Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCO[CH2:21][CH2:22]Cl.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CCOCC>[CH2:24]([N:26]([CH2:21][CH3:22])[CH2:27][CH2:28][O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[CH3:25]
Reactant: ClCCOCCCl
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)CCOC(C(=O)c1ccccc1)c1ccccc1

Procedure:
14 g (0.05 mole) of benzoin-2-chloroethyl ether are stirred with 75 g of diethylamine for 24 hours at 55° C. After cooling, the reaction mixture is diluted with ether and extracted with dilute hydrochloric acid. The aqueous layer is made alkaline with K2CO3 and extracted with ether. The ether layer is washed with ice water, dried over Na2SO4 and concentrated. The residual oil is dried in a high vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCC#Cc1ccccc1
Product: O=Cc1cccc(C#CCCCCC#Cc2ccccc2)c1

Procedure:
Similarly, following the procedure of Example 7(b), 3-bromobenzaldehyde was reacted with 1-phenylocta-1,7-diyne to yield 3-(8-phenyl-1,7-octadiynyl)benzaldehyde which was reduced to 3-(8phenyloctyl)benzaldehyde and the latter was reacted as described in Example 35(a), (b) and (c) to give 3-(2-carboxyethylthio)-3-[3-(8phenyloctyl)phenyl]-2-hydroxypropanoic acid, dipotassium salt, hydrate as a mixture of isomers, -log KB value 6.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C:3]=1[F:18].O.NN>CO.[Ni]>[F:18][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(F)c2F)cc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2cccc(F)c2F)cc1
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
Into a 500 mL, 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1,2-difluoro-3-(4-nitrophenoxy)benzene (21.2 g, 84.40 mmol, 1.00 equiv) in methanol (200 mL), and Raney Nickel (2 g). A solution of hydrazine hydrate (12.67 g, 3.00 equiv) in methanol (50 mL) was added dropwise with stirring in 15 min. The resulting solution was stirred for 12 h at 25° C. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with 200 mL of ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 16.3 g (87%) of 4-(2,3-difluorophenoxy)aniline as black oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[I:18]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:16][C:11]1[CH:12]=[CH:13][C:14]([I:18])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:17]
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(I)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.1 %

Procedure:
To an ice cold stirring suspension of N-(5-chloropyridin-2-yl)-2-aminobenzamide (1.01 g, 4.09 mmol) in ethanol (80 mL) was added a mixture of iodine (1.04 g, 4.10 mmol) and silver sulfate (1.29 g, 4.09 mmol). The mixture was stirred at room temperature for 3 d and filtered. The filtrate was concentrated, partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with a step gradient of 5-10% ethyl acetate in dichloromethane. The chromatography product was slurried in isopropanol and filtered to give 0.49 g (32%) of an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].Cl.[CH2:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][C@H:47]([C:55]([O:57][CH3:58])=[O:56])[NH:46]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:46]2[C@@H:47]([C:55]([O:57][CH3:58])=[O:56])[CH2:48][C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:45]2)=[O:11])[C:6]=1[CH3:7]
