Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[C:5]([O-:8])(=O)C.[C:9]([O-])(=O)[CH3:10].[C:13]([O-])(=O)[CH3:14].[Pb+4].[C:18](=O)([O-])[O-].[K+].[K+].[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCC>[CH2:18]([O:4][CH:1]([CH2:2][CH2:13][CH2:14][CH2:9][CH3:10])[CH:5]=[O:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)[O-]
Reactant: c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Pb+4]
Solvent: CCCCCC
Product: CCCCCC(C=O)OCc1ccccc1
Reaction time: 0.05 h

Procedure:
After 260 mg of lead tetraacetate was added at 4° C. to a mixture of 200 mg of the diol [27] described above, 60 mg of potassium carbonate and 4.5 ml of anhydrous benzene, the mixture was stirred for 3 minutes. After completion of the reaction, 100 ml of hexane was added to the reaction solution. The reaction solution was filtered through Celite 545 and the filtrate was washed with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with hexane twice. The extracts were combined and washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl ether:hexane=1:2 (volume)) to give 160 mg (yield, 80%) of (S) 2-benzyloxyheptanal [2].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH2:11][C:12]([NH2:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([NH2:14])=[O:13])#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccc(OCC(N)=O)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A mixture of 3-hydroxybenzonitrile (2.38 g, 20.0 mmol), 2-bromoacetamide (3.04 g, 22.0 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (30 mL) was stirred at 75° C. overnight. It was then cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (1.00 g, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([Cl:20])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[Cl:20][C:13]1[CH:12]=[C:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:19]=[CH:18][C:14]=1[C:15](=[O:17])[NH:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)O)c(Cl)c1
Reactant: NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)NC2CCCC2)c(Cl)c1
Yield: 97.5 %

Procedure:
To a round bottom flask with stir bar was added (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (450 mg, 1.20 mmol), cyclopentylamine (355 μL, 3.60 mmol), EDC HCl (460 mg, 2.40 mmol), 1-hydroxy-7-aza-benzotriazole (229 mg, 1.68 mmol) and DMF (6 mL). To this mixture was then added DIEA (629 μL, 3.60 mmol). Reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phases were combined, washed with twice with water, brine, dried (Na2SO4), filtered and concentrated to a brown crystalline of (S)-tert-butyl 1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethylcarbamate (476 mg, 1.17 mmol, 97% yield). LCMS m/z 367.0 (M+H)+, Rt 0.90 min.
Reaction SMILES: CS(O[C@H:6]1[C:30]2[C@:25]([CH3:32])([CH2:26][CH2:27][C:28](=[O:31])[CH:29]=2)[C@@H:24]2[C@H:8]([C@H:9]3[C@:21]([CH3:33])([CH2:22][CH2:23]2)[C@@H:12]([C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+].C(O)(=O)C>CO>[N:39]([C:6]1[C:30]2[C@:25]([CH3:32])([CH2:26][CH2:27][C:28](=[O:31])[CH:29]=2)[C@@H:24]2[C@H:8]([C@H:9]3[C@:21]([CH3:33])([CH2:22][CH2:23]2)[C@@H:12]([C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:40]=[N-:41]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
In a manner similar to that described in Example 6C, treat 6β,7β-dimethanesulfonyloxy-4-cholestene-3-one with sodium azide in aqueous methanol in the presence of acetic acid. Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-4,6-cholestadiene-3-one.
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=O.[CH3:23][NH2:24]>CO>[CH3:23][NH:24][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=[O:2]
Reactant: COC(=O)C1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a stirred solution of 3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 67, Step 4, 150 mg, 0.49 mmol) in MeOH (2 mL) is added MeNH2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is then stirred for 30 minutes at room temperature. Solvent is removed and the residue is washed with ether to give the title compound as a white solid (120 mg, 80%), 1H NMR (300 MHz, DMSO) a 8.37 (d, 1H), 7.44–7.07 (m, 3H), 5.04 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H), 3.23 (s, 3H), 2.86 (t, 2H), 2.65 (d, 3H), 2.50 (m, 2H); MS for C15H17N3O4 m/z 304.5 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(C)C.FC1C=CC=CC=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][CH:9]([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:3][CH:4]=1)=[O:12]
Reactant: C1CCNCC1
Reactant: CC(C)C(=O)c1ccc(F)cc1
Agent: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Fc1ccccc1
Product: CC(C)C(=O)c1ccc(N2CCCCC2)cc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
49.86 (0.30 mol) of 1-(4-fluorophenyl)-2-methylpropan-1-one, prepared by a Friedel-Crafts reaction from isobutyryl chloride with fluorobenzene analogously to European Patent Application No. 3,002, and 25.5 g (0.30 mol) of piperidine are dissolved in 120 ml of dimethyl sulfoxide, and the solution is heated to 110° C. together with 41.5 g (0.30 mol) of potassium carbonate. After 16 hours of stirring at 110° C. the suspension is cooled down and is poured onto an ice-water mixture. The crystals are filtered off, are washed with water and are recrystallised from hexane.
Reaction SMILES: [C:1]1([C:14]2[CH:15]=[C:16](Br)[CH:17]=[C:18]([C:20]3[C:32]4[NH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:39](OC)([O:42]C)[O:40]C.Cl>O1CCCC1>[C:1]1([C:14]2[CH:15]=[C:16]([B:39]([OH:42])[OH:40])[CH:17]=[C:18]([C:20]3[C:32]4[NH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COB(OC)OC
Reactant: Brc1cc(-c2cccc3c2[nH]c2ccccc23)cc(-c2cccc3c2[nH]c2ccccc23)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2cccc3c2[nH]c2ccccc23)cc(-c2cccc3c2[nH]c2ccccc23)c1
Reaction time: 0.5 h

