Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C@H:6]([CH2:15][OH:16])[NH:7]C(OC(C)(C)C)=O)[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O.C(Cl)Cl>CCOCC>[CH2:1]([O:4][C:5](=[O:17])[C@H:6]([CH2:15][OH:16])[NH2:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](N)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
N-tert-butoxycarbonyl-L-serine allyl ester (27.2 g) was placed in a 500 ml r. b. flask and cooled to 0° C. To this yellow oil, 50% TFA/CH2Cl2 (100 ml) was added under positive N2 pressure. The reaction mixture was stirred at 0° C. (30 min), warmed to room temperature, and stirred for 2 h. TFA and CH2Cl2 were removed by rotoevaporation to yield a yellow oil. The yellow oil was dissolved in ether (200 ml). After 3 h at 4° C., the product completely precipitated. The precipitated product was collected by filtration and washed with ether (50 ml) and hexane (20 ml). The white precipitate was dried in a vacuum oven overnight. Dry L-serine allyl ester (3) was obtained (15.6 g, 100% yield). TLC in CH2Cl2/CH3OH/H2O (65:25:4) showed a pure product (Rf=0.58). FTIR: (thin film, cm−1) 2994.54, 2960.64, 2891.49, 1747.28, 1674.06, 1201.52, 11.45.92. 1H NMR (300 MHz, CDCl3, δ ppm): 5.86 (1H, m), 5.30 (2H, m), 4.59 (2H, d, J=6.43 Hz), 4.09 (2H, m), 3.77 (1H, m). FAB-MS [M+H+] calcd for C6H11NO3 146.2, found 146.0.
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[S:12][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:20]1[CH:19]=[CH:18][C:11]2[S:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]=2[CH:21]=1
Reactant: BrBr
Reactant: COC(=O)c1sc2ccccc2c1-c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Add 29.3 g. bromine (10 ml; 0.37 mole) to 8.0 g. (0.03 mole) of methyl 3-phenylbenzo[b]thiophene-2-carboxylate in 100 ml of acetic acid and stir the mixture overnight at room temperature. Add a saturated solution of sodium bisulfite. Decant the supernatant and wash the oil with water. Triturate with methanol. Recrystallize from methanol to yield the title compound; m.p. 125°-126°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20](=O)[CH2:21]Br>>[F:14][C:15]([F:27])([F:28])[O:16][C:17]1[CH:18]=[C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:21]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: O=C(CBr)c1cccc(OC(F)(F)F)c1
Product: COC(=O)c1cccc(-c2nc(-c3cccc(OC(F)(F)F)c3)cs2)c1
Yield: 34 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 3-trifluoromethoxyphenacyl bromide to obtain methyl 3-[4-(3-trifluoromethoxyphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 34%. Colorless prisms. Melting point: 84 to 85° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:11]([CH2:17][CH2:18][OH:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>ClCCl>[C:27]([O:19][CH2:18][CH2:17][N:11]1[C:12]([CH:14]([CH3:16])[CH3:15])=[CH:13][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)c1cc(OCc2ccccc2)nn1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc(OCc2ccccc2)nn1CCOC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 3-benzyloxy-1-(2-hydroxyethyl)-5-isopropyl-1H-pyrazole (2.41 g) in dichloromethane (45 mL) were added triethylamine (1.40 g) and benzoyl chloride (1.43 g) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/6-1/1) to give the title compound (1.35 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([Li])CCC.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O>O1CCCC1>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Nc2ccccc2N)c(F)c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 2-fluoro-4-methylaniline (6.8 mL, 60 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. and treated with n-butyllithium (26 mL of a 2.5 M solution in hexanes, 66 mmol) and stirred for 1 h. A solution of 2-fluoronitrobenzene (6.3 mL, 60 mmol) in tetrahydrofuran (20 mL) was added dropwise over 5 min, and the reaction mixture was stirred at −78° C. for 0.5 h, then warmed to 22° C. After 16 h, the reaction mixture was concentrated, diluted with ethyl ether (200 mL), washed with 2 M hydrochloric acid (200 mL), dried (Na2SO4), and concentrated to a black oil. A solution of this black oil in a mixture of methanol (100 mL) and ethyl acetate (100 mL) was treated with 10% palladium on carbon (1 g) and stirred under a hydrogen atmosphere at 65 psi for 2 h, and then the reaction mixture was filtered, and concentrated. Flash chromatography (SiO2, 10→100% dichloromethane/hexanes) provided N-(2-fluoro-4-methylphenyl)benzene-1,2-diamine (7.0 g) as an orange solid:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=1)=O)C.[BH4-].[Na+]>C(O)C>[OH:3][CH2:4][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(-c2ccccn2)no1