Reactant: COC(=O)[C@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@@H]2C(=O)OC)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 50 mg, 0.080 mmol) in CH2Cl2 (890 μL) was added 1-chloro-N,N-2-trimethylprop-1-en-1-amine (21 μL, 0.16 mmol). After stirring for 30 min at room temperature, (R)-methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (20 mg, 0.088 mmol) in THF (900 μL) was added followed by i-Pr2EtN (42 μL, 0.24 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then quenched with sat. aq. NH4Cl solution and extracted with EtOAc (1×). The organic layer was washed with 1N aq. HCl solution, and the combined aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (24 mg, 37%). 1H NMR (1:1 CD3OD:CDCl3, 1:1 mixture of amide rotamers) δ 8.62 (d, J=15.9 Hz, 1H), 8.20 (dd, J=13.9, 9.0 Hz, 1.5H), 8.13-7.85 (m, 5H), 7.63-7.52 (m, 1.5H), 7.47 (d, J=8.4 Hz, 1H), 7.24-7.06 (m, 3.5H), 6.93 (d, J=6.8 Hz, 0.5H), 5.17 (t, J=5.4 Hz, 0.5H), 5.02 (d, J=17.6 Hz, 0.5H), 4.75 (d, J=5.9 Hz, 1H), 4.49 (d, J=18.0 Hz, 1.5H), 3.64 (br s, 1.5H), 3.55-3.41 (m, 2.5H), 3.27-3.09 (m, 4H), 3.05-2.99 (m, 0.5H), 2.31 (s, 1.5H), 2.24 (s, 1.5H), 1.50-0.95 (m, 8H), 0.95-0.82 (m, 3H), 0.74 (t, J=7.5 Hz, 1.5H), 0.71-0.63 (m, 1.5H); MS(ESI+) m/z 798.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH2:13])=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([CH2:19][C:18]4[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=4)=[CH:28][CH:27]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1cc2c(CCN)c[nH]c2cc1Cl
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(CCNC(=O)c3ccc(Cc4cccc(F)c4)cc3)c[nH]c2cc1Cl
Yield: 14.1 %

Procedure:
N-(2-(6-Chloro-5-methyl-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine (0.172 g; 0.825 mmol), 4-(3-fluorobenzyl)benzoic acid (0.190 g, 0.825 mmol), HATU (0.313 g; 0.825 mmol) and N,N-diisopropylethylamine (0.355 mL; 2.06 mmol) in DMF (5 mL). The crude material was purified by preparative HPLC (method 2) to afford 0.049 g (14%) of the title compound as a white solid.
Reaction SMILES: C[Al](C)C.[NH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:24]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)=[N:25][O:26][C:27]=2[CH2:28][OH:29])=[N:17][CH:16]=1>O1CCOCC1>[F:37][C:32]1[CH:31]=[C:30]([C:24]2[C:23]([CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([NH:5][CH:6]4[CH2:11][CH2:10][O:9][CH2:8][CH2:7]4)=[O:13])=[CH:16][N:17]=3)=[C:27]([CH2:28][OH:29])[O:26][N:25]=2)[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 532 μL, 1.06 mmol) was added to a solution of 4-aminotetrahydropyran (111 mg, 1.06 mmol) in dioxane (5 mL). 6-[3-(3,4-Difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution (2 M in toluene, 500 μL, 1.0 mmol) was added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (silica, dichloromethane:methanol=100:0 to 95:5) to afford the title compound (60 mg, 50%) as a white solid. MS: m/e=446.4 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.C([Cl:16])(=O)C>>[Cl-:16].[CH3:1][N+:2]([CH3:3])=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[CH3:4]
Reactant: CNC
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1C=O
Product: Cc1ccccc1C=[N+](C)C
Product: [Cl-]

Procedure:
The reaction of 14.0 ml (0.108 mol) dimethylamine solution and 4.6 ml (0.040 mol) 2-methylbenzaldehyde in accordance with general synthesis instructions 1 and subsequent reaction with 2.4 ml (0.040 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 5.3 g (corresponding to 73% of the yield calculated by theory) dimethyl-(2-methyl-benzylidene)-ammonium chloride.
