Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17](Br)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B(O)O)[CH:28]=2)[CH:23]=[CH:22]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:27]3[CH:28]=[C:29]4[C:24]([CH:23]=[CH:22][NH:21]4)=[CH:25][CH:26]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(Br)o1)C1CCCCC1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3cc[nH]c3c2)o1)C1CCCCC1
Temperature: 100 °C

Procedure:
In a pressure vial 5-Bromo-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (190 mg, 0.55 mmol), indole-6-boronic acid (106 mg, 0.66 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (39 mg, 0.05 mmol) are dissolved in DMF (3 mL). A 2M sodium carbonate solution (3.0 mL) is added and the resulting solution is degassed with Argon during 5 min. The vessel was heated at 100° C. for 20 min in the Microwave. Upon cooling the resulting mixture is diluted with EtOAc/H2O and the aqueous phase is extracted with EtOAc. The combined organic extracts are washed with brine, dried over MgSO4, and the solvent is evaporated. The residue is purified using reversed phase (HPLC). 137 mg, 65% LC/MS ESI m/z (M+H)+=380.5.
Reaction SMILES: [NH2:1][C@@H:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH2:18]([CH:20]1[O:22][CH2:21]1)[Cl:19]>CO>[Cl:19][CH2:18][CH:20]([OH:22])[CH2:21][NH:1][C@@H:2]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cccc([C@@H](N)c2ccc(Cl)cc2)c1
Reactant: ClCC1CO1
Solvent: CO
Product: N#Cc1cccc([C@@H](NCC(O)CCl)c2ccc(Cl)cc2)c1

Procedure:
A solution of 14.0 g (58 mmole) of 3-[(S)-amino(4-chlorophenyl)methyl]benzonitrile and 10.8 g (120 mmole) of epichlorhydrin in 200 mL of methanol was stirred in the dark for 72 hours. The solution was partitioned between CH2Cl2 and water and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to afford the title compound, which was used in the next step without purification; 335 (M+1, 35Cl); 337 (M+1, 37Cl).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[C:4]([F:13])[CH:3]=1.[BH4-].[Na+].O>CO.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[OH:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1CCCc2c(F)cc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: OC1CCCc2c(F)cc(Br)cc21
Reaction time: 2 h

