was extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1), and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Thereafter, the insolubles were filtered, and the filtrate was concentrated under reduced pressure, to obtain 220 mg of tert-butyl[(1S)-1-(4-{hydroxy[(2R)-1-methylpyrrolidin-2-yl]methyl}phenyl)ethyl]carbamate [54-1] (hereinafter, referred to as the compound [54-1]).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([N:15]2[CH2:19][CH:18]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:17]3[CH2:16]2)=[O:14])=[N:5][CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]1[CH:17]2[CH2:22][NH:21][CH2:20][CH:18]2[CH2:19][N:15]1[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)=[O:14]
Reactant: Cn1ncnc1-c1ccccc1C(=O)N1CC2CN(C(=O)OC(C)(C)C)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncnc1-c1ccccc1C(=O)N1CC2CNCC2C1
Reaction time: 2 h

Procedure:
Intermediate 60 (100 mg, 0.252 mmol), DCM (2.5 mL), TFA (0.5 mL) were stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DCM and treated with Dowex 550 A resin. After stirring for 2 h the resin was removed by filtration and the filtrate was concentrated in vacuo to a colorless oil which was taken on to the next step without further purification. MS (ESI) mass calculated for C16H19N5O, 297.16; m/z found, 298.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26](O)=[O:27])=[CH:23]3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:26]([C:22]2[CH:23]=[C:24]3[C:19]([CH:18]=[CH:17][C:16]([O:15][C:13]4[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=4)=[CH:25]3)=[CH:20][CH:21]=2)=[O:27])=[CH:32][C:31]=1[C:37]([F:38])([F:39])[F:40]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3ccc(C(=O)O)cc3c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3ccc(C(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3c2)ccn1
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of 7-({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}oxy)-2-naphthoic acid (350 mg, 0.92 mmol) in DCM (9.0 mL), was added 4-chloro-3-(trifluoromethyl)aniline (198.0 mg, 1.0 mmol); EDCl (194 mg, 1.0 mmol) and DMAP (124 mg, 1.0 mmol). The mixture was allowed to stir for 18 h then diluted with EtOAc and washed with water and then brine. The organic phase was dried (Na2SO4) and evaporated, and the residue was triturated with DCM/EtOAc/MeOH to yield the title compound as a white solid (420 mg, 81.8%). LCMS: (FA) ES+ 558.1, ES− 556.1.