Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, light yellow solid (72 mg, 64%), MS (ISP) m/z=451.3 [(M+H)+], mp 213° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-fluoro-benzoic acid.
Reaction SMILES: CC(S([NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH2:19])=[O:18])[CH:12]=1)[CH2:9][CH3:10])=O)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH2:19])=[O:18])[CH:12]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C(N)=O)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1ccnc(C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of 85% 4-[(S)-1-(2-methyl-propane-2-sulfinylamino)-propyl]-pyridine-2-carboxylic acid amide (5.5 g, 16.5 mmol) in methanol (50 mL) was added a 4 N solution of HCl in dioxane (4.33 mL, 17.32 mmol). After 2 hour, additional 4 N HCl in dioxane (0.5 mL) was added. The reaction was monitored by TLC (eluting with EtOAc). After 1.5 hours, the mixture was concentrated in vacuo to remove MeOH and EtOAc (400 mL) was added. The mixture was washed with saturated sodium carbonate solution (100 mL) and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 4-((S)-1-amino-propyl)-pyridine-2-carboxylic acid amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[Cl:14])[CH:10]=[N:11]O)=[CH:5][CH:4]=1>CC(OC(C)=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[Cl:14])[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cl)=C(C=NO)c2ccc(OC)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C(Cl)=C(C#N)c2ccc(OC)cc2)cc1

Procedure:
1.0 g of 2,3-Bis(4-methoxyphenyl)-3-chloro-acrylaldoxime (3.14 mmoles) was refluxed for 2 hours in 25 ml of acetanhydride. After cooling, the mixture was poured onto water. The crystalline solid substance which had precipitated was suction-filtered and recrystallized from methanol. Melting point: 140° to 142° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][O:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([N:19]=[C:20]=[S:21])=[O:18])=[CH:15][CH:14]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[S:21])[NH:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:5]
Reactant: COc1ccc(C(=O)N=C=S)cc1
Reactant: NC(=O)c1ccccc1N
Solvent: CCOCC
Product: COc1ccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)cc1
Reaction time: 8 h
Yield: 833 %

Procedure:
To a stirred mixture of 7.5 g of 2-aminobenzamide and 150 ml of ether was added dropwise, a mixture of 1.0 g of 4-methoxybenzoyl isothiocyanate in ether over 15 minutes. After stirring overnight, the solid was collected, giving 14.2 g of the desired product as grey crystals, mp 193°-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:25]1[C:26]([OH:34])=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:25]1[C:26]([OH:34])=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cc3c(cc2O)OCC3)c2c(Cl)cccc2N1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one (9.25 g, 19.1 mmol) in dichloromethane (25 mL) was added triethylsilane (10 mL). The mixture was cooled to 0° C. followed by the addition of trifluoroacetic acid (10 mL) slowly over 5 min. The resultant mixture was stirred at ambient temperature for 5 h and concentrated in vacuo to dryness. The residue was triturated in diethyl ether (25 mL) in a Branson ultrasonic bench top water bath to afford 4-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one (8.90 g, quantitative) as a beige solid: MS (ES+) m/z 468.0 (M+1), 470.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:15])[CH:4]=[CH:5][C:6]=1[S:7]([NH:10]C(C)(C)C)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH3:15])[CH:4]=[CH:5][C:6]=1[S:7]([NH2:10])(=[O:8])=[O:9]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccc(S(N)(=O)=O)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.4 %

Procedure:
To a solution of 7.11 g (24 mmol) of 2-bromo-N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 50 mL methylene chloride under a nitrogen atmosphere was added 50 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the crude residue and was removed by evaporation to remove residual TFA, which yielded 1.23 g of the title compound as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][C:25](=O)[CH3:26])[CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-trifluoromethyl-phenyl)-butan-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:17][CH2:18][O:9][C:4]=2[CH:3]=1
Reactant: BrCCBr