Procedure:
To a solution of 7-bromo-5-fluoro-3,4-dihydro-2H-naphthalen-1-one (0.290 g, 1.145 mmol) in methanol (8 mL) and dichloromethane (2 mL) at 0° C. is added sodium borohydride (0.066 g, 1.718 mmol) in one portion. After 2 hours at 0° C., water (30 mL) is added and the volatile organics are removed in vacuo. The resulting mixture is extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated to afford 7-bromo-5-fluoro-3,4-dihydro-2H-naphthalen-1-ol, which is used in the next step without further purification.
Reaction SMILES: B.[O:2]1CCCC1.[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([C@@H:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1)[CH:25]=[CH2:26])[CH2:21][CH2:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].OO>O1CCCC1.O>[Br:33][C:29]1[CH:28]=[C:27]([C@H:24]([N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:20][CH2:21]2)[CH2:25][CH2:26][OH:2])[CH:32]=[CH:31][CH:30]=1
Reactant: C=C[C@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: OCC[C@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Temperature: 0 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A 1.0 M solution of borane-tetrahydrofuran complex (BH3-THF) in tetrahydrofuran (38.1 ml, 38.10 mmol) was added dropwise to a magnetically stirred solution of (1R)-(−)-7-benzyloxy-1-[1-(3-bromophenyl)prop-2-enyl]indoline (16.0 g, 38.1 mmol) in dry tetrahydrofuran (200 ml) under nitrogen at 0° C. The reaction mixture was heated under reflux for 8.5 h, during which time two further aliquots of 1.0 M BH3-THF in tetrahydrofuran were added (1×15.0 ml and 1×5.0 ml) until TLC inspection indicated that no further starting olefin remained. The reaction mixture was cooled to 0° C., sequentially treated with water (21.0 ml), 3M sodium hydroxide solution (21 ml) and 30% hydrogen peroxide (21.0 ml) then stirred at room temperature for 16 h. Quenched with brine (400 ml), extracted with ethyl acetate (3×200 ml), the combined organic phases were washed with brine (200 ml), dried (Na2SO4) and evaporated to yield a brown oil. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4) gave the title compound as a pink oil (11.70 g, 70%). [α]D25 −280° (c=0.011 gml−1, CHCl3); νmax (thin film)/cm−1 3391 (br. OH), 3063, 3031, 2939, 1591; δH (270 MHz) 1.89 (1H, m, 1×2-H); 2.26 (1H, m, 1×2-H); 2.69 (2H, m, indoline 2×2-H); 3.13 (1H, m, indoline 1×3-H); 3.30 (1H, bs, 1-OH); 3.43 (1H, m, indoline 1×3-H); 3.81 (2H, m, 2×1-H); 5.17 (2H, s, CH2Ph); 5.59 (1H, dd, 3-H, 3J3,2=11.2 Hz, 3J3,2′=4.0 Hz); 6.77 (3H, m, indoline 4-H, 5-H, 6-H); 7.06 (2H, m, 5′-H,6′-H); 7.31-7.51 (7H, ArH). δC (67.8 MHz) 29.1 (2-C); 32.7 (indoline 2-C); 45.6 (indoline 3-C); 58.2 (1-C); 61.7 (3-C); 70.9 (CH2Ph); 112.2 (indoline 6-C); 118.1 (indoline 5-C); 120.6 (indoline 4-C); 122.3 (3′-C); 133.4 (indoline 3a-C); 136.7 (1′-C); 139.0 (benzyl ipso-C); 142.4 (indoline 7a-C); 145.7 (indoline 7-C). The remaining signals lie between 126.5-130.7 ppm and cannot be assigned with any certainty; m/z 439.1, 437.1 (2.69, 3.32, M+), 394.2, 392.2 (1.06, 1.09), 348.1, 346.1 (5.33, 5.60), 225.1 (18.26), 172.0, 170.0 (33.75, 34.31), 134.0 (100), 118.0 (2.79), 91.1 (67.26).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].Cl[CH:18]([CH3:28])/[CH:19]=[CH:20]/[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:26]([N:23]([CH2:24][CH3:25])[C:21](=[O:22])/[CH:20]=[CH:19]/[CH:18]([S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH3:28])[CH3:27]
Reactant: Nc1cc(Cl)nc(S)n1
Reactant: CCN(CC)C(=O)/C=C/C(C)Cl
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)/C=C/C(C)Sc1nc(N)cc(Cl)n1
Reaction time: 15 h

Procedure:
To (E)-N,N-Diethyl-4-hydroxy-2-pentenamide (0.67 g, 3.93 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dichlorotriphenylphosphorane (1.40 g, 4.33 mmol). The reaction is warmed to ambient temperature, quenched by addition of ice (10 ml), extracted with methylene chloride (3×20 ml), washed with saline (30 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (75/25). The appropriate fractions are combined (Rf =0.48, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give (E)-4-chloro-N,N-diethyl-2-pentenamide. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.56 g, 2.19 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.12 g, 4.82 mmol) at ambient temperature followed by the addition of (E)-4-chloro-N,N-diethyl-2-pentenamide (0.41 g, 2.19 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×25 ml). The extracts are combined, washed with saline (25 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with a gradient of hexane/ethyl acetate (80/20-60/40). The appropriate fractions are combined (Rf =0.27, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, mp 152-153° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][OH:4].CO[C:21]([CH3:23])=[CH2:22].O.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:22][C:21]1([CH3:23])[O:1][CH:2]([C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:3][O:4]1
Reactant: C=C(C)OC
Reactant: O=C(NCc1ccccc1C(O)CO)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(c2ccccc2CNC(=O)C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1.93 g of N-[2-(1,2-dihydroxyethyl)benzyl]-2,2,2-trifluoroacetamide and 20 ml of acetone were added 1.1 ml of 2-methoxyprop-1-ene and 140 mg of 4-methylbenzenesulfonic acid monohydrate under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.2 g of N-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)benzyl]-2,2,2-trifluoroacetamide.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[C:8]([CH3:15])[C:6]=2[N:7]=1.[CH3:16][N:17]1[C:21](O)=[CH:20][CH:19]=[N:18]1.C(#N)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.O.C(N(CC)CC)C>[CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([O:14][C:21]3[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=3)=[O:13])=[C:8]([CH3:15])[C:6]=2[N:7]=1
Reactant: CNc1nc2c(C)c(C(=O)O)ccc2s1
Reactant: Cn1nccc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC#N
Solvent: O
Product: CNc1nc2c(C)c(C(=O)Oc3ccnn3C)ccc2s1

