Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([N:20]2[CH2:23][C:22]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21]2)[CH2:15][CH2:14]3)=[N:9][CH:10]=1)[CH3:4].[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38](O)=[O:39])=[N:35][CH:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[CH2:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([N:20]2[CH2:23][C:22]4([CH2:28][CH2:27][N:26]([C:38](=[O:39])[CH2:37][C:34]5[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=5)[CH2:25][CH2:24]4)[CH2:21]2)[CH2:15][CH2:14]3)=[N:9][CH:10]=1)[CH3:4]
Reactant: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)nc1
Reactant: COc1ccc(CC(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)Cc4ccc(OC)cn4)CC3)C2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To a solution of 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1c, 630 mg, 1.38 mmol) in dimethylformamide (5 mL) was added (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 230 mg, 1.38 mmol), HBTU (523 mg, 1.38 mmol) and triethylamine (1.20 mL, 8.5 mmol). The solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residual DMF was azeotroped with toluene. The residue was partitioned between 50 mL of ethyl acetate and 50 mL 1N NaOH solution. The organic layer was collected, washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column (1-10% MeOH in CH2Cl2 in 20 minutes) to afford the desired product (554 mg, 79.4%) as an off-white foam. The solid was stirred in 50 mL of refluxing diisopropyl ether for 6 hours and filtered to afford a light-grey powder (490 mg, 71%). MS (ES+) 498.5 (M+H)+. 1H NMR (CDCl3) δ 1.28 (t, 3H), 1.53-1.77 (m, 4H), 1.77-2.01 (m, 1H), 2.03-2.22 (m, 1H), 2.65 (q, 2H), 2.76-2.94 (m, 1H), 2.95-3.18 (m, 5H), 3.30-3.54 (m, 4H), 3.69-3.86 (m, 5H), 3.88-4.04 (m, 1H), 7.14 (dd, 1H), 7.19-7.26 (m, 1H), 7.33 (d, 1H), 8.13-8.29 (m, 3H), 8.60 (s, 2H). [α]D20=+40.0 deg (c=10 mg/mL, MeOH).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[CH:24].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[C:25]1([C:23]#[C:24][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc(-c2cnc3[nH]cc(I)c3n2)cc(OC)c1OC
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3[nH]cc(C#Cc4ccccc4)c3n2)cc(OC)c1OC
Temperature: 70 °C
Yield: 90.8 %

Procedure:
7-Iodo-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (500 mg, 1.22 mmol), PdCl2(PPh3)2 (43 mg, 0.061 mmol), and cuprous iodide (6 mg, 0.031 mmol) were added to a 20 ml microwave vial. The vial was capped and purged with nitrogen. Ethynyl benzene (0.4 ml, 3.6 mmol), triethylamine (5 ml) and N,N-dimethylformamide (5 ml) were added through the septum and the vial was purged again with nitrogen. The mixture was heated in a microwave reactor at 70° C. for 30 minutes. The crude mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water/brine. The organic layer was filtered through celite and concentrated. The residue was triturated with a mixture of ethyl acetate and hexanes and filtered, washed with hexanes, and dried to give 427 mg of 7-phenylethynyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine. MS: (M+H)+=386.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19].[C:23](O)(=[O:34])[CH2:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>C(OCC)(=O)C>[CH3:22][CH:17]([NH:16][C:23](=[O:34])[CH2:24][NH:25][C:26](=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: CC(N)C(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(NC(=O)CNC(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
2.2 g of dicyclohexylcarbodiimide were added to 30 ml of an ethyl acetate solution containing 1.0 g of 3-amino-2,2-dimethylbutane and 1.7 g of hippuric acid in an ice bath. The reaction solution was stirred for 2 hours at room temperature and then allowed to stand overnight. The solid material which separated was filtered off, after which the filtrate was washed with a 10% w/v aqueous solution of sodium hydroxide, then with 1N aqueous hydrochloric acid, and finally with a saturated aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate. The reaction solution was concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 1.65 g (yield 64%) of the title product melting at 124°-126° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCN(CCCl)Cc1ccccc1

