Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9].N>CO.[Ni]>[NH2:9][CH2:8][C:7]1[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1)[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14]
Reactant: COc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(C#N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(CN)c1

Procedure:
A solution of the above nitrile (258 mg, 0.69 mmol) in MeOH saturated with NH3 (15 mL) was hydrogenated (40 psi) over Raney-nickel for 4 hours. The mixture was filtered with suction through a pad of celite, washing with excess MeOH. The filtrate was concentrated under reduced pressure, giving the crude amine as a purple foam.
Reaction SMILES: C([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[C:16]1(/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=CC=1>C(Cl)Cl>[C:24]1([C:23]2[CH:19]=[CH:20][CH:21]=[CH:16][CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Agent: CC[Zn]CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ICI
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) CH2Cl2 (22 mL) was added diethylzinc (1M in hexanes, 60.5 mL, 60.5 mmol) under nitrogen followed by the dropwise addition of trifluoroacetic acid (5.1 mL, 66.2 mmol) in 10 mL CH2Cl2 over 15 min. The reaction was stirred for 15 min, and then diiodomethane (5.4 mL, 66.9 mmol) in 10 mL CH2Cl2 was added dropwise to the reaction. The reaction was continued to stir at 0° C. for 1 hr, and then (E)-1,2-diphenylethene (2 g, 11.10 mmol) in 10 mL CH2Cl2 was added. The mixture was removed from the cold bath and stirred at ˜25° C. under nitrogen for 20 h. The reaction was quenched with 0.1N HCl (50 mL), the layers were separated, and the aqueous layer was extracted with hexanes (2×100 mL). The combined organic phase was washed with saturated NaHCO3 (aq) (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was submitted to a silica gel flash chromatography (hexanes) to afford biphenyl M9.3a as a colorless oil (1.6 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.34-7.31 (m, 4H), 7.24-7.17 (m, 6H), 2.22-2.18 (m, 2H), 1.51-1.47 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:10]=1[C:11](Cl)=[O:12].Cl.Cl.[NH2:22][CH2:23][C:24]1[C:25]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[C:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[NH:27][CH:28]=1.O>O1CCCC1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[NH:27][CH:28]=[C:24]([CH2:23][NH:22][C:11](=[O:12])[C:10]3[C:9]([F:8])=[CH:17][C:16]([F:18])=[CH:15][C:14]=3[F:19])[C:25]=2[C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[CH:34][CH:33]=1
Reactant: NCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.5 %

Procedure:
265 μl (1.905 mmol) of triethylamine and 96 mg (0.493 mmol) of 2,4,6-trifluorobenzoyl chloride were added to a suspension of 162 mg (0.476 mmol) of 4-aminomethyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole dihydrochloride [prepared as described in Example 5 above] in 3.3 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for 4 hours. At the end of this time, water was added to the reaction mixture and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was washed with diethylether to give 78 mg (yield 38%) of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH2:16])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.O.C(=O)(O)[O-].[Na+].[F:24][C:25]([F:36])([F:35])[C:26]([F:34])([F:33])[C:27]([F:32])([F:31])[C:28](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[CH:6][C:5]2[NH:16][C:28]([C:27]([F:31])([F:32])[C:26]([F:33])([F:34])[C:25]([F:36])([F:35])[F:24])=[N:17][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 2 %

Procedure:
A solution of 4-chloro-5-(4-fluorophenoxy)benzene-1,2-diamine (400 mg, 1.58 mmol) in heptafluorobutanoic acid (3 ml) was stirred overnight at 110° C. in an oil bath. The solution was poured into water (150 ml), adjusted pH to 8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×100 ml). The combined organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a off-white solid (12.0 mg, 2%).
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[C@@H:8]1([CH2:16][OH:17])[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15].COC1C=CC(C=O)=CC=1>O.C(O)C.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OCC)(=O)C.C(Cl)Cl>[C@H:9]12[CH2:14][O:15][C:16](=[O:17])[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: OC[C@@H]1CCCC[C@@H]1CO
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: O=C1OC[C@@H]2CCCC[C@H]12
Yield: 92.6 %