Procedure:
3.1 g of 2-methylamino-4-methylbenzothiazole-5-carboxylic acid (0.014 mol) and 1.4 g of 1-methyl-5-hydroxypyrazole (0.015 mol) were dissolved in 110 ml of abs. acetonitrile and admixed with 2.67 g of EDC (0.014 mol), 1,2 ml of triethylamine and a catalytic amount of DMAP. After the reaction had ended, the solution was poured into water and the mixture was extracted with ethyl acetate. The organic phase was washed and dried, and the product was then purified by crystallization. Yield: 2.2 g (52%).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.[Ni]>[NH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:13]1[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:11][CH:12]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 93.6 %

Procedure:
A solution of compound 81 (0.5 g, 1.346 mmol) in dry methanol (20 mL) was treated with hydrazine hydrate (0.41 mL, 13.461 mmol) followed by Raney-Ni (0.1 g) and the resulting mixture was refluxed for 30 min. The reaction was brought to room temperature, filtered through celite bed, washed with CH2Cl2:methanol (1:1, 3 20 mL). The combined organic layer was evaporated and crude was purified by column chromatography (EtOAC: Hexanes, 1:1) to obtain compound 98 (0.43 g, 94%) as a foam. 1H NMR (DMSO-d6) δ: 1.38-1.41 (m, 11H), 1.76-1.86 (m, 2H), 2.14-2.42 (m, 2H), 2.73 (s, 3H), 4.05-4.15 (m, 1H), 4.49 (s, 2H), 6.00 (brs, 1H), 6.48 (dd, 1H, J=1.8, 8.2 Hz), 6.99 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.16 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS m/z (%): 364 (M+Na+, 7), 342 (MH+, 11), 286 (100).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 216 h
Yield: 94 %

Procedure:
Ethyl-4′-methoxy-4-biphenylcarboxylate (1.29 g) was dissolved in methanol (7.5 mL) and sodium hydroxide (2 N in water, 7.5 mL) was added. The reaction was stirred at room temperature for 9 days and concentrated to dryness. Water (50 mL) was added and the mixture was made acidic with HCl (6 N in water). The precipitate was removed by filtration and dried under vacuum giving 4′-methoxy-4-biphenylcarboxylic acid (1.08 g). Yield=94%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)C1(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CNc2c(N)cnc3ccccc23)CC1

Procedure:
A suspension of 5% platinum on carbon (0.80 g) and ethyl l-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopropanecarboxylate (8.0 g, 25 mmol) in ethyl acetate was placed under hydrogen pressure (30 psi, 2.1×105 Pa) on a Parr apparatus for three hours and filtered through a layer of CELITE filter agent. The filter cake was washed with ethyl acetate (50 mL), and the combined filtrates were concentrated under reduced pressure to provide ethyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclopropanecarboxylate as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[N:3]=[CH:2]1.[OH-].[Na+]>CO>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[N:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1CCOc1ccccc1-c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1CCOc1ccccc1-c1c[nH]cn1
Temperature: 60 °C
Yield: 80.6 %