Reaction SMILES: C(N[C:6]([C@:8]1([N:25]([C@H](C2C=CC=CC=2)C)C(=O)C)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][CH2:14][CH2:15][B:16]1[O:20]C(C)(C)C(C)(C)[O:17]1)=[O:7])(C)(C)C.N.[Li].[O:39]1CCCC1>>[NH2:25][C@@:8]1([C:6]([OH:7])=[O:39])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][CH2:14][CH2:15][B:16]([OH:20])[OH:17]
Reactant: C1CCOC1
Reactant: CC(=O)N([C@@H](C)c1ccccc1)[C@@]1(C(=O)NC(C)(C)C)CCC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: N
Agent: [Li]
Product: N[C@@]1(C(=O)O)CCC[C@@H]1CCCB(O)O
Temperature: -45 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
A cold (−50° C.) solution of (1S,2S)—N-(tert-butyl)-1-(N—((S)-1-phenylethyl) acetamido)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentane carboxamide (0.400 g, 0.802 mmol) in anhydrous tetrahydrofuran (5 mL) under an inert atmosphere of nitrogen was gradually combined (in small portions), with liquid ammonia (20 mL) and lithium wire (0.14 g, 20 mmol) over a time interval of several minutes. After stirring for 1.5 h at −40 to −50° C., the deep blue reaction was quenched with solid ammonium chloride, warmed slowly to room temperature, and residual ammonia driven off using nitrogen. Water (3 mL) was then added to the reaction flask and the mixture extracted with methylene chloride (3×30 mL). The combined organic layer was dried using Na2SO4 and concentrated in vacuo prior to purifification by HPLC to afford the subject compound (100 mg, 50%) as a white foam. NMR (D2O) δ 2.32 (m, 1 H), 2.00 (m, 2 H), 1.77-1.90 (m, 2 H), 1.70 (m, 1 H), 1.35-1.50 (m, 3 H), 1.24 (m, 1 H), 1.12 (m, 1 H), 0.60-0.75 (m, 2 H). MS (M+1): 216.3; MS (M−H2O+1): 198.2; MS (M−2H2O+1): 180.3.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=CC=1.[CH3:7][NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]([C:23]3[N:24]=[CH:25][N:26]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:27]=3)=[O:22])[CH:17]=2)[CH:12]=1)=[O:10].Cl.[C:48]([O:51]CC)(=[O:50])[CH3:49]>O1CCCC1>[OH:22][C@@:21]([C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][CH3:7])=[O:10])[CH:12]=2)[CH:17]=1)([C:23]1[N:24]=[CH:25][N:26]([C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:27]=1)[CH2:49][C:48]([O:51][CH2:6][CH2:5][CH3:4])=[O:50]
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Under argon atmosphere, 0.49 g (1.66 mmol, 1.25 equivalents) of (+)-cichonine was added to 6.2 mL (3.3 mmol, 2.5 equivalents) of the solution of n-propyl bromozincacetate in tetrahydrofuran obtained in Example 57 at 3˜4° C. 0.43 mL (5.32 mmol, 4 equivalents) of pyridine was added dropwise at 4˜6° C. The mixture was stirred at 3˜5° C. for 20 minutes. A solution of 0.69 g (1.32 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 6.9 mL of THF was added dropwise at −41˜−35° C. 2.5 mL (1.32 mmol, 1 equivalent) of the solution of n-propyl bromozincacetate in tetrahydrofuran obtained in Example 57 was added at −43˜−36° C., and the mixture was stirred at −43˜−37° C. for 2 hours. 10 mL of 1N hydrochloric acid was added at 0° C. or lower, followed by dilution with 30 mL of ethyl acetate. The layers were separated. The organic layer was washed successively with 5 mL (×3) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing and concentration under reduced pressure, 2 mL of IPE was added, crystals were loosened, filtered, and washed with 1 mL (×2) of IPE. After washing, vacuum drying (4° C.) to a constant weight afforded 0.73 g of n-propyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 89%, enantiomer excessive rate 96.0% ee).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](=[O:13])(=[O:12])[NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=2[O:17][CH3:16])=[CH:6][CH:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1ccc(CS(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CS(=O)(=O)NCc2ccc(OC)cc2OC)cc1

Procedure:
