Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[Li]CCCC.[CH3:29][O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=O.O>C1COCC1>[CH3:29][O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[C:2]([CH3:4])[CH3:3]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCC=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a stirred suspension of isopropyltriphenylphosphonium bromide (10.9 g, 28.3 mmol) in THF (60 mL) was added dropwise n-BuLi (12.0 mL, 2.5 M solution in hexanes, 30.0 mmol) at 0° C. under N2. The resulting solution was stirred at this temperature for 30 min and cooled to −78° C. A solution of 6-oxo-hexanoic acid methyl ester (3.95 g, 19.7 mmol) in THF (10 mL) was added quickly. The resulting mixture was then allowed to warm to room temperature and stirred overnight. Water (30 mL) was added. The aqueous phase was extracted with hexane. The combined organic phases were washed with saturated aqueous NH4Cl and brine and dried. Concentration and purification of the residue by flash chromatography on silicagel (hexane:ethyl acetate, 10:1) afforded 7-methyl-oct-6-enoic acid methyl ester (3.39 g, 72%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.08 (1H, m), 3.64 (3H, s), 2.29 (2H, t, J=7.2 Hz), 1.97 (2H, m), 1.66 (3H, s), 1.62 (2H, m), 1.58 (3H, s), 1.36 (2H, m); 13C NMR (75 MHz, CDCl3) δ 174.26, 140.05, 131.80, 124.27, 51.67, 34.29, 29.60, 27.89, 25.97, 24.87, 17.94.
Reaction SMILES: [CH:1]([CH:4]1[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][O:5]1)=[CH:2][CH3:3].[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14]>>[C:12]([O:16][CH:2]([CH3:3])[CH2:1][CH:4]1[O:5][CH2:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9]1)(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)O
Reactant: CC=CC1OCC(C)(C)CO1
Product: C=CC(=O)OC(C)CC1OCC(C)(C)CO1

Procedure:
2-Propenyl-5,5-dimethyl-1,3-dioxane (PDD) was reacted with acrylic acid under the same conditions as the reaction with EDD (see Monomer VIII).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11](#[N:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>C(O)C.O.C(O)C>[OH:3][NH:2][C:11](=[NH:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCC#N
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCCCC(=N)NO
Reaction time: 0.03 h
Yield: 26.5 %