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(5-ethoxycarbonyl-isoxazol-3-yl)-pyridine (6.5 gm), in ethanol (80 ml) was added sodium borohydride (2 gm) in lots at 30° C. It was stirred at 30° C. over a period of 1.5 h. The reaction was monitored by TLC. Upon consumption of starting material, aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate. Combined organic layers was washed with water and concentrated under vacuum to provide title compound in 7.7 gm quantity. It was purified by using silica gel column chromatography to afford tile compound in 4.5 g (85%) quantity as off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cc1ccnc2cc(O)ccc12
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCCCN1CCCC1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mol), (prepared as described for the starting material in Example 9), was reacted with 7-hydroxy-4-methylquinoline (80 mg, 0.5 mol), (Chem. Berich. 1967, 100, 2077), to give 6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (155 mg, 87%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:19]([OH:21])=O)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1.[CH3:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:19]([NH:30][CH2:29][C:26]2[CH:27]=[N:28][C:23]([CH3:22])=[CH:24][CH:25]=2)=[O:21])[CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:11]=1
Reactant: COCCOc1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: Cc1ccc(CN)cn1
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: COCCOc1cc(C(=O)NCc2ccc(C)nc2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(2-methoxyethoxy)-4′-methylbiphenyl-3-carboxylic acid (50 mg, 0.18 mmol) in N,N-dimethylformamide (1 mL) were added (6-methylpyridin-3-yl)methanamine (45 mg, 0.37 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was stirred for 16 hours at 25° C. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC to afford the title product.
Reaction SMILES: [CH3:1][O:2]C1C=C2C(C(C(O)=O)=CN2)=CC=1.[N:15]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]([NH2:29])=[O:28])[CH:19]=1)=[C:16]=[O:17]>>[N:15]([C:18]1[C:26]2[C:21](=[CH:22][C:23]([O:2][CH3:1])=[CH:24][CH:25]=2)[N:20]([C:27]([NH2:29])=[O:28])[CH:19]=1)=[C:16]=[O:17]
Reactant: NC(=O)n1cc(N=C=O)c2ccccc21
Reactant: COc1ccc2c(C(=O)O)c[nH]c2c1
Product: COc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from 6-methoxy-indole-3-carboxylic acid using the protocol described for the preparation of 3-isocyanato-indole-1-carboxylic acid amide scheme A1.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3]([O:5]CC)=[O:4].C[O-].[Na+].Br[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>O.CO>[CH:17]1([CH2:16][CH:2]([C:3]([OH:5])=[O:4])[C:1]([OH:9])=[O:8])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrCC1CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CCCC1)C(=O)O
Reaction time: 3 h
Yield: 58.7 %

Procedure:
A solution of diethyl malonate (36.91 g, 230.4 mmol), anhydrous methanol (400 mL), and NaOMe (25% in methanol, 49.79 g, 230.4 mmol) is stirred at reflux for one hour under nitrogen. Bromomethyl-cyclopentane (31.31 g, 192.0 mmol) is added to the mixture, and stirred for an additional 3 hours. A solution of NaOH (23.04 g, 576.0 mmol) in water (400 mL) is added, and the mixture is stirred for an additional 1 hour at reflux. The mixture is cooled, diluted with water, and extracted with ether. The ether layer is discarded, and the aqueous layer is acidified with 1N HCl to pH=1. The aqueous layer is extracted with EtOAc. The EtOAc layers are combined, dried over Na2SO4, and concentrated. This gives 2-cyclopentylmethyl-malonic acid (21.0 g, 59% yield) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCC=O
Reactant: CC(C)Oc1cccc(N)c1
Product: CCCCNc1cccc(OC(C)C)c1
Yield: 88.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3-isopropoxyaniline (485 μL, 3.31 mmol) and butyraldehyde (310 μL, 3.47 mmol) were converted to the title compound (610 mg, 84%). 1H NMR (CDCl3) δ 7.15-6.96 (m, 1H), 6.37-6.01 (m, 2H), 4.60-4.39 (m, 1H), 3.75 (br s, 1H), 3.10 (t, J=7.0 Hz, 2H), 1.68-1.52 (m, 2H), 1.50-1.38 (m, 2H), 1.34 (s, 3H), 1.33 (s, 3H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[F:11][C:12]([F:50])([F:49])[C:13]1[CH:14]=[C:15]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:16][N:17]([C:37]1[NH:41][N:40]=[N:39][N:38]=1)[C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:20]2[C:31]([CH3:36])=[C:32]([CH3:35])[CH:33]=[CH:34][C:19]1=2.O>CN(C=O)C.C(OCC)(=O)C>[F:46][C:45]([F:48])([F:47])[C:43]1[CH:42]=[C:15]([CH:14]=[C:13]([C:12]([F:49])([F:11])[F:50])[CH:44]=1)[CH2:16][N:17]([C:37]1[N:38]=[N:39][N:40]([CH2:8][CH2:9][OH:10])[N:41]=1)[C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:20]2[C:31]([CH3:36])=[C:32]([CH3:35])[CH:33]=[CH:34][C:19]1=2