Reactant: Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A mixture of 4-methylbenzene-1,2-diol (10.0 g, 80.5 mmol) and potassium carbonate (111.3 g, 805.0 mmol) in acetone (300 mL) was stirred at room temperature for 1 h. After this time, 1,2-dibromoethane (27.7 mL, 322.0 mmol) was added and the reaction stirred at reflux for 5 d. After this time, the solvents were removed under reduced pressure and the solids redissolved in water (500 mL). The aqueous layer was then extracted three times with ethyl acetate (200 mL). The combined organic extracts were then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1:20 ethyl acetate/hexanes) afforded 6-methyl-2,3-dihydrobenzo[b][1,4]dioxine (6.4 g, 54%) as a green oil: 1H NMR (500 MHz, CDCl3) δ 6.74 (d, J=8.5 Hz, 1H), 6.67 (d, J=2.0 Hz, 1H), 6.63 (dd, J 2.0, 8.0 Hz, 1H), 4.22 (m, 4H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].[CH3:13][C:14]1([CH3:21])[O:18][C@H:17]([CH2:19]O)[CH2:16][O:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:13][C:14]1([CH3:21])[O:18][C@H:17]([CH2:19][O:11][C:10]2[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:1][CH3:2])[CH2:16][O:15]1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(C)c1OC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (2.89 g, 17.9 mmol) in THF (80 mL), (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol (2.84 g, 21.5 mmol) followed by triphenylphosphine (5.81 g, 21.5 mmol) is added. The mixture is cooled with an ice-bath before DEAD (9.36 g, 21.5 mmol) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 85:15 to give (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (4.45 g) as a pale yellow oil; LC-MS**: tR=0.75 min, [M+1]+=not detected; 1H NMR (CDCl3): δ1.25 (t, J=7.5 Hz, 3H), 1.44 (s, 3H), 1.49 (s, 3H), 2.34 (s, 3H), 2.65-2.77 (m, 2H), 3.80-3.90 (m, 2H), 3.94-4.00 (m, 1H), 4.21 (t, J=7.3 Hz, 1H), 4.52 (quint, J=5.8 Hz, 1H), 7.35 (s, 1H), 7.38 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[O:8][C:4]=2[CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: Cc1ccc2nc(C(=O)CC(=O)C(F)(F)F)oc2c1
Agent: Cl
Product: Cc1ccc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)oc2c1

Procedure:
The procedure of Example 9 was repeated using 1-(6-methylbenzoxazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-methyl-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzoxazole.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[ClH:9].CN.[CH2:12]([N:14](CC)CC)C>ClCCCl>[ClH:9].[CH3:12][NH:14][CH:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CCN(CC)CC
Reactant: CC1CCC(=O)CC1
Agent: CN
Agent: Cl
Solvent: ClCCCl
Product: CNC1CCC(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,2-dichloroethane (35 ml) were suspended 4-methylcyclohexanone (2.5 g), methylamine hydrochloride (1.6 g) and triethylamine (3.3 ml), and to the suspension was added sodium triacetoxy boron hydride (6.6 g) under ice-cooling. The mixture was stirred under nitrogen atmosphere at room temperature overnight. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated. To the residue was added. 4N hydrochloric acid-ethyl acetate, and the solvent was evaporated to give N, 4-dimethyl-cyclohexylamine hydrochloride (2.6 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:21])[CH3:20]>CN(C)C=O>[C:19]([O:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[NH:3][C:2](=[O:1])[CH:11]=[CH:10]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:21])[CH3:20]
Reactant: Oc1ccc2cccc(O)c2n1
Reactant: CCCCCCC(OC(C)=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC(OC(C)=O)c1ccccc1COc1cccc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6.5 g of 2,8-dihydroxyquinoline, 5.5 g of anhydrous ground potassium carbonate are stirred in 100 ml of dimethylformamide at 25° C. for 1 hour. After addition of 13.1 g of 1-(2-bromomethylphenyl)heptyl acetate in 50 ml of dimethylformamide, the mixture is stirred at 25° C. for 20 hours. The solvent is removed in vacuo, the residue is taken up in 100 ml of water and the mixture is extracted 3 times with 50 ml of ethyl acetate each time. The organic phases are washed once with 50 ml of water each time, dried over Na2SO4 and concentrated in vacuo. The oil which remains is chromatographed over silica gel 60 with CH2Cl2 /ethyl acetate 10:1. The resulting product slowly crystallizes out.