Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:47])[O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:47])[O:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: CCOc1ccc(OC(=O)Cl)cc1
Product: CCOc1ccc(OC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
4-Ethoxyphenyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (41 mg, 0.14 mmol) and 4-ethoxyphenyl carbonochloridate (22.6 mg, 0.14 mmol) according to General Procedure H to give 50 mg (78.3%) of white solid. Anal. Calcd. for C27H35N5O2 m/z 461.3, found: 462.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.41 (d, J=9 Hz, 2H), 7.28 (q, J=3.0 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 6.8 (d, J=9 Hz, 2H), 5.97 (d, J=7.8 Hz, 1H), 3.95 (q, J=7.0 Hz, 2H), 3.88 (d, J=11.4 Hz, 1H), 3.77 (d, J=13 Hz, 1H), 3.25 (m, 1H), 2.78 (m, 1H), 2.58 (m, 1H), 2.39 (m, 2H), 1.88 (m, 3H), 1.68 (m, 1H), 1.61 (m, 3H), 1.47 (m, 1H), 1.30 (t, J=7.0 Hz, 3H), 1.2 (m, 4H), 1.11 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.O.[Br:12]Br>CC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1ccc(B(O)O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: CC(Cl)(Cl)Cl
Product: OB(O)c1ccc(CBr)cc1
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A mixture of 4-methylphenylboronic acid (27.2 g; 0.2 mole) in methyl chloroform (250 ml) was heated at reflux with azeotropic removal of water until approximately 2.5 ml of water was collected and a crystalline slurry was formed. A solution of azo(bisisobutyronitrile) (1.0 g) and bromine (32 g) in methyl chloroform (25 ml) was added to the refluxing slurry over 2-3 hours. The mixture was then refluxed until the bromine colour was discharged. The reaction mixture was allowed to cool and stirred at 10°-15° C. for 30 minutes. The suspended solid was collected by filtration, washed with methyl chloroform (2×50 ml) and dried at ambient temperature to give the anhydride of 4-bromomethylphenylboronic acid (29 g) (Compound A) as a white, crystalline solid.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CC(C)c2ccccc2)[nH]n1
Yield: 6.9 %