Reactant: OCCBr
Reactant: Cc1ccc2c(c1C)N(C(=O)OC(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1C)N(C(=O)OC(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
Add potassium carbonate (58 mg, 0.42 mmol) and 2-bromoethanol (0.038 mL, 0.53 mmol) to a solution of (S)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8,9-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 56, Step 5) (120 mg, 0.21 mmol) in DMF (0.4 mL) at room temperature in a tube. Seal the tube and stir the mixture at 50° C. for 3 h. Cool the mixture at room temperature and add water and ethyl acetate. Separate the layers, dry the organic phase over anhydrous Na2SO4, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexane/ethyl acetate, to provide 58 mg (45%) of the title compound. MS (ES+): 615 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)=[CH2:2].[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=O.CCCCCC>CO.C(OCC)C>[CH3:18][C:12]1[NH:11][C:21]([CH3:23])=[C:20]([C:19]([O:25][CH3:26])=[O:24])[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[CH:1]=[CH2:2])[C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC(C)=O
Reactant: COC(=O)/C=C(/C)N
Reactant: C=Cc1ccccc1C=O
Solvent: CCOCC
Solvent: CO
Solvent: CCCCCC
Product: C=Cc1ccccc1C1C(C(=O)OC)=C(C)NC(C)=C1C(=O)OC
Reaction time: 8 h

Procedure:
To the Compound 2a (106 mmol) in anhydrous methanol (100 ml) was added methyl 3-aminocrotonate (106 mmol) and methyl acetoacetate (106 mmol) and the resulting solution heated at reflux under nitrogen for 4 days. The solvent was removed in vacuo to give a viscous yellow oil which was diluted in diethyl ether (75 ml) and then hexane (50 ml). After stirring overnight, a yellow solid was collected by filtration and purified by flash chromatography on silica gel eluted with hexane:diethyl ether (1:2) to give Compound 2b as a yellow solid (Rf =0.4, m.p. 140°-148°).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].C(N(CC)CC)C.[C:21](Cl)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)(Cl)Cl>[C:21]([NH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)Nc1cccc(C(=O)O)c1C
Yield: 72 %

Procedure:
A stirred solution of ethyl 3-amino-2-methylbenzoate (17.9 g) in chloroform (150 ml), containing triethylamine (15 ml), was treated with a solution of n-hexadecanoyl chloride (28 g) in chloroform (50 ml), during 30 minutes. The temperature of the reaction mixture was maintained at 0°-10° C. during the addition by ice cooling. The mixture was then refluxed for 90 minutes, washed with water (2×150 ml) and was dried over magnesium sulphate. The solvent was removed in vacuo to give a white solid, which was recrystallised from ethanol. The solid was dissolved in warm ethanol (500 ml) and the solution was treated with sodium hydroxide (10 g) in water (50 ml). The mixture was then refluxed for one hour and was poured onto a mixture of crushed ice and dilute hydrochloric acid (150 ml of strength 2N). The solid was collected and was recrystallised from ethanol (1000 ml) to give 3-(n-hexadecanamido)-2-methylbenzoic acid (28 g), in the form of a white solid, m.p. 163°-165° C.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[C@@H:10]([CH3:23])[C:11]([CH3:22])([CH3:21])[C@H:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:24][CH3:25])[CH:4]=[CH:5]2.CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[C@@H:10]([CH3:23])[C:11]([CH3:22])([CH3:21])[C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:24][CH3:25])[CH:4]=[CH:5]2
Reactant: COc1ccc2c3c1O[C@H]1[C@H](O)C(C)(C)[C@H](C)[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc2c3c1O[C@H]1C(=O)C(C)(C)[C@H](C)[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 69.4 %

Procedure:
Compound 6b (710 mg, 2 mmole) in CH2Cl2 (10 ml) was oxidized using DMSO (0.35 ml. 5 mmole) and trifluoroacetic anhydride (0.70 ml, 3.75 mmole) in methylene chloride (CH2Cl2) (8 ml) at -65° as described above. After the addition of TEA (1 ml), workup gave a residue which was purified by chromatography to give 474 mg (67%) of 7b as a glass whose structure was confirmed by NMR. This material was converted to the HCl salt which crystallized from methanol-ethyl acetate (MeOH-EtOAc) to give analytically pure 7b.HCl, mp 246°-248° which was confirmed by elemental analysis.