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[O:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH:45]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:45][C:41]1[O:40][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)[C@H](CNCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)[C@H](CN(Cc1ccc(-c2ccccc2)cc1)Cc1ccco1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 657 and was subjected to reductive amination as per procedure E with furan-2-carbaldehyde (0.009 g, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(biphenyl-4-ylmethyl-furan-2-ylmethyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.030 g, 60%). 1H-NMR(400 MHz, DMSOd6): 3.21 (m, 2H), 4.0 (m, 3H), 6.7 (d, 1H), 7.6 (m, 2H), 7.8 (m, 8H), 8.24 (m, 8H); LC/MS (m/z): 599.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].[CH2:10]([C:12]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH2:15][CH3:16])[CH:13]=[O:14])[CH3:11].[NH4+].[Cl-]>O1CCCC1>[CH2:10]([C:12]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH2:15][CH3:16])[CH:13]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:14])[CH3:11]
Reactant: Fc1ccc(Br)cc1
Reactant: CCC(C=O)(CC)Cc1cccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(Cc1cccnc1)C(O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 48 %

Procedure:
20.4 g (0.116 mol) of 4-fluorobromobenzene in 250 ml of tetrahydrofuran are added dropwise to 2.8 g of magnesium turnings (0.166 mol) and stirring is carried out for half an hour at RT. 11 g (0.058 mol) of 2-ethyl-2-(pyrid-3-ylmethyl)-butanal in 100 ml of tetrahydrofuran are then slowly added dropwise. After 2 hours, the mixture is poured onto ice water and brought to pH 8 with saturated NH4Cl solution. It is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is then evaporated off. 8 g (48%) of the title compound are obtained as a viscous oil (compound No. 70 in the Table).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][NH:39][O:40][CH3:41]>C(#N)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([N:39]([O:40][CH3:41])[CH3:38])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)C[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (3R)-3-[(tert-butoxycarbonyl)amino]butanoic acid (1 g, 5 mmol) in acetonitrile (40 mL) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 1.05 g, 5.5 mmol), 1-hydroxybenzotriazole (HOBt; 810 mg, 6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.0 g, 10 mmol) and triethylamine (1.4 mL) and stirred at room temperature for 2 d. The solution was evaporated and the residue purified by flash chromatography on a Biotage® system (silica gel, 40-90% ethyl acetate/hexane gradient) to yield the desired product as a colorless viscous oil. MS 269.1 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1)OCc1ccccc1
Yield: 86.9 %

Procedure:
Treatment of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.9 g, 5.75 mmol) with diisopropylethylamine (1.11 g, 8.62 mmol) followed by benzyl chloroformate (1.18 g, 6.89 mmol) generally according to the procedure described for Intermediate 12 gave 2.14 g (87%) of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 87-89° C.; Anal. calcd. for C23H19Cl2NO3: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.65; H, 4.78; N, 3.08. Chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel AD, methanol:water 95:5) provided two fractions. Fraction 1 (Rt=8.094 min, Chiralcel AD, methanol:water 95:5); Fraction 2 (Rt=9.152 min, Chiralcel AD methanol:water 95:5).
Reaction SMILES: [NH2:1][C:2](=[N:21][OH:22])[C:3]1[CH:4]=[CH:5][C:6]([F:20])=[C:7]([CH:19]=1)[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[CH3:41])[C:29](O)=O>>[F:20][C:6]1[CH:5]=[CH:4][C:3]([C:2]2[N:1]=[C:29]([C:28]3[CH:32]=[CH:33][C:34]([N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]4[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:27]=3)[O:22][N:21]=2)=[CH:19][C:7]=1[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Reactant: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Product: COCc1cc(-c2nc(-c3ccc(F)c(CN(C)CC(=O)OC(C)(C)C)c3)no2)ccc1N1CCCCC1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 60 (256.87 mg; 0.83 mmol) and Intermediate 58 (197.50 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.31 (d, J=2.1 Hz, 1H), 8.22 (dd, J=7.0, 2.2 Hz, 1H), 8.11-8.06 (m, 2H), 7.23-7.14 (m, 2H), 4.67-4.55 (m, 2H), 4.16-4.08 (m, 2H), 3.89 (s, 2H), 3.49 (s, 3H), 3.27 (s, 2H), 3.18-3.12 (m, 1H), 3.06-2.99 (m, 1H), 2.67-2.59 (m, 1H), 2.46 (s, 3H), 1.89-1.76 (m, 2H), 1.73-1.65 (m, 2H), 1.51 (s, 9H), 0.89 (d, J=6.3 Hz, 3H). LC/MS (Method B): 539.4 (M+H)+. HPLC (Method A) Rt 3.84 min (Purity: 99.1%).