Procedure:
Hydroxylamine hydrochloride (0.90 g, 12.9 mmol) was added to a solution of triethylamine (1.79 mL, 12.9 mmol) in 50% ethanol/water (4 mL) and the mixture was stirred for 2 minutes. Tridecane nitrile (2.02 g, 10.4 mmol) in ethanol (10 mL) was added and the mixture refluxed for 2 hours, allowed to cool, and poured into water (50 mL). The precipitate was collected, stirred with hexanes, and filtered to yield a white solid (0.63 g, 26%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:37]=[CH:36][C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][C:21]3[CH:22]=[C:23]([C:28]4([O:34][CH3:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:24]=[C:25]([F:27])[CH:26]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)#[N:8].O.[OH-].[Na+]>C1COCC1>[NH2:8][CH2:7][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20][C:21]3[CH:22]=[C:23]([C:28]4([O:34][CH3:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:24]=[C:25]([F:27])[CH:26]=3)=[CH:18][CH:19]=2)=[CH:36][CH:37]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(Cc4ccc(C#N)cc4)cc3)c2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC1(c2cc(F)cc(Sc3ccc(Cc4ccc(CN)cc4)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Lithium aluminium hydride (1M in THF. 1.5 ml) was added dropwise to a stirred solution of 4-[3-(4-(4-cyanobenzyl)phenylthio)-5-fluorophenyl]-4-methoxytetrahydropyran (0.675 g) in THF (9 ml) and the mixture was stirred at ambient temperature for 1 hour. Water (5 ml) and 4N aqueous sodium hydroxide solution (5 ml) were added in turn. The mixture was extracted with diethyl ether. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in diethyl ether (5 ml) and a solution of oxalic acid in diethyl ether was added. The precipitate was isolated. There was thus obtained the mono-oxalate salt of 4-[3-(4-(4-aminomethylbenzyl)phenylthio)-5-fluorophenyl]-4-methoxytetrahydropyran (0.34 g), m.p. 142°-146° C.
Reaction SMILES: [F:1][C:2]1([F:31])[CH2:30][CH:5]2[CH:6]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[CH:22][CH:21]=3)[O:7][C:8]3[C:13]([CH:4]2[CH2:3]1)=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][C:9]=3[C:18]#N.C[Li].C([Li])CCC.CN(C=[O:43])C.[BH4-].[Na+]>C1COCC1.CCOCC.CCOC(C)=O>[F:1][C:2]1([F:31])[CH2:30][CH:5]2[CH:6]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[CH:22][CH:21]=3)[O:7][C:8]3[C:9]([CH2:18][OH:43])=[CH:10][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:12][C:13]=3[CH:4]2[CH2:3]1
Reactant: CN(C)C=O
Reactant: COCOc1ccc(C2Oc3c(C#N)cc(OCOC)cc3C3CC(F)(F)CC32)cc1
Agent: [BH4-]
Agent: [Li]C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2Oc3c(CO)cc(OCOC)cc3C3CC(F)(F)CC32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of preparation 16 (97 mg, 0.20 mmol) in 2 mL of THF at −78° C. add methyl lithium (0.062 mL of a 1.6 M solution in Et2O, 0.10 mmol) followed by n-butyllithium (0.25 mL of a 1.6 M solution in hexanes, 0.40 mmol). Stir the solution for 15 min and then add DMF (0.077 mL, 1.0 mmol). Stir the solution for 30 min and then quench the reaction with saturated aqueous ammonium chloride. Let the solution warm to room temperature, separate; and back extract the aqueous solution with EtOAc. Wash the combined organic solutions with ½ brine, brine, dry over Na2SO4, filter and concentrate. Dissolve the material in 1 mL of THF and 1 mL of methanol. Add sodium borohydride (35 mg, 0.93 mmol). Let the solution stir for 30 min and quench the reaction with saturated aqueous ammonium chloride. Dilute the solution with EtOAc, wash with brine, dry over Na2SO4, filter and concentrate. Adsorb the material to silica gel and purify by silica gel flash chromatography (10 g, 0-30% A/B, A=EtOAc, B=10% CH2Cl2 in hexanes) to afford 68 mg (0.16 mmol, 87%) of preparation 20. 1H NMR (400 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.03-7.07 (m, 2H), 6.91 (d, 1H, J=2.6 Hz), 6.72 (d, 1H, J=2.6 Hz), 5.17 (s, 2H), 5.11 (d, 1H, J=10.5 Hz), 5.09 (d, 1H, J=10.1 Hz), 5.03 (bs, 1H), 4.73 (dd, 1H, J=6.6, 13.2 Hz), 4.68 (dd, 1H, J=6.6, 13.2 Hz), 3.66 (dt, 1H, J=3.5, 8.8 Hz), 3.47 (s, 3H), 3.46 (s, 3H), 2.86 (ddt, 1H, J=2.2, 10.1, 7.5 Hz), 2.72 (m, 1H), 2.31 (m, 1H), 2.18 (t, 1H, J=6.6 Hz), 2.13 (m, 1H), 1.86 (dt, 1H, J=7.5, 14.5 Hz).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][CH:26]=2)[NH:21]1>>[F:29][C:24]1[CH:23]=[C:22]2[C:27]([CH2:28][CH:20]([CH3:19])[N:21]2[C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:26][CH:25]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2ccc(F)cc2N1
Agent: [Na+]
Product: CC1Cc2ccc(F)cc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1

Procedure:
The product is prepared by following the procedure described in example 15c using 115 mg of sodium (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and 62 mg of (+)-2-methyl-6-fluoro-2,3-dihydro-1H-indole [reference example 9c, step 5c]. After silica column purification: eluent 98/02 then 95/05 dichloromethane/methanol, 84 mg of -[2-((−)-6-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C([Li])CCC.C1COCC1.I[C:35]1[N:39]([CH3:40])[CH:38]=[N:37][CH:36]=1>[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:35]4[N:39]([CH3:40])[CH:38]=[N:37][CH:36]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: Cn1cncc1I
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cncn4C)cc3C)c(C)nc12
Yield: 14.7 %