Under inert gas, 10 g of 4-[(chlorosulfonyl)methyl]benzoic acid methyl ester were initially charged in 100 ml of DCM, then, at a temperature of 0° C., 12.1 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was filtered and the filtrate was washed with 1 N HCl. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. This gave the product (14.2 g) with a molecular weight of 379.4 g/mol (C18H21NO6S).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11](=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22]([O:28]CC4C=CC(OC)=CC=4)=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=3)=[CH:15][C:14]=2[F:38])=[CH:6][C:5]=1[C:40]([F:43])([F:42])[F:41])[CH3:2].C(O)(C(F)(F)F)=O.[OH-].[Na+].C(Cl)[Cl:54]>>[ClH:54].[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11](=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([O:25][CH2:26][CH3:27])[C:22](=[O:28])[NH:21][CH:20]=3)=[CH:15][C:14]=2[F:38])=[CH:6][C:5]=1[C:40]([F:41])([F:43])[F:42])[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(OCC)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ncc(NC(=O)Cc2ccc(-c3c[nH]c(=O)c(OCC)c3)cc2F)cc1C(F)(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a mixture of N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (40 mg, 0.067 mmol) in DCM (10 mL) was added TFA (0.701 mL, 9.10 mmol). The mixture was stirred at 25° C. for 2 h. Then the reaction residue was added to NaOH (2.5 m, 3 mL) and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, basic condition) to yield a white solid of N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (15.66 mg, 0.030 mmol, 49.8% yield): 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.49-7.41 (m, 1H), 7.40-7.31 (m, 3H), 7.26 (d, J=2.0 Hz, 1H), 4.47 (m, 2H), 4.15 (m, 2H), 3.82 (s, 2H), 1.49 (t, J=7.0 Hz, 3H), 1.40 (t, J=7.0 Hz, 3H); ES-LCMS m/z 480.2 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([OH:13])[CH3:12]>>[C:5]1([N:4]2[CH:3]=[CH:2][CH:12]=[CH:11][O:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCO
Reactant: OCCNc1ccccc1
Product: C1=CON(c2ccccc2)C=C1
Temperature: 80 °C

Procedure:
0.271 g of P-(2-phenyl-2-chloro acetyl)dimethylaminobenzene (1 mmole) and 0.274 g of N-(2 hydroxy ethyl)aniline (2.0 mmole) were dissolved in 3 ml of dry ethanol and heated in a sealed tube at 80° C. for 8 hours. On cooling the product crystallized out as pale yellow needles, which was filtered and dried to yield 0.2 g of N-phenyl oxazine Compound 15.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]([O:15][CH3:16])([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].O.B1([O-])O[O:19]1.O.O.O.O.[Na+]>C1COCC1>[Si:5]([O:8][CH2:9][C:10]([O:15][CH3:16])([CH3:14])[CH2:11][CH2:12][CH2:13][OH:19])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7]
Reactant: [O-]B1OO1
Reactant: C=CCC(C)(CO[Si](C)(C)C(C)(C)C)OC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(CCCO)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(2-methoxy-2-methylpent-4-en-1-yl)oxy]dimethylsilane (2.45 kg, 10.04 mol) in THF (3.5 L) at <5° C. was added BH3 in THF (1M solution, 11.05 L, 11.05 mol) via a funnel while maintaining the reaction temperature at <15° C. The reaction mixture was stirred for 30 minutes and quenched with water (11.75 L, 652 mol). To the stirred mixture was added sodium perborate tetrahydrate (4.64 kg, 30.2 mol) and the mixture was stirred overnight at ambient temperature. The reaction mixture was then filtered, and the filter cake washed with 14 L MTBE. The combined organic layers were washed with brine/water (7 L/3 L). The aqueous layer was extracted with MTBE (14 L). The combined organic layers were sequentially washed with 18.75 L of 5% aqueous sodium thiosulfate/brine/water (10 L/5 L/3.75 L) and then concentrated in vacuo to provide crude material. Flash column chromatography (multiple runs) eluted with 0% to 100% DCM in heptane, then 1% to 50% EtOAc in DCM provided the desired alcohol. 1H NMR (300 MHz, CDCl3): δ 3.65-3.59 (m, 2 H); 3.47 (dd, J=23.9, 10.1 Hz, 2 H); 3.24 (s, 3 H); 2.21-2.07 (m, 1 H); 1.63-1.54 (m, 4 H); 1.05-0.70 (m, 9 H); 0.04 (s, 6H).