Reaction SMILES: Br[C:2]1[S:13][C:12]2[N:11]=[C:10]([CH3:14])[C:9]3[N:5]([C:6]([CH2:16][CH2:17][CH3:18])=[N:7][C:8]=3[CH3:15])[C:4]=2[N:3]=1.[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:2]1[S:13][C:12]2[N:11]=[C:10]([CH3:14])[C:9]3[N:5]([C:6]([CH2:16][CH2:17][CH3:18])=[N:7][C:8]=3[CH3:15])[C:4]=2[N:3]=1
Reactant: CCCc1nc(C)c2c(C)nc3sc(Br)nc3n12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)c2c(C)nc3sc(OC)nc3n12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Bromo-5,6-dimethyl-8-propyl-3-thia-1,4,7,8a-tetraaza-as-indacene was dissolved in 5 mL of methanol and sodium methoxide (4.98 mg, 0.092 mmol) was added. The resulting mixture was stirred at 60° C. for 1 h. LC-MS showed complete consumption of 2-bromo-5,6-dimethyl-8-propyl-3-thia-1,4,7,8a-tetraaza-as-indacene. After removal of the solvent under reduced pressure, 5 mL of water and 10 mL of EA were added. The organic layer was concentrated, crude product was purified by prep-HPLC to give 4 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([CH:8]([CH:17]1[O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18]1)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:7])=[O:6].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[C:2]([CH2:3][CH2:4][S:5]([CH:8]([CH:17]1[O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18]1)[CH:9]=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:6])=[O:7])([OH:25])=[O:1]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C1CCCC(C(C=Cc2ccccc2)S(=O)(=O)CCCO)O1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCS(=O)(=O)C(C=Cc1ccccc1)C1CCCC(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 6-[1-(hydroxypropylsulphonyl)-3-phenyl-2-propenyl]tetrahydro-2H-pyran-2-one, (see Example 24) (1.0 g) and pyridinium dichromate (4.67 g) in dimethyl formamide (10 ml) was stirred at room temperature for 20 hours. The mixture was diluted with water and extracted with ethyl acetate to give 6-[1-(carboxyethylsulphonyl)-3-phenyl-2-propenyl]tetrahydro-2H-pyran-2-one as an oil. The lactone was hydrolysed and the disodium salt prepared, as described in Example 22(b) to give the disodium salt of the title compound, m.p. about 203° C.
Reaction SMILES: [NH2:1][C@@:2]([C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)([CH2:6][CH2:7][CH2:8][CH2:9][B:10]([OH:12])[OH:11])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.CN(C)C=O.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[S:39])=[CH:33][CH:32]=1>Cl>[ClH:30].[ClH:30].[NH2:1][C:2]([C@H:13]1[CH2:17][CH2:16][N:15]([C:38](=[S:39])[NH:37][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH2:14]1)([CH2:6][CH2:7][CH2:8][CH2:9][B:10]([OH:12])[OH:11])[C:3]([OH:5])=[O:4]
Reactant: N[C@@](CCCCB(O)O)(C(=O)O)[C@@H]1CCNC1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(CCCCB(O)O)(C(=O)O)[C@H]1CCN(C(=S)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
A solution of (R)-2-amino-6-borono-2-((R)-pyrrolidin-3-yl)hexanoic acid (200 mg, 0.8 mmol) and triethylamine (700 mg, 6 mmol) in N,N-dimethylformamide (4 mL, 50 mmol) was treated with 4-chlorophenyl isothiocyanate (300 mg, 1.8 mmol) in a single portion. After stirring at room temperature for 30 min, the reaction was diluted with 1 N HCl (20 mL) and washed with ethyl acetate (20 mL). The aqueous solution was concentrated and purified by HPLC to give 2-amino-6-borono-2-((S)-1-(4-chlorophenylcarbamothioyl)pyrrolidin-3-yl)hexanoic acid hydrochloride hydrochloride (81 mg, 20%). 1H NMR (400 MHz, D2O, Mixture of diastereoisomers) δ 7.40-7.23 (m, 4H), 4.29-3.46 (m, 4H), 2.95-2.81 (m, 1H), 2.41-1.76 (m, 4H), 1.58-1.40 (br. m, 2H), 1.36-1.20 (br, m, 1H), 0.90-0.80 (br. m, 2H); MS ESI found for C17H25BClN3O4S m/z (M-water+H)+396.2; MS (ESI−) m/z (M−H)− 412.3, (M-water-H)− 394.3