Reaction SMILES: [CH3:1][N:2]([C@@H:12]([C:24](=[O:39])[N:25]([CH3:38])[C@@H:26]([C:34](=[O:37])[NH:35][CH3:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:3](=[O:11])/[CH:4]=[CH:5]/[CH2:6][C:7]([NH2:10])([CH3:9])[CH3:8].C(O)(=O)C.[Si:44]([O:51][C@H:52]([CH3:55])[CH:53]=O)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].C([BH3-])#N.[Na+]>CO>[Si:44]([O:51][C@H:52]([CH3:55])[CH2:53][NH:10][C:7]([CH3:8])([CH3:9])[CH2:6]/[CH:5]=[CH:4]/[C:3]([N:2]([C@H:12]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:24]([N:25]([C@H:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]([NH:35][CH3:36])=[O:37])[CH3:38])=[O:39])[CH3:1])=[O:11])([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:46])[CH3:45]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N
Reactant: C[C@H](C=O)O[Si](C)(C)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide (318 mg, 0.60 mmol) was dissolved in methanol (20 ml) and glacial acetic acid (0.48 ml, 8.4 mmol). 3 Å mol sieves (9 g) and a solution of (2R)-2-(tert-butyldimethylsilyloxy)propanal (1.33 g, 7.06 mmol) in methanol (10 ml) were added successively. Sodium cyanoborohydride (220 mg, 3.53 mmol) was added as a solid. The reaction mixture was stirred at room temperature for 45 min, before a second batch of sodium cyanoborohydride (220 mg, 3.53 mmol) was added. The reaction mixture was stirred for 16 h at room temperature. The mol sieves was filtered off through a plug of celite. The celite was washed with methanol (200 ml). The solvents of the combined filtrates were removed in vacuo. The residue was dissolved in 1 N sodium hydroxide solution (50 ml) and tert-butyl methyl ether (50 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (35 g), using ethyl acetate/heptane/triethylamine (20:10:1) as eluent, to give 99 mg of (2R)-2-(N-((2R)-2-(N-((2E)-5-((2R)-2-(tert-butyldimethylsilyloxy)propylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-N-methyl-3-phenylpropionamide.
Reaction SMILES: [O:1]=[C:2]=[N:3]C1CC(C)(C)CC(C)(CN=C=O)C1.C1OC1.C1OC1CC.OC1C=CC(C(C2C=[CH:39][C:38]([OH:41])=CC=2)(C)C)=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[C:58]([O:62]CCO)(=[O:61])[CH:59]=[CH2:60]>>[C:58]([OH:62])(=[O:61])[CH:59]=[CH2:60].[NH2:3][C:2]([O:41][CH2:38][CH3:39])=[O:1]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: C=CC(=O)OCCO
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CCC1CO1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1CO1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Into a reaction vessel equipped with a stirrer, 168.2 gm of isophorone diisocyanate, 1,044.6 gm of copolymer of ethylene oxide, 1,2-butylene oxide, and bisphenol A (1:7:1 by weight) with a number average molecular weight of 2,052, and 0.3 gm of 2,6-di-tert-butyl-4-methyl phenol, as a polymerization inhibitor, were charged. After cooling the mixture to 15° C. in an ice-cooled bath, 1 gm of dibutyltindilaurate was added to initiate the reaction at 30 to 40° C. for 2 hours. After the addition of 47.2 gm of hydroxyethyl acrylate, the mixture was stirred for 5 hours at a temperature of 50° to 60° C. to obtain urethane acrylate [A-2] with a number average molecular weight of 6,140.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[N:6]=1>C(O)(C)C>[Cl:11][C:7]1[CH:8]=[N:9][CH:10]=[C:5]([N:2]([CH3:3])[CH3:1])[N:6]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CNC
Solvent: CC(C)O
Product: CN(C)c1cncc(Cl)n1
Reaction time: 3 h
Yield: 94.2 %

Procedure:
Cuprous chloride (50 mg) is added to a solution of dimethylamine (36 g, 0.8 mole) in 260 ml of isopropanol. 2,6-Dichloropyrazine (49.9 g, 0.33 mole) is added to the mixture with stirring and cooling to maintain the temperature at 35°-40° C. After 3/4 hr. the cooling bath is removed and the reaction mixture is stored at ambient temperature for 16 hours and finally at 42°-48° C. for 3 hours. The solvent is removed under vacuum and the residue is dissolved in dilute hydrochloric acid. The aqueous solution is extracted with ether and then made basic with solid sodium bicarbonate and extracted with methylene chloride. The organic extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to obtain 49 g of product, melting point 46°-8° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=O)[CH:22]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:31][C:23]2[CH:22]=[N:21][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1cnc2ccccc2c1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.64 min.; [M+H]+: 379.06 g/mol.