Procedure:
Hydrazine hydrate (0.134 mL, 2.76 mmol) was added to a stirring room temperature solution of 56 0.7230 g, 2.76 mmol) in EtOH (2.8 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (50 min): The reaction was concentrated and purified by preparative reverse phase HPLC with the following conditions: 0 to 24 min, 55:45 H2O:CH3CN; 24-25 min, 55:45 to 0:100H2O:CH3CN; 20 mL/min.; λ=214 nM; 100 mg/mL, 0.2 mL/injection. 0.0489 g of 57 was obtained. 1H (CDCl3, 300 MHz): δ 10.77 (1H, broad s), 7.36-7.14 (5H, m), 6.49 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.16-2.86 (3H, m), 1.33 (3H, t, J=7.0 Hz), 1.27 (3H, d, J=5.9 Hz) ppm. 13C (CDCl3, 75 MHz): δ 162.01, 145.94, 145.75, 141.50, 128.43, 126.76, 126.32, 106.98, 60.87, 39.94, 34.64, 21.34, 14.12 ppm. DEPT (CDCl3, 75 MHz): CH3 carbons: 21.34, 14.12; CH2 carbons: 60.87, 34.64; CH carbons: 128.43, 126.77, 126.32, 106.98, 39.94 ppm. HPLC: 10.052 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[Li]C(C)(C)C.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C1COCC1>[CH3:14][O:13][C:5]1[CH:4]=[CH:3][C:2]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:7][C:6]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(Br)cc1N1CCCC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a −78° C. solution of 1-(5-bromo-2-methoxy-phenyl)-pyrrolidine (270 mg, 1.1 mmol) in THF (17 mL) was added dropwise a solution of t-BuLi (1.3 mL, 1.7 M solution in pentane, 2.2 mmol). The resultant yellow solution was stirred for 30 min, treated with additional t-BuLi (1.3 mL, 1.7 M solution in pentane, 2.2 mmol), stirred for 45 min, and treated dropwise with 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.8 mL, 4.4 mmol). The reaction was allowed to slowly warm to room temperature, stirred at room temperature overnight, and partitioned between saturated NH4Cl and EtOAc. The combined organic phases were dried with Na2SO4 and concentrated to give a tan oil. The crude product was purified by flash chromatography using 25 g of silica gel and 0-50% EtOAc in hexanes as eluant to afford 120 mg (35%) of 1-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine as a white solid. M+H 304.
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:24]=1C(OC)=O.Cl>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([C:30]2[CH:29]=[CH:24][C:23]([Cl:22])=[CH:32][C:31]=2[Cl:33])=[O:21])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
436 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −60° C. under a nitrogen atmosphere, 400 ml of THF are added, a solution of 75 g of 4-bromophenylacetic acid in 100 ml of THF is then added dropwise and the mixture is left stirring at −70° C. for 1 hour 30 minutes. 67.9 g of methyl 2,4-dichlorobenzoate are subsequently added dropwise, the mixture is left stirring for 30 minutes and then the temperature is allowed to rise to 5° C. The reaction mixture is poured onto an ice/1 liter of 2N HCl mixture and extracted with ether, the organic phase is washed with a saturated NaHCO3 solution and with water and dried over Na2SO4, the solvent is evaporated under vacuum to a volume of 200 ml, pentane is added and the crystalline product formed is filtered off. 80 g of the expected compound are obtained.
Reaction SMILES: [CH2:1]([C@@H:4]([C@H:12]([CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:13]([O:15][CH3:16])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:2]=C.[O:36]=[O+][O-].CSC>ClCCl>[CH2:29]([N:18]([CH2:17][C@@H:12]([C@H:4]([CH2:1][CH:2]=[O:36])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:13]([O:15][CH3:16])=[O:14])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=[O+][O-]
Reactant: C=CC[C@H](C(=O)OC(C)(C)C)[C@H](CN(Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)OC
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)[C@@H](CN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@H](CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of 4-methyl 1-tert-butyl(2S,3R)-2-allyl-3-({benzyl[(benzyloxy)cabonyl]amino}methyl)butanedioate (2.336 g, 4.851 mmol) in dichloromethane (97 mL) at −78° C. was bubbled ozone. After the solution turned blue, ozone bubbling continued for additional 15 min. Nitrogen was then bubbled into the mixture until the blue color disappeared. The reaction was quenched with dimethyl sulfide (1.78 mL, 24.26 mmol) and the solution was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was purified by Combiflash (15-25% EtOAc/hexane) to provide 1.853 g (79%) of 1-methyl 4-tert-butyl(2R,3S)-2-({benzyl[(benzyloxy)cabonyl]amino}methyl)-3-(2-oxoethyl)butanedioate as a colorless viscous oil (1.853 g, 79% in yield). MS (ESI): 506.1 (M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[CH2:21][C:22]([O-])=[O:23].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:27]([O:26][C:20](=[O:25])[CH2:21][C:22]([NH:18][C@@H:12]([CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:19])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (1.45 g, 3.8 mmol, prepared as described in WO PCT 0250019) was dissolved in 38 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with mono-benzyl malonate (745 mg, 3.8 mmol), N,N-diisopropylethylamine (6.7 mL, 38 mmol) and HATU (1.75 g, 4.6 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid benzyl ester (1.5 g, 91% yield). MS found: (M+H)+=439.4. The entirity of this material was dissolved in THF (18 mL). This solution was charged sequentially with MeOH (6 mL) and aq. LiOH (84 mg LiOH in 6 mL water) and stirred for 12 h at RT. The mixture was concentrated in vacuo, and the residue was lyopholized from 1:1 acetonitrile/water to provide the lithium salt of N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid. MS found: (M+H)+=355.3.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([OH:57])=[O:56].[O:58]1[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1>C(Cl)Cl>[O:58]1[CH2:63][CH2:62][CH:61]([O:57][C:55](=[O:56])[NH:3][CH:4]2[C:22](=[O:23])[N:21]3[CH:17]([CH2:18][CH:19]([O:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)[CH2:20]3)[C:16](=[O:35])[NH:15][C:14]3([C:36]([NH:38][S:39]([CH:42]4[CH2:43][CH2:44]4)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]3)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:60][CH2:59]1
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: C1CCOCC1
Reactant: O=C(O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O)OC1CCOCC1
Yield: 52 %