Procedure:
Using the procedure analogous to Example 31, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol), 1.34M n-Bu-Li (0.80 mL, 1.07 mmol), 0.5M ZnCl2 in THF (2.14 mL, 1.07 mmol), 5-iodo-1-methyl-1H-imidazole (0.24 g, 1.22 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) furnish the title compound (0.061 g, 0.15 mmol, 15%). 1H NMR (CDCl3) δ 0.89 (t, J=7.4 Hz, 6H), 1.75-1.93 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H), 2.53 (s, 3H), 3.24-3.38 (m, 1H), 3.61 (s, 3H), 6.68 (s, 1H), 7.02 (s, 1H), 7.23 (s, 1H), 7.55 (s, 1H). LC/MS (m/z): calcd. for C22H27N5S (M+H)+: 394.3; found: 394.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:22](S(=O)(=O)N(C)C)[N:23]=[CH:24][C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:22][NH:23][CH:24]=[C:11]2[N:10]=1
Reactant: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C(=O)O)ccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c[nH]nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
A 250 ml round-bottomed flask is charged with 1.46 g of 5-(2,6-difluorophenyl)-1-(dimethylsulphamoyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylic acid in 100 ml of DCM and then 20 ml of TFA are added. The mixture is stirred at RT for 16 h. It is concentrated under RP and the solid obtained is taken up in 30 ml of saturated aqueous NaHCO3 solution and extracted with three times 30 ml of AcOEt. The aqueous phase is acidified to a pH of 1 by addition of 37% HCl and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP to give 927 mg of 5-(2,6-difluorophenyl)-2H-pyrazolo[4,3-c]isoquinoline-7-carboxylic acid (beige solid), LC-MS-DAD-ELSD: 326(+)=(M+H)(+).
Reaction SMILES: [CH:1]([C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:20][NH:21][CH3:22].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:20][N:21]([CH3:22])[CH2:1][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSc1ccccc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A solution of Example 134A (1.25 g, 4.44 mmol), 2M dimethylamine in THF (2.7 mL, 5.4 mmol), and NaBH(OAc)3 (1.32 g, 6.22 mmol) in dichloromethane at room temperature was stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 311 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCBr)c(F)c1
Yield: 60.7 %

Procedure:
A suspension of 3-fluoro-4-hydroxybenzonitrile (20 g, 0.1459 mol, from step (iv) above), anhydrous. K2CO3 (40.33 g, 0.2918 mol) and 1,2-dibromo ethane (76.8 ml, 0.8754 mol) in dry DMF (150 ml) was stirred at 60° C. for 5 days under nitrogen atmosphere. The reaction mixture wasfiltered through celite and solvent evaporated under reduced pressure. The residue was purified by column chromatography over silica gel using 2% ethyl acetate in petroleum ether, as eluent to yield the sub-title compound (21.6 g) as a solid.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Cl)[N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[Cl:18][C:19]1[N:20]=[C:21]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Clc1cccc(Cl)n1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Clc1cccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2,6-dichloropyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). MW: 331.81; mp: 122.0-123.0° C.; 1H-NMR (DMSO) δ: 8.22 (1H, t, J=7.9 Hz), 7.91 (1H, d, J=16.1 Hz), 7.79-7.72 (3H, m), 7.67-7.63 (2H, m), 7.50-7.47 (1H, m), 746-7.28 (5H, m), 7.23 (1H, d, J=16.1 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:14][C:15]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:14][C:15]1[C:24]([NH:25][C:9](=[O:11])[C:8]2[C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][CH:5]=[N:6][CH:7]=2)=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)c2cnccc2C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Trifluoromethyl)nicotinic acid (88; 1.00 g, 5.23 mmol) was taken up in DMF (8 mL) along with methyl 2,3-diaminobenzoate (118; 0.86 g, 5.23 mmol), HATU (2.98 g, 7.84 mmol) and DIEA (1.82 mL, 10.5 mmol). The reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc, washed with water, dried (Na2SO4) and concentrated under reduced pressure to afford crude methyl 2-amino-3-(4-(trifluoromethyl)nicotinamido)benzoate. This material was taken up in 5 mL of glacial acetic acid and stirred at 60° C. for 18 h. The reaction mixture was stirred at 90° C. for an additional 8 h. It was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with EtOAc, washed with dilute aqueous NaHCO3, dried (Na2SO4) and concentrated under reduced pressure to afford crude methyl 2-(4-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylate. This material was taken up in MeOH (8 mL) and H2O (8 mL) containing LiOH (0.4 g) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and neutralized with 6 N HCl. The resulting solids were collected by filtration and dried to afford 570 mg of 2-(4-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid (35% yield from methyl 2,3-diaminobenzoate) 119. MS (ESI) calcd for C14H8F3N3O2: 307.06; found: 308 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:24]([C:25]([CH3:28])([CH3:27])[CH:26]=1)=[C:7]1[CH:8]=[C:9]3[C:22](=[CH:23][C:6]1=[CH:5]2)[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]1[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=1.[CH3:29][C:30]1([CH3:64])[C:54]2[C:34]([CH:35]=[C:36]3[CH:53]=[C:52]4[C:39]([C:40]5[C:45]([C:46]6[C:51]4=[CH:50][CH:49]=[CH:48][CH:47]=6)=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:38][C:37]3=2)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.CO.C1(C)C=CC=CC=1>[CH3:27][C:25]1([CH3:28])[C:24]2[C:4]([CH:5]=[C:6]3[CH:23]=[C:22]4[C:9]([C:10]5[C:15]([C:16]6[C:21]4=[CH:20][CH:19]=[CH:18][CH:17]=6)=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:8][C:7]3=2)=[CH:3][C:2]([C:32]2[CH:33]=[C:34]3[C:54]([C:30]([CH3:64])([CH3:29])[CH:31]=2)=[C:37]2[CH:38]=[C:39]4[C:52](=[CH:53][C:36]2=[CH:35]3)[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]4=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:26]1
Reactant: CC1(C)C=C(Br)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)C=C(C2=CC(C)(C)C3=c4cc5c6ccccc6c6ccccc6c5cc4=CC3=C2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 48 %