Procedure:
Under an Ar atmosphere, 3,5-dicarbazolylbromobenzene (4.87 g, 0.01 mol) and 100 mL THF (tetrahydrofuran) were added into a 250 mL single-necked flask, then 9.4 mL n-BuLi (n-butyllithium) (1.6 M n-hexane solution) was added, stirred and reacted at −78° C. for 1.5 h. After this, trimethyl borate was added and reacted for 12 h, and then 20 mL hydrochloric acid solution was added, acidified for 0.5 h. After the reaction was completed, we carried out liquid separation, drying, and concentrating under reduced pressure, and obtained 3,5-dicarbazolylphenylboronic acid by column chromatography. The reaction process is as follows:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][CH:34]=[C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:26]=3)[CH2:31]2)=[CH:9][N:8]=1
Reactant: c1ccc(-c2ccc3c(c2)CCNC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3cc(-c4ccccc4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.5 %

Procedure:
A suspension of 0.20 g (0.00080 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 10 ml of dimethylformamide was treated with 0.34 ml (0.0024 mol) of triethylamine and 0.19 g (0.00097 mol) of 6-phenyl-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 60 hours The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/methanol 5:1 as the eluent and digested in diethyl ether. 0.16 g (61%) of 2-methyl-5-(6-phenyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 186°-188°. A further 0.03 g of pale yellow crystals was recovered from the mother liquor.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH2:9])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1.Br[CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:19][CH:33]=[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:9]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(-c2ccccn2)n1
Temperature: 85 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
2-Picolinamide (3.1 g, 25.4 mmol) was dissolved in toluene (25 mL) and treated with Lawesson's Reagent (5.1 g, 0.5 equivalents). The reaction was heated to 85° C. and stirred for 48 hrs. The reaction was quenched with water and extracted and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed by evaporation. This material was dissolved in ethanol (50 mL) and treated with ethyl bromopyruvate (3 mL, about 1 equivalent) and powdered 3 A molecular sieves (10 g). The reaction was refluxed for 16 hrs. The reaction was then filtered and the solvent was removed by evaporation. The material was dissolved in ethyl acetate, washed with a saturated solution of sodium bicarbonate, washed with brine, and dried over magnesium sulfate. The reaction was filtered and the solvents were removed by evaporation. This material was purified using dichloromethane:ethyl acetate (3:1) to give 1.98 g of the title compound (33%).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:30]([N:32](CC)CC)C.N#CBr>ClCCl>[C:30]([N:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=1)#[N:32]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCN(CC)CC
Agent: N#CBr
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(C#N)Cc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (12 g; 29.34 mmol) and triethylamine (4.5 ml; 32.27 mmol) in 100 ml of dichloromethane was treated under nitrogen with cyanogen bromide (10.3 ml of a 3M solution in dichloromethane; 30.9 mmol). After 1.5 hr, additional triethylamine (2 ml) and cyanogen bromide (2.5 ml) were added and stirred another 30 minutes. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water (three times) and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography using ethyl acetate-hexane mixtures (5–40% gradient) afforded ethyl 2-[4-(2-{cyano[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (10.9 g; 85% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.O.[OH-].[Na+].Cl[CH:16]([F:18])[F:17]>O1CCOCC1.CCOCC>[F:17][CH:16]([F:18])[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)c1ccc(OC(F)F)cc1C
Temperature: 65 °C
Reaction time: 1.25 h
Yield: 80.9 %

Procedure:
To a stirred suspension of 1-(4-hydroxy-2-methyl-phenyl)-ethanone (15 g, 100 mmol) in dioxane (30 mL) is added water (25 mL) followed by the addition of NaOH (20 g, 500 mmol). Reaction is heated to 65° C. and passed gaseous chlorodifluoromethane (30 g, 150 mmol) using a glass tube dipped below the solution level for 75 minutes. Stirred for 30 min longer and left at RT over the weekend. Water (100 mL) and ether (40 mL) are added after transferring to a reparatory funnel. A semi-gelatinous material settled at the bottom of the aqueous layer after some time. The bottom aqueous layer is drained off and extracted with ether (2×40 mL). The combined ether layers are washed with water (5×25 mL), dried over solid K2SO4, evaporated and distilled (0.04 mm Hg, 61-64° C.) to afford 1-(4-difluoromethoxy-2-methyl-phenyl)-ethanone (A4) (16.2 g, 81%). Rf in tlc 0.60 with ether.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9]([N:16]=[C:17]=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:9]([NH:16][C:17]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CCCN1C(=O)NCc1ccccc1