Procedure:
Prepared from cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl]-amide bis hydrochloride (50 mg, 0.075 mmol, 44 μL (0.25 mmol) of DIPEA and 0.17 mL (0.1 mmol) of tetrahydropyran chloroformate (prepared by treating tetrahydro-pyran-4-ol with phosgene) in DCM as described in the procedure above to give 28 mg (52%) of a white solid. Preparative HPLC condition: YMC XTERRA, S5, 19×100 mm, gradient: 50% B to 100% B, 10 min, hold 2 min, flow rate 25 mL/min. LC-MS (Method A, retention time: 3.13 min), MS m/z 724 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[N:17]#[C:18]Br.[OH-].[Na+]>C(O)C.O>[C:18]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)#[N:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#CN1CCc2ccc([N+](=O)[O-])cc21
Temperature: 4 °C
Reaction time: 21 h
Yield: 83.9 %

Procedure:
To a cooled (4° C.) and stirred solution of 6-nitroindoline (3.04 g) in a mixture of glacial acetic acid (22 ml), water (11 ml) and absolute ethanol (23 ml) was added solid cyanogen bromide (2.93 g) followed by 1N aqueous sodium hydroxide solution (25 ml) over 3 minutes. The mixture was then allowed to warm to room temperature, stirred for a further 21 hours and the solid formed was collected by filtration, washed with water and dried over phosphorous pentoxide to give the title compound (2.94 g) as a solid; δH (250 MHz, DMSO-d6) 7.90 (1H, dd, J=8.1 and 2.2 Hz), 7.55-7.50 (2H, m), 4.23 (2H, t, J=8.4 Hz), 3.30 (2H, t, J=8.4 Hz); m/z (CI) 189 (M-).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.[CH3:32][NH:33][CH:34]1[CH2:36][CH2:35]1.Cl>CN(C=O)C>[F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:33]([CH:34]2[CH2:36][CH2:35]2)[CH3:32])[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl
Reactant: CNC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N(C)C1CC1
Yield: 14.6 %

Procedure:
To a mixture of 6.0 g (0.017 mol) of product from Example 105, 1.71 g (0.017 mol) of triethylamine in 30 ml of DMF was added 1.76 g (0.025 mol) of N-methylcyclopropylamine at such a rate that the temperature remained below 30° C. After 4 hours the reaction mixture was poured into 3.7% HCl and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 5.8 g of a green oil. The crude product was purified by HPLC in 5% ethyl acetate/cyclohexane, followed by kugelrohr distillation at 67 Pa, oven temperature 150° C., affording 1.02 g (15.5%) of product as a green oil, nD25 1.4758.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:68]([C:65]1[CH:64]=[CH:63][C:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[O:55][CH3:54])=[CH:67][CH:66]=1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 44.1 %

Procedure:
DIPEA (140 mg, 0.19 mL, 1.08 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (119 mg, 0.38 mmol) in DMF (5 mL). HOBT (45 mg, 0.33 mmol) and EDCI (118 mg, 0.61 mmol) were then added at room temperature. After 2 minutes, 2′-Methoxy-biphenyl-4-carboxylic acid (70 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by preparative HPLC to afford 71 mg (44.1% yield) 2′-Methoxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 98.92%. 1H NMR (CDCl3): δ 7.94-7.84 (t, 1H), 7.8-7.72 (d, 1H), 7.7-7.56 (m, 4H), 7.5-7.44 (t, 1H), 7.4-7.3 (m, 3H), 7.1-7.0 (dd, 2H), 4.4-4.2 (m, 2H), 4.1-3.86 (m, 2H), 3.84-3.8 (s, 3H), 3.76-3.5 (m, 4H), 3.44-3.38 (t, 1H), 3.3-3.2 (bs, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].[CH3:12][C:13]([NH:15][C:16]([CH3:18])=O)=O>N1C=CC=CC=1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[N:10]1[C:16]([CH3:18])=[N:15][C:13]([CH3:12])=[N:11]1
Reactant: CC(=O)NC(C)=O
Reactant: NNc1cc(F)ccc1Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nc(C)n(-c2cc(F)ccc2Br)n1
Yield: 89.6 %