Procedure:
Bis-(2-chloro-ethyl)-amine hydrochloride was suspended in 150 mL acetonitrile. Added were 34.8 g K2CO3 (3 equiv.) and 10.0 mL benzylbromide (1 equiv.). The mixture was refluxed overnight. Concentration on silica and purification with flash column chromatography (eluents PA:ether=95:5) yielded 4.11 g of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 2.93 (t, J=7 Hz, 4H), 3.50 (t, J=7 Hz, 4H), 3.74 (s, 2H), 7.22-7.37 (m, 5H).
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C([O:8][CH:9]([CH2:14][N:15]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:10]([F:13])([F:12])[F:11])=O.N>CO>[F:34][C:30]1[CH:29]=[C:28]([N:15]([CH2:14][CH:9]([OH:8])[C:10]([F:11])([F:12])[F:13])[C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(OC(CN(C(=O)c1cccc(C(F)(F)F)c1)c1cccc(F)c1)C(F)(F)F)c1cccc(C(F)(F)F)c1
Agent: N
Solvent: CO
Product: O=C(c1cccc(C(F)(F)F)c1)N(CC(O)C(F)(F)F)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.9 %

Procedure:
A solution of 2,2,2-trifluoro-1-[[(3-fluorophenyl)[3-(trifluoromethyl)benzoyl]amino]-methyl]ethyl 3-trifluoromethyl-benzoate (600 mg, 1.06 mmol) from EX-662 in methanol was treated with 28% ammonia solution (122 μL). The solution was stirred at room temperature for 10 h. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 255 mg (61%) of the desired N-(3-fluorophenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-3-(trifluoromethyl)benzamide product as a white powder, 97% pure by HPLC analysis. 1H NMR (CDCl3) δ 7.56 (m, 3H), 7.32 (m 2H), 6.98 (m, 1H), 6.90 (m, 2H), 4.49 (dd, 1H), 4.34 (d, 1H), 4.26 (m, 1H), 4.01 (dd, 1H). 19F NMR (CDCl3) δ −64.7 (s, 3F), −80.3 (s, 3F), −111.0 (m, 1F). HRMS calcd. for C17H12F7NO2: 396.0854 [M+H]+, found: 396.0821.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:41]=[C:42]([CH:50]=[CH:51][C:52]=3[CH3:53])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=2)[O:33][C:32]=1[C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1>CO.CS(C)=O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:46]([O:45][C:43]([C:42]1[CH:50]=[CH:51][C:52]([CH3:53])=[C:40]([C:37]2[CH:38]=[C:39]3[C:31]([C:43]([O:45][CH3:46])=[O:44])=[C:32]([C:54]4[CH:55]=[CH:56][C:57]([F:60])=[CH:58][CH:59]=4)[O:33][C:34]3=[N:35][CH:36]=2)[CH:41]=1)=[O:44])([CH3:48])([CH3:49])[CH3:47]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1-c1cnc2oc(-c3ccc(F)cc3)c(Br)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)OC(C)(C)C)ccc3C)cc12
Reaction time: 8 h
Yield: 190.8 %