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. Cis-1,2-cyclohexane dimethanol (10.0 grams) is added to the glycine solution with stirring until dissolution occurs, followed by the addition of β-NAD+ (Sigma, 2 grams) and flavin mononucleotide (Sigma, 30 grams). To the resulting clear orange solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent 1:1 ethyl acetate-methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (1R,6S)-(+)-8-oxabicydo[4.3.0]nonan-7-one (9 grams) as an orange oil. The product may be further purified by distillation at reduced pressure to yield a colorless oil, [∂]D=+46° c=1.1, chloroform. The enantiomeric excess is 98% as determined by chiral gas chromatography (Lipodex D column, column temperature 165=° C., injection temperature 180=° C., detector temperature=260° C.).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][C@@H:13]([CH2:19][OH:20])[O:12][C:11](=[O:21])[C:10]2[C:22]([CH3:29])=[C:23]([O:27][CH3:28])[CH:24]=[C:25]([OH:26])[C:9]=2[CH2:8][S:7][CH2:6]1)=O>CO.C(N)C#C>[CH2:16]([NH:17][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][C@@H:13]([CH2:19][OH:20])[O:12][C:11](=[O:21])[C:10]2[C:22]([CH3:29])=[C:23]([O:27][CH3:28])[CH:24]=[C:25]([OH:26])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:2])[C:15]#[CH:14]
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)O[C@H](CO)CCC(=S)N1
Agent: C#CCN
Solvent: CO
Product: C#CCNC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)O[C@H](CO)CCC(=S)N1
Temperature: 50 °C
Yield: 50.7 %