Procedure:
Methyl 2-(2-(2-(1H-imidazol-4-yl)phenoxy)ethyl)benzoate (30 mg, 0.093 mmol) was dissolved in methanol (3 mL) and aqueous NaOH (2M, 0.47 mL, 0.931 mmol) was added. The reaction mixture was heated at 60° C. for 16 h and methanol was evaporated under reduced pressure. The aqueous solution was neutralized to pH 7 and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried and concentrated. The crude product was purified by flash column chromatography to give the desired acid as a white solid (23 mg, 0.075 mmol, 79%). 1H NMR (CD3OD): 3.52 (t, 2H, J=6.4 Hz), 4.39 (t, 2H, J=6.4 Hz), 6.96 (t, 1H, J=7.4 Hz), 7.07 (d, 1H, J=8.4 Hz), 7.22 (t, 2H, J=7.8 Hz), 7.31 (d, 2H, J=6 Hz), 7.45 (s, 1H), 7.69-7.71 (m, 2H), 7.91 (d, 1H, J=4.8 Hz).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14](O)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:29](Cl)(OC1C=CC=CC=1)([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14]([PH:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)OCCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OCCOC(=O)[C@H]([PH](=O)Oc1ccccc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Yield: 78 %

Procedure:
Following the general procedure for phosphorylation of Description 23, (ethoxycarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (32) (0.43 g, 1.0 mmol) dissolved in 10 mL of anhydrous dichloromethane (DCM) was reacted with 0.58 mL (0.67 g, 2.5 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) (0.12 g, 1.0 mmol) and triethylamine (TEA) (0.35 mL, 0.25 g, 2.5 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude material was further purified by silica gel column chromatography using ethyl acetate (EtOAc) as eluent to provide 0.43 g (65% yield) of the title compound (51a) as a colorless oil. Rf=0.45 (EtOAc). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.09-1.10 (2s, 3H), 1.12-1.13 (2s, 3H), 1.26-1.32 (m, 3H), 1.45-1.52 (2d, J=5.6, 5.6 Hz, 3H), 1.86-1.87 (2s, 3H), 2.01-2.06 (m, 2H), 3.15-3.17 (m, 2H), 3.39-3.34 (m, 2H), 3.98-4.05 (m, 2H), 4.15-4.22 (m, 3H), 4.87-4.91 (2d, J=7.6, 7.6 Hz, 1H), 6.30-6.34 (br. m, 1H), 6.81-6.83 (m, 1H), 7.18-7.26 (m, 6H), 7.33-7.38 (m, 4H) ppm. MS (ESI) m/z 660.11 (M+H)+, 681.94 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([CH3:12])[C:6]=2[CH:13]=1.IC1C=CC2CCNCC(C)C=2C=1.FC(F)(F)C1C=CC2CCNCC(C)C=2C=1.FC(F)(F)C1C=CC2CCNCC(CC)C=2C=1.[Cl:60]C1C=CC2CCNCC(CC)C=2C=1.BrC1C=CC2CCNCC(CC)C=2C=1.IC1C=CC2CCNCC(CC)C=2C=1.ClC1C(Cl)=CC2C(C)CNCCC=2C=1.ClC1C(Cl)=CC2C(CC)CNCCC=2C=1.ClC1C(F)=CC2CCNCC(C)C=2C=1.ClC1C(F)=CC2CCNCC(CC)C=2C=1>>[Cl:60][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CC1CNCCc2ccc(Br)cc21
Reactant: CCC1CNCCc2ccc(Cl)cc21
Agent: CC1CNCCc2cc(Cl)c(Cl)cc21
Agent: CC1CNCCc2cc(F)c(Cl)cc21
Agent: CC1CNCCc2ccc(C(F)(F)F)cc21
Product: CC1CNCCc2ccc(Cl)cc21