Procedure:
1,3-bis(diphenylphosphino)propane (119 mg, 0.287 mmol) was added to a stirring solution of palladium(II) acetate (32 mg, 0.144 mmol) and tert-butyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (231 mg, 0.479 mmol) in MeOH (1.6 mL) and DMSO (3 mL) at 80° C. in a PARR bomb which was then charged with 300 psi CO (g) and allowed to stir overnight. The mixture was diluted with EtOAc and filtered through a pad of celite. The filtrate was washed with sat. aq. NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product methyl 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate (211 mg, 0.457 mmol, 95% yield) crude by LCMS which was used directly in the next step. LC-MS retention time: 2.32 min; m/z (MH+): 462. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: N1C2N[C:8]3[CH:16]=[CH:15]C=CC=3[C:10](=[O:12])NC=2C=CC=1.Cl.CN1C[CH2:26][C:22]([C:23](Cl)=O)=CC1.C(=O)([O-])[O-:29].[K+].[K+]>C1(C)C=CC=CC=1>[CH:22]([O:29][CH:16]([CH3:15])[CH3:8])([CH3:23])[CH3:26].[CH3:10][OH:12]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: CN1CC=C(C(=O)Cl)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)OC(C)C
Product: CO
Temperature: 0 °C

Procedure:
A mixture of 10.6 gm (0.05 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 10.8 gm (0.055 mol) of 1-methyl-1,2,5,6-tetrahydroisonicotinic acid chloride hydrochloride, 20.7 gm (0.15 mol) of potassium carbonate, and 200 ml of anhydrous toluene was refluxed for 48 hours under thorough stirring. After the mixture cooled, it was stirred into 500 ml of ice water, the organic layer was separated off, and the aqueous layer was exhaustively extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and then concentrated by evaporation in vacuo. The residue was purified by column chromatography, first on silica gel with a particle size of from 0.1 to 0.4 mm, 1,2-dichloroethane/methanol (volume ratio of 9:1) being used as eluant, and secondly on silica gel with a particle size of from 0.032 to 0.063 mm, methylene chloride/methanol (volume ratio of 10:1) being used as eluant. The appropriate fractions were worked up in the usual way to produce colorless crystals, m.p.: 226°-227° C. (diisopropylether/methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>O1CCOCC1.C(N(CC)CC)C>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:22][CH2:21][C:17]1[N:16]=[C:15]2[CH2:14][O:13][C:12](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:20]2=[CH:19][CH:18]=1)[CH3:24]
Reactant: CCNCC
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCN(CC)CCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 100 °C
Yield: 17.7 %

Procedure:
A solution of 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (60 mg, 0.20 mmol) and diethylamine (250 mg, 3.42 mmol) are reacted in a sealed tube at 100° C. for 2 h. The reaction vessel is cooled and additional diethylamine (250 mg, 3.42 mmol) in dioxane (10 mL) is added. The reaction vessel is sealed and heated at 100° C. overnight. The reaction mixture is cooled and treated with triethylamine (15 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, MeOH-Chloroform). The product containing fractions are concentrated to provide the title compound (13 mg, 18%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH2:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([C:7]([F:10])([F:8])[F:9])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:30])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Yield: 63.6 %