Procedure:
A solution of 45 mg of the product of Example 12 in a mixture of 1 ml of methanol and 1 ml of prop-2-ynylamine was heated to 50° C. for 5 h. The mixture was evaporated in vacuo and the residual oil was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent. The purified product was crystallized from ethyl acetate/hexane to yield 12 mg of (4R,9S)-15-hydroxy-9-hydroxymethyl-13-methoxy-12-methyl-11-oxo-6-thioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid prop-2-ynylamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:15](OCC)=[O:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([C:11]([F:14])([F:12])[F:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:15][OH:16]
Reactant: CCOC(=O)c1[nH]c2c(C(F)(F)F)cccc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CO)[nH]c2c(C(F)(F)F)cccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A solution of ethyl 3-methyl-7-(trifluoromethyl)-1H-indole-2-carboxylate (2.2 g, 8.1 mmol) in THF (50 mL) was added to an ice cooled solution of 1M LAH in THF (16.2 mL, 16.2 mmol) and stirred overnight. The reaction was quenched with ethyl acetate and sodium hydroxide, filtered through celite and evaporated to afford the title compound (1.03 g, 57%). 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.12 (t, J=4.7 Hz, 1H), 4.81 (s, 2H), 2.26 (s, 3H)
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1(C(OC(C)(C)C)=O)CCNCC1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid (470 mg, 1.13 mmol), tert-butyl piperazine-1-carboxylate (250 mg, 1.36 mmol) and triethylamine (0.30 mL) in DMF (5 mL) was added HATU (520 mg, 1.36 mmol). The reaction mixture was stirred at rt for 1 h, diluted with H2O (˜6 mL) and extracted with EtOAc (2×10 mL). The combined organics were washed with brine (10 mL), dried (MgSO4), filtered and concentrated. The residue was dissolved into MeOH//THF (1:1, 10 mL) and treated with 1M aqueous NaOH (1.4 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 30 min in a sealed tube, additional 1M aqueous NaOH (0.50 mL.) was added and the reaction was reheated at 80° C. for 15 min. The clear solution was diluted with H2O (10 mL), neutralized with 1M aqueous HCl (1.9 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O, dried under vacuum and purified by preparative HPLC (MeOH/H2O with NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]carbonyl] (335 mg, 0.59 mmol, 43%) as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 8.23 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.5, 1.2 Hz, 1H), 7.65 (br d, J=6.4 Hz, 1H), 7.60-7.53 (m, 3H), 7.03 (s, 1H), 5.18 (br s, 1H), 4.43 (br s, 1H), 3.42-3.25 (m, 8H), 2.95-2.86 (m, 1H), 2.21-1.19 (m, 10H). LCMS: m/e 568 (M−H)−, ret time 1.36 min, column D, 2 minute gradient.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C[O:19][C:20](=[O:32])[CH:21]([O:30][CH3:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:29][C:25]2[CH:24]=[C:23]([CH2:22][CH:21]([O:30][CH3:31])[C:20]([OH:32])=[O:19])[CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccc(-c3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from 4-(3-bromo-propoxy)-biphenyl (Example 291, Step 7) and 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 4) (0.3 g, 1.42 mmol) via the same procedure used for the preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3). The crude material was submitted to chiral HPLC separation to afford the single enantiomer of isomer 1. 1H-NMR (CDCl3, 200.15 MHz): 7.57–7.17 (m, 7H), 6.99 (dd, 2H, J=6.7, 2.2), 6.85–6.80 (m, 3H), 4.19 (dd, 4H, J=13.4, 6.4), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 0.14 (dd, 1H, J=14.0, 4.3), 2.98 (dd, 1H, J=14.8, 7.5), 2.28 (qui, 2H, J=5.9).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[Br-:12].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:12][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11])=[O:10]
Reactant: CC(=O)c1ccc(Br)cc1C
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of 1-(4-bromo-2-methylphenyl)ethanone (0.525 g, 2.464 mmol) in THF was added phenyltrimethylammonium tribromide (0.926 g, 2.464 mmol). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was filtered through a plug of diatomaceous earth (Celite®), and the filtrate was concentrated to yield 2-bromo-1-(4-bromo-2-methylphenyl)-ethanone (0.61 g) as a white solid. LC/MS (Cond. N-1): [M+H]+ 290.84, Rt=3.88 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)=S)[N:8]=[C:7]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[C:6]=2[CH:41]=1.[Na+].[Na+].[N:44]#[C:45][NH-:46].N#C[NH-]>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)=[N:46][C:45]#[N:44])[N:8]=[C:7]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[C:6]=2[CH:41]=1
Reactant: CN1C(=O)C(NC(=S)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: N#C[NH-]
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)C(NC(=NC#N)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
As illustrated in the scheme above, a solution of N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[4-(4-morpholinyl)-1-naphthalenyl]-thiourea (EXAMPLE 11, made according to General Procedure 3) (0.058 g, 0.1 mmol) and silver triflate (0.077 g, 0.3 mmol) in dichloromethane (2 ml) was combined with cyanamide disodium salt (1 mmol) and stirred at room temperature for 3 h. The reaction mixture was then diluted with dichloromethane (10 ml) and washed with brine (2×5 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was washed with ether (2×10 ml) and the polar isomer of the title compound (0.023 g, 380%) was obtained as pale yellow solid. The ether layer was concentrated in vacuo and purified by column chromatography (1:1 EtOAc:CH2Cl2) to give the non-polar isomer of the title compound (0.009 g, 15%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N+:26]([O-])=O)[CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5]>[Pd].CO>[NH2:1][C:2]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH2:26])[CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5]
Reactant: Cc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine prepared above, 5% palladium-activated carbon (15 mg), and methanol (2 mL) was stirred under a hydrogen atmosphere at room temperature for 4 h. The Pd catalyst was filtered off through Celite and the filtrate was concentrated. Preparative TLC (SiO2, ethyl acetate/MeOH=3/1) gave 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-methylbenzyl)piperidine (Compound No. 2114) (2.9 mg, 13%): The purity was determined by RPLC/MS (100%.); ESI/MS m/e 446.1 (M++H, C23H29F2N5O2).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[N+:17]([C:14]1[CH:13]=[N:12][C:11]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[N:16][CH:15]=1)([O-:19])=[O:18]
Reactant: C1CN2CCC(CC2)N1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(N2CCN3CCC2CC3)nc1
Reaction time: 15 h