Procedure:
L-Proline (23.3 g), benzyl isocyanate (22.9 g) and triethylamine (20.5 g) were stirred at room temperature for 1 hour in DMF (250 ml) to give a solution of N-(benzylaminocarbonyl)-L-proline. Thereto were added HOBt (29.7 g), water-soluble carbodiimide hydrochloride (42.13 g), L-proline benzyl ester hydrochloride (48.3 g) and triethylamine (27.9 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 10% potassium hydrogensulfate, a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (73.6 g).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C=O)o1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Agent: [Cl-]
Product: Cc1ccc(CNCCNc2ccc3ccccc3c2Cl)o1
Yield: 57 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and 5-methylfuran-2-carbaldehyde in 57% yield as a yellow oil.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:14][C:15](=[O:19])[CH2:16][CH2:17]Cl)[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])([O-:5])=[O:4].O>CS(C)=O.O1CCCC1>[N+:3]([C:6]1[CH:7]=[C:8]([N:14]2[CH2:17][CH2:16][C:15]2=[O:19])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])([O-:5])=[O:4]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1NC(=O)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c([N+](=O)[O-])cc1N1CCC1=O

Procedure:
5 g of sodium hydride (in the form of a 55% strength dispersion in oil) are stirred in 100 ml of dimethylsulphoxide until no further evolution of gas can be detected. 21.5 g (0.084 mol) of N-(3-nitro-4,6-dimethylphenyl)-β-chloropropionamide, suspended in 500 ml of tetrahydrofurane, are then added in the course of 5-10 minutes. The reaction temperature is kept at 15° for 1/2 an hour and water is then added dropwise in order to destroy excess sodium hydride. The reaction solution is taken up in methylene chloride and washed with water and saturated NaCl solution, dried (MgSO4) and evaporated. The crude product is subjected to fractional filtration on silica gel in chloroform. This gives 14.5 g (78%) of product; melting point 102°.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:36](=O)[CH:37]([CH3:39])[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=[O:43])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:43])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:6]1
Reactant: CC(C)C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CN1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and isobutyraldehyde (0.060 mL, 0.65 mmol), stirred for 2.5 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 16 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-isobutylpyrrolidine-3-carboxylic acid (44 mg, 26%) as a white semisolid. NMR (D2O) δ 3.90 (m, 1 H), 3.50 (m, 1 H), 2.90-3.20 (m, 4 H), 2.50 (m, 1 H), 1.90 (m, 1 H), 1.50 (m, 1 H), 0.80-1.30 (m, 9 H), 0.65 (m, 2 H). MS (m+1): 273.2; MS (m−H2O+1): 255.2; MS (m−2 H2O+1): 237.2.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:30](N(CC)C(C)C)(C)[CH3:31].BrCC>C1COCC1.ClCCl>[CH2:30]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:31]
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
100 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine were dissolved in THF, 2 equiv. of N,N-diisopropylethylamine were added followed by 2 equiv. of bromoethane. The reaction was stirred at 80° C. overnight. The reaction was diluted with dichloromethane and washed with 1N aqueous NaOH solution. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford 1-ethyl-2-phenyl-4-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine as the free base. Addition of 1 equiv. of 1M HCl in dioxane and drying in vacuo afforded the title compound as hydrochloride salt. Yield 35% ES MS m/z 425
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)nc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Cl)nc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 6-chloropyridine-3-amine (1.00 g, 7.78 mmol) and pyridine (0.761 ml, 9.33 mmol) in tetrahydrofuran (25 ml) was added 2,2,2-trichloroethyl chloroformate (1.29 ml, 9.33 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was poured to the residue and a solid was collected by filtration to obtain the desired product (2.17 g, 92.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:12]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10][CH3:11]>>[CH2:8]([C:12](=[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(C(=O)OCC)C(=O)C(=O)OCC
Reactant: Nc1ccccc1
Product: CCCCC(C(=O)OCC)=C(Nc1ccccc1)C(=O)OCC
Temperature: 75 °C
Reaction time: 72 h
Yield: 45.2 %

Procedure:
A mixture of 1 g of aniline and 2.65 g of the product of Step A and 150 mg of siliporite® NK10 was stirred for 3 days at 75° C. and the reaction mixture was cooled and chromatographed on silica eluant: hexane - ethyl acetate (9-1) to obtain 1.55 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:24][NH2:25]>O1CCOCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH3:24])=[O:5]
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a mixture of 2-amino-4-bromobenzoic acid (5.0 g, 23.1 mmol) and dioxane (50 mL) was added triphosgene (2.3 g, 7.75 mmol). The reaction mixture was heated to reflux and stirred for 4 h. Methylamine (40% in water, 2 mL, 23.1 mmol) was added dropwise after the mixture was cooled to room temperature. After stirring for 30 min, the solution was evaporated under reduced pressure and the residue was redissolved in DCM which was washed with sat. NaHCO3 aqueous solution, dried over Na2SO4, filtered, and evaporated to give 4.6 g of the target compound. MS (ESI): 229, 231 (MH+).