Procedure:
3-(4-Chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.03 g, 0.11 mmol) was treated with 4-fluorophenyl isocyanate (0.02 g, 14.6 μL, 0.13 mmol, 1.2 equiv.) in CH2Cl2 (4.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 40 (0.03 g, 0.07 mmol, 63% yield) as a white solid: LCMS m/z (%)=443 (M+H37Cl, 100), 445 (M+H35Cl, 36). 1H NMR (400 MHz, MeOH-d4) δ: 7.58 (dd, J=10.0, 2.0 Hz, 1H), 7.42 (dd, J=4.0 Hz, 2H), 7.40 (dd, J=8.0, 4.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.03 (dd, J=10.0, 6.0 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li+].[Br-].P(Br)(Br)[Br:23].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:23])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc(CO)cc1Oc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CBr)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
To a solution in DMF (10 mL) of 4-hydroxymethyl-2-phenoxybenzoic acid methyl ester (2.82 g), prepared as in Example 157C, was added LiBr (1.04 g) and PBr3 (3.65 g) and the reaction mixture was stirred for 20 minutes at ambient temperature. The reaction mixture was poured into water and extracted with toluene. The organic phase was washed twice with water, dried over Na2SO4, filtered, and concentrated in vacuo to give 4-bromomethyl-2-phenoxybenzoic acid methyl ester (3.37 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].Cl.[CH3:14]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([O:9][CH3:14])=[O:8])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1cccc(O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)CCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 ml of 10% hydrogen chloride-methanol was added to 1.64 g (10 mmol) of 3-hydroxycinnamic acid and the mixture was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with water and dried (MgSO4). The solvent was distilled off. The residue was dissolved in 25 ml of methanol, 0.5 g of 10% palladium-carbon was added and the mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1 (v/v)) to obtain 1.75 g (9.71 mmol) of methyl 3-(3-hydroxyphenyl)propionate as a colorless oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4](C(C2C=CC=CC=2)=O)[C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH:10]=O)[N:7]=1.[CH3:22][C:23]12[CH2:28][C:27]1([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)[CH2:26][NH:25][CH2:24]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([N])(=O)C1C=CC=CC=1>ClCCCl>[Br:1][C:2]1[C:3](=[O:21])[NH:4][C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH2:10][N:25]2[CH2:26][C:27]3([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=4)[C:23]([CH3:22])([CH2:28]3)[CH2:24]2)[N:7]=1
Reactant: O=CCCn1nc(Br)c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: CC12CNCC1(c1ccc(C(F)(F)F)cc1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N]C(=O)c1ccccc1
Agent: [Na+]
Solvent: ClCCCl
Product: CC12CN(CCCn3nc(Br)c(=O)[nH]c3=O)CC1(c1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.7 %

Procedure:
3-[6-bromo-3,5-dioxo-4-(phenylcarbonyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl]propanal (P7, 201 mg, 0.572 mmol) was dissolved in dry 1,2-Dichloroethane (DCE) (1.144 mL), then 1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (P15, Enantiomer 2, 138 mg, 0.572 mmol) was added and the mixture was stirred at room temperature for 10 minutes. The mixture was then cooled to 0° C. and left stirring at that temperature for 15 minutes. Afterwards, sodiumtriacetoxy borohydride (133 mg, 0.629 mmol) was added and the mixture was stirred at 0° C. for 2 hours. In situ cleavage of the benzoyl nitrogen protecting group was observed. It was then quenched with NH4Cl saturated solution and extracted with DCM. Organic phase was dried and concentrated under reduced pressure affording a crude as a yellow oil. The latter was purified by flash chromatography (SiO2, eluent: DCM to DCM/MeOH 95:5) affording 6-bromo-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (Enantiomer 2, 48 mg, 0.101 mmol, 17.73% yield) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].S(O[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)(C1C=CC(C)=CC=1)(=O)=O>CC(N(C)C)=O.O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:28]1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Cn2ncc3c([N+](=O)[O-])cccc32)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 4-nitro-1H-indazole (0.200 g, 1.23 mmol) in DMA (3 mL) was added 60% sodium hydride (0.074 g, 1.84 mmol) at ambient temperature. After 30 minutes, tert-butyl 3-(tosyloxymethyl)piperidine-1-carboxylate (0.544 g, 1.47 mmol) was added. The mixture was heated at 100° C. overnight, diluted with water, extracted with DCM, dried (phase separator silicone treated filter paper), concentrated and the residue purified on silica gel (10-50% EtOAc in DCM) to provide tert-butyl 3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.176 g, 40% yield) as a yellow gum.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21](I)[CH:20]=[C:19]([C:24]([F:27])([F:26])[F:25])[N:18]=1.[C@@H:28]1(N)[CH2:33][CH2:32]CC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:32]1([C:17]2[CH:22]=[C:21]([N:12]3[CH2:13][CH2:14][N:10]([C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:4]=4[CH:1]4[CH2:3][CH2:2]4)[C:11]3=[O:15])[CH:20]=[C:19]([C:24]([F:27])([F:26])[F:25])[N:18]=2)[CH2:33][CH2:28]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1N(c2cc(C3CC3)nc(C(F)(F)F)c2)CCN1c1cnccc1C1CC1
Yield: 502.9 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 260 mg, 1.2807 mmol) was reacted with 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (471 mg, 1.5369 mmol), copper iodide (24 mg, 0.1280 mmol), trans-cyclohexane-1,2-diamine (15 mg, 0.1280 mmol), potassium phosphate (816 mg, 3.8421 mmol) and 1,4-dioxane (5 mL) to afford crude product. Purification by column chromatography on silica gel (1% methanol in chloroform) afforded 250 mg of pure product (51.1% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O.[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:21]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:19][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCCOc1ccccc1-c1ccccc1