Reaction SMILES: [OH:1][C@:2]1(CO)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1.ClC1C=C(N(C2C=CC=CC=2)C(Cl)=O)C=CC=1.Cl>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([CH2:13][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:10][CH2:11][CH:2]([OH:1])[CH2:3]2)=[O:15])[CH3:18]
Reactant: CCOC(=O)COc1cccc2c1CC[C@](O)(CO)C2
Agent: Cl
Agent: O=C(Cl)N(c1ccccc1)c1cccc(Cl)c1
Solvent: c1ccncc1
Product: CCOC(=O)COc1cccc2c1CCC(O)C2
Temperature: 100 °C
Reaction time: 24 h
Yield: 192.8 %

Procedure:
A mixture of (2R)-2-hydroxy-2-(hydroxymethyl)-5-[(ethoxy carbonyl)methoxy]-1,2,3,4-tetrahydronaphthalene (465 mg) and N-(3-chlorophenyl)-N-phenylcarbamoyl chloride (2.21 g) in pyridine (10 mL) was stirred at 100° C. for 24 hours. After cooling, the reaction mixture was poured into 3N hydrochloric acid (50 mL) under ice-cooling and extracted with EtOAc The organic layer was washed with water, saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 3:2) to give (2R)-2-{N-(3-chlorophenyl)-N-phenylcarbamoyloxy]methyl}-5-[(ethoxycarbonyl)methoxy]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (800.6 mg) as a solid.
Reaction SMILES: Br[CH2:2][F:3].[Na].[CH3:5][O:6][C:7](=[O:18])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[CH:9][OH:10].C(OCC)(=O)C>CN(C)C=O>[CH3:5][O:6][C:7](=[O:18])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[CH:9][O:10][CH2:2][F:3]
Reactant: COC(=O)C(=CO)c1ccccc1C
Reactant: FCBr
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(=COCF)c1ccccc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 14.9 g of bromofluoromethane in 20 ml of dimethylformamide is added dropwise at 10° C. to a solution of 20 g of the sodium salt of 3-hydroxy-2-(o-tolyl)-acrylic acid methyl ester in 125 ml of dimethylformamide and the reaction mixture is then stirred at room temperature for 2.5 hours. The reaction mixture is then poured onto 400 ml of ice-water and exhaustive extraction is carried out with ethyl acetate. Washing with saturated sodium chloride solution is followed by drying over sodium sulfate, filtering and concentration by evaporation. Chromatography on silica gel with hexane/ethyl acetate (6:1) yields pure 3-fluoromethoxy-2-(o-tolyl)-acrylic acid methyl ester in the form of a colourless oil.
Reaction SMILES: C([C:8]1[CH:19]=[C:18](O)[CH:17]=[CH:16][C:9]=1[CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])C1C=CC=CC=1.[CH:21]1([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[C:34]([CH2:42][C:43]([CH3:45])=O)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:46]([OH:48])[CH3:47]>CO>[CH:28]1([NH:27][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1.[CH2:46]([O:48][C:18]1[CH:19]=[CH:8][C:9]([CH2:10][C@H:11]([NH:12][C:43]([CH3:45])=[CH:42][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)[C:47]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: CCO
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N[C@@H](Cc1ccc(O)cc1Cc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CO
Product: CC(=CC(=O)c1ccccc1)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 5.42 g (20 mmol) o-benzyl-L-tyrosine, 4.4 mL (22 mmol) dicyclohexylamine and 3.24 g (20 mmol) 1-benzoylacetone in 100 mL MeOH was refluxed for 24 h. 500 mL abs. ethanol was then added slowly to the solution and the MeOH was distilled out from the reaction flask with the same rate. The solution was then cooled to 0° C., stirred for 30 min, then filtered. The white solid was washed with 15 mL cold (−20° C.) abs. ethanol three times then dried to yield 7.60 g of the title compound: low resolution MS (FAB+) m/e 597 (MH+), 182 (DCAH+); Anal. (C38H48N2O4) Calcd. C, 76.47; H, 8.10; N, 4.69 Found C, 76.44; H, 8.16; N 4.63.