Procedure:
A mixture of 4.2 g (10 mmol) of 12-bromo-10,10-dimethyl-10H-indeno[1,2-b]triphenylene, 5.2 g (11 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.12 g (0.1 mmol) of Tetrakis(triphenylphosphine)Palladium, 15 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After finishing the reaction, The mixture was allowed to cool to room temperature. Than 100 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 3.3 g (yield 49%) of yellow product which was recrystallized from chloroform. MS (m/z, EI): 686.7. 1H NMR (CDCl3, 400 MHz): δ 9.05 (s, 2H), 8.86 (d, J=7.88 Hz, 2H), 8.79 (d, J=7.76 Hz, 2H), 8.74 (s, 2H), 8.71 (d, J=7.84 Hz, 4H), 8.10 (d, J=7.64 Hz, 2H), 7.84 (s, 2H), 7.81 (d, J=7.80 Hz, 2H), 7.76˜7.67 (m, 8H), 1.77 (s, 12H).
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]3[O:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:17][N:18]=3)=[C:7]2[N:6]=[N:5]1.S([O-])(O[O-])(=O)=[O:26].[K+].[K+].OOS([O-])=O.[K+]>CN(C=O)C.O>[CH3:1][S:2]([CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]3[O:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:17][N:18]=3)=[C:7]2[N:6]=[N:5]1)=[O:26]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSCn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)Cn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O
Temperature: 0 °C
Yield: 90 %

Procedure:
To a 0° C. solution of 3-(methylthiomethyl)-8-(5-phenyl-1,3,4-oxadiazol-2-yl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.337 mmol, 115 mg, 1 eq.) in DMF (6 mL) was added potassium peroxymonosulfate (Oxone™) (0.37 mmol, 114 mg, 1.1 eq.) dissolved in water (1.2 mL) drop wise. The formed suspension was stirred at 0° C. and stepwise additions of Oxone™ in water were made until reaction completion. The reaction mixture was filtered and the obtained solid was washed with water, acetonitrile and ether, and dried under vacuum to give the title compound. Yield 90%. δH (DMSO-d6) 9.15 (1H, s), 8.13 (2H, dd, J: 7.96, 2.25), 7.70 (3H, m), 5.67 (1H, d, J: 13.06), 5.52 (1H, d, J: 13.06), 2.81 (3H, s).
Reaction SMILES: N[C:2]([C@:4]1([CH3:30])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3].[OH:31][Li].O>CO>[CH3:27][C:26]([O:25][C:23]([N:5]1[C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8][C@@:4]1([CH3:30])[C:2]([OH:31])=[O:3])=[O:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(N)=O
Reactant: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(=O)O
Yield: 93.4 %

Procedure:
A solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-2-methyl-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D7, 0.977 g, 2.29 mmol) and LiOH.H2O (192 mg, 4.59 mmol, dissolved in 7 ml H2O) in methanol (7 ml) was heated in a microwave synthesizer for 1 hour at 100° C. After evaporation of methanol, the aqueous phase was acidified to pH 3 with 1M HCl and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (white solid, 880 mg, 93%); Rf (cyclohexane:ethyl acetate=6:4): 0.24; Rt (HPLC): 6.07 min. MS: (ES/−) m/z: 410 [M−H]; C24H29NO5 requires 411; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 12.92-12.23 (br. s, 1H); 7.48-7.40 (m, 4H); 7.40-7.33 (m, 2H); 7.31 (t, 1H); 6.92 (t, 2H); 5.08 and 5.06 (s, s, 2H); 4.85 and 4.76 (d, d, 1H); 2.48-2.34 (m, 1H); 2.19-2.05 (m, 1H); 1.81-1.72 (m, 1H); 1.64-1.57 (m, 1H); 1.46 and 1.43 (s, s, 3H); 1.32 and 1.03 (s, s, 9H).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][CH2:15][N:16]([CH2:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:7])(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl.CCOCC>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH2:17][N:16]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:44])[CH2:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38])=[O:31]
Reactant: COc1ccc(CN(CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(CCC(=O)N2CCC[C@@H]2C(=O)O)CCC(=O)N2CCC[C@@H]2C(=O)O)cc1OC
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred solution of 150 mg (0.24 mmol) (R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3oxo-propyl]-(3,4dimethoxy-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after trituration in ether, 130 mg (87%) of the title compound as a yellow crystalline solid. MS m