Procedure:
1-Chloro-6-(p-toluenesulphonyloxy)hexane (100 g), 2-hydroxybiphenyl (59 g) and potassium carbonate (60 g) were heated with stirring in dimethylformamide at 70° for 16 hours. The solution was cooled and added to water, then extracted with ether. The extract was washed with water, dried and evaporated, and the residue was chromatographed on silica gel (1800 g) eluting with 99:1 hexane; ethyl acetate, so as to afford the title compound as an oil.
Reaction SMILES: [BrH:1].C(O)(=O)C.C1(OC)C=CC=CC=1.C(OC([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([NH:31][C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:26][CH2:25]1)=O)C1C=CC=CC=1>C(OCC)C>[BrH:1].[N:27]1([NH:31][C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:28][CH2:29][CH2:30][NH:24][CH2:25][CH2:26]1
Reactant: O=C(NN1CCCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Agent: Br
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: O=C(NN1CCCNCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 25% hydrogen bromide-acetic acid (1.5 ml) and anisole (0.09 ml) was added N-(4-benzyloxycarbonyl-1-homopiperazinyl)-p-fluorobenzamide (529 mg) dropwise for 3 minutes under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3.5 hours and diluted with diethyl ether. The resulting precipitate was collected and washed with diethyl ether to give N-(l-homopiperazinyl)-4-fluorobenzamide hydrobromide (606 mg). This product was used for next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][C:7]1[CH:8]=[C:9]([C:16]([N+:19]([O-])=[O:20])=[CH:17][CH:18]=1)[CH2:10][C@@H:11]([C:13](O)=[O:14])[NH2:12])#[N:2].[ClH:25]>O1CCOCC1.CCOCC>[ClH:25].[NH2:12][C@H:11]1[CH2:10][C:9]2[C:16](=[CH:17][CH:18]=[C:7]([O:6][C:5]3[CH:4]=[C:3]([CH:24]=[CH:23][CH:22]=3)[C:1]#[N:2])[CH:8]=2)[N:19]([OH:20])[C:13]1=[O:14]
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C[C@H](N)C(=O)O)c2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1cccc(Oc2ccc3c(c2)C[C@H](N)C(=O)N3O)c1
Reaction time: 1.5 h
Yield: 97 %

Procedure:
3-(3-Cyanophenoxy)-6-nitro-L-phenylalanine (87) N-(tert-Butoxycarbonyl)-3-(3-cyanophenoxy)-6-nitro-L-phenylalanine (86) (1.6 g, 3.8 mmol) was dissolved in a solution of HCl in dioxane (4 N, 70 mL). After 1.5 h, the reaction mixture was diluted with Et2O (200 mL) and filtered. The solid was washed with Et2O and dried at 50° C. under vacuum to afford the title compound as a white solid (1.3 g, 97%). LCMS m/z 328.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.41 (dd, J=13.8, 7.5 Hz, 1H), 3.66 (dd, J=13.8, 7.4 Hz, 1H), 4.34 (t, J=7.4 Hz, 1H), 7.12-7.15 (m, 2H), 7.43-7.49 (m, 1H), 7.52-7.54 (m, 1H), 7.63-7.68 (m, 2H), 8.22-8.25 (m, 1H).