Procedure:
A mixture of 1,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol), 2-chloro-5-nitro-pyrimidine (1.56 g, 6.27 mmol) and dioxane (75 ml) was stirred at room-temperature for 15 h. Aqueous sodium bicarbonate (20 ml, 10%) was added followed by extraction with ethylacetate (3×20 ml). The organic phase was dried and evaporated and a yellow powder was isolated. Yield 0.86 g (55%). Mp 135-139° C.
Reaction SMILES: [I: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=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:45])[CH2:23][CH2:24][C:25]([NH:27][C:28]1[CH:44]=[CH:43][C:31]([C:32]([NH:34][NH:35]C(OC(C)(C)C)=O)=[O:33])=[CH:30][CH:29]=1)=[O:26]>C(O)(=O)C>[I: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=[N:35][NH:34][C:32]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:45])=[CH:44][CH:43]=1)=[O:33]
Reactant: COC(=O)CCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 92 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-{4-[(4-methoxy-4-oxobutanoyl)amino]benzoyl}hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and an orange solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. for 60 min gave 89 mg of the title compound (92%) as an orange solid in 98.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]12[CH:7]([C:8]([OH:10])=O)[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:13]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:8]([CH:7]3[CH:4]4[CH2:3][CH2:2][CH:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:13]2)=[CH:20][CH:21]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)C1C2CCC1CC2
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1C2CCC1CC2

Procedure:
7-Norbornanecarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-7-norbornanecarboxamide.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=2[N:11]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[C:5]2[N:11]=[C:2]([CH3:1])[S:3][C:4]=2[CH:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c[n+]([O-])ccc2s1
Product: Cc1nc2c(Cl)nccc2s1

Procedure:
2-Methyl-thiazolo[4,5-c]pyridine 5-oxide (230 mg, 1.38 mmol) was refluxed 2 hrs in 4 ml of phosphoryl chloride. The reaction mixture was evaporated and extracted with ethyl acetate and saturated sodium bicarbonate-solution. The organic extracts were dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->0:100 gradient). The desired product was obtained as a light yellow solid (180 mg, 70%), MS: m/e=185.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:17][O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>[Cl-].[Na+].O.C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:25][C@H:22]2[CH2:23][CH2:24][C@H:19]([O:18][CH3:17])[CH2:20][CH2:21]2)[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: CO[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Temperature: 127 °C

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine.hydrochloride (1.5 equiv), NMP and DIEA were combined and heated to 127° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to 35° C. over 4 h. The batch was transferred to a mixture of ethyl acetate and 5% brine. The aqueous layer was removed and the organic layer containing the batch was washed successively with 5% brine and water. The organic layer containing the batch was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected by vacuum filtration. The filter cake was washed with MTBE and the product was dried in a vacuum to give 41% yield of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate (1 equiv), water and 85% phosphoric acid (3:1) was heated to 80° C. over 1 h. Heating was maintained for 18 h to effect reaction completion. Upon reaction completion, the mixture was cooled to 25° C. and filtered to give a crude product as tan solid. The resulting solids were washed with water, slurried in water and filtered. The filter cake was washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to give 89% yield of 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine (1 equiv), sodium carbonate (3 equiv) and PdCl2(AmPhos)2 (0.003 equiv) were combined in isopropanol and heated at 70° C. for 1.5 h. Standard work-up and purification afforded the protected compound in 93% yield. Deprotection using standard conditions for removal of a trimethylsilyl-group and isolation gave the title compound.