Procedure:
8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7,8-Dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and 8-Chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1OC(C(F)(F)F)=CC=1.[CH3:21][O:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][C:26]2[C:31]3([CH2:41][O:42][C:25]=2[CH:24]=1)[C:39]1[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH:33][C:32]3=[O:40].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[CH3:21][O:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][C:26]2[C:31]3([CH2:41][O:42][C:25]=2[CH:24]=1)[C:39]1[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=1)[N:33]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:32]3=[O:40]
Reactant: COc1cc2c(cc1C#N)C1(CO2)C(=O)Nc2ccccc21
Reactant: BrCc1ccccn1
Agent: Br
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1cc2c(cc1C#N)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-methoxy-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (80%): mp 187-189° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57-8.55 (m, 1H), 7.70-7.64 (m, 1H), 7.27-7.20 (m, 3H), 7.12-7.00 (m, 3H), 6.91-6.89 (m, 1H), 6.55 (s, 1H), 4.97 (ABq, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.7, 165.8, 164.1, 154.9, 149.6, 142.3, 137.1, 131.2, 129.4, 128.8, 123.7, 123.6, 122.9, 122.0, 121.7, 116.7, 109.8, 94.6, 81.2, 56.9, 56.3, 45.9; MS (ES+) m/z 383.8 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH:10]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]([CH2:21][C:22]#[N:23])=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:14][C:15](/[C:21](=[CH:10]\[CH:9]=[CH:8]\[C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)/[C:22]#[N:23])=[C:16]([C:19]#[N:20])[C:17]#[N:18]
Reactant: N#CCC(N)=C(C#N)C#N
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Product: N#CC(C#N)=C(N)/C(C#N)=C\C=C\c1ccc([N+](=O)[O-])cc1

Procedure:
The compound was prepared as described in Example 3 by adding 4-nitrocinnamaldehyde (0.051 g, 0.29 mmol) to 2-amino-1-propene-1,1,3-tricarbonitrile (0.038 g, 0.29 mmol). After refluxing for 4 h and recrystallization from ethanol a yellow solid was obtained (0.08 g, 51%). The product gave the following analytical data:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)=[C:4]([CH3:20])[CH:3]=1.[O:21]1[C:23]2([CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[OH:21][C:23]1([CH2:22][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=3)=[C:4]([CH3:20])[CH:3]=2)[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1
Reactant: C1CC2(CCS1)CO2
Reactant: COC(=O)c1ccc(C)c(-c2c(C)cc(O)cc2C)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-c2c(C)cc(OCC3(O)CCSCC3)cc2C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of methyl 4′-hydroxy-2′,6,6′-trimethylbiphenyl-3-carboxylate (199 mg, 0.74 mmol) and 1-oxa-6-thiaspiro[2.5]octane (116 mg, 0.89 mmol) in N,N-dimethylformamide (2.5 mL) was added potassium carbonate (123 mg, 0.89 mmol) and the mixture was stirred overnight at 100° C. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) to give the title compound (191 mg, yield 64%) as a colorless oil.
Reaction SMILES: C1C2C(C[O:15][C:16]([N:18]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[OH:58][C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=1[OH:68])C(O)=O>>[OH:58][C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=1[OH:68])[C:16]([N:18]([C:39]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:15]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CNC(=O)CC[C@@H](C(=O)NCCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CNC(=O)CC[C@@H](C(=O)NCCc1ccc(O)c(O)c1)N(C(=O)c1ccc(O)c(O)c1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
This compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]dopamine (705 mg, 0.9 mmol, example 48, step A) as described for example 48 (step B) using 3,4-dihydroxybenzoic acid (215 mg, 1.4 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 40%, 50% and 60% EtOAc/CH2Cl2/1% AcOH as the eluent. The title compound was obtained as a white powder (100 mg, 16%).