Procedure:
A mixture of 1-(2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (24.15 g, 100 mmol) and diacetamide (10.1 g, 100 mmol; Aldrich) in anhydrous pyridine (100 mL) was stirred in an oil bath heated at 125–130° C. under nitrogen for 2 h. After cooling the mixture was concentrated in vacuo to dryness, and the residue diluted with EtOAc (100 mL) was washed with water (50 mL), and then with brine (30 mL), dried (Na2SO4), filtered and concentrated to obtain 24.2 g of the title compound as a brownish oil: HPLC rt=1.59 min. LC/MS m/z 270/272 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 2.30 (3H, s, 9-Me), 2.39 (3H, s, 10-Me), 7.10–7.15 (2H, m, 3,5-CH), 7.67 (1H, dd, J=8.5, 5.5 Hz, 6-H); 13C NMR (CDCl3, 125.8 Hz) δ ppm 12.4 (9-CH3), 13.8 (10-Me), 116.5 (d, J=4 Hz, 1-C), 117.2, (d, J=24 Hz, 3-CH), 118.9 (d, J=22 Hz, 5-CH), 134.7 (d, J=8.5 Hz, 6-CH), 137.8 (d, J=10 Hz, 2-C), 153.9 (7-C), 160.9 (8-C), 161.8 (d, J=251 Hz, 4-CF); HRMS (ESI) calcd for C10H10BrFN3 (M+H) 270.0042. found 270.0048 (δ +2.2 ppm). This triazole was also prepared in 62% yield from 1-(2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride and 2,4,6-trimethyl-s-triazine by refluxing them in EtOH.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5]1)[C:2]#[CH:3].CO.[C-:13]#[N:14].[Na+]>[C-]#N.[Na+].O.C(O)(=O)C>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][N:4]([CH2:1][C:2]#[CH:3])[CH:5]=1)[C:13]#[N:14]
Reactant: C#CCn1ccc(CO)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C#CCn1ccc(C(O)C#N)c1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
0.44 ml of acetic acid was added to a solution of 510 mg of the product of Step B of Example 1, 7 ml of methanol and 2 ml of water another 0.44 ml of acetic acid was added. The mixture was cooled to 20° C. and 2.82 mg of sodium cyanide were added, after which the mixture was stirred for 90 minutes at 20° C., then cooled to ±10° C. Another 1.4 g of sodium cyanide and 2.2 ml of acetic acid were added and after stirring for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and dried, then concentrated to dryness to obtain 590 mg of α-hydroxy-1-(2-propynyl)-1H-pyrrole-3-acetonitrile.
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.N1CCCCC1.CCOCC>C(O)C>[Br-:1].[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N+:14]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:25][CH:24]=1
Reactant: CCCCCCCCCCCC[n+]1ccccc1C
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCCCCCCC[n+]1ccccc1C=Cc1ccc(N(C)C)cc1
Yield: 50.7 %

Procedure:
1-Dodecyl-2-methylpyridinium bromide (3.42 g, 0.01 mole) and 4-dimethylaminobenzaldehyde (1.6 g, 0.011 mole) were refluxed in ethanol (15 ml) in the presence of piperidine (0.2 ml) under nitrogen for two hours. The solution was cooled and ether was added when an orange solid crystallised which was collected giving 2-[4-(dimethylamino)styryl]-1-dodecylpyridinium bromide quarter hydrate (2.4 g), melting point 197°-198° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12.C([Sn](CCCC)(CCCC)[C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1-c1ccco1
Temperature: 110 °C
Reaction time: 23 h
Yield: 64.2 %

Procedure:
A mixture of 7-bromo-5H-dibenzo[c,g]chromene-3,9-diol (450 mg, 1.32 mmol), 2-(tributylstannyl)furan (0.622 ml, 1.97 mmols) and tetrakis(triphenylphosphine)palladium(0) (153 mg, 0.132 mmoles) in toluene (26 ml) is heated at 110° C. with stirring for 23 h. The mixture was filtered through celite, concentrated and purified by reverse-phase preparative HPLC to yield 280 mg (64%) of the title compound as a light brown solid. It is further purified by triturating with CH2Cl2 to yield a gray solid: mp 158-163° C.; 1H NMR (DMSO-d6): δ 5.04 (2H, s), 6.61 (1H, d, J=3.11 Hz), 6.67-6.69 (2H, m), 6.85 (1H, dd, J=8.47 Hz, J=2.33 Hz), 6.95 (1H, dd, J=8.72 Hz, J=2.27 Hz), 6.99 (1H, d, J=1.98 Hz), 7.77 (1H, d, J=8.77 Hz), 7.82 (1H, d, J=8.53 Hz), 7.85 (1H, d, J=1.32 Hz), 8.24 (1H, s), 9.70 (1H, s), 9.75 (1H, s); MS (ESI) m/z 329 (M−H)−, 331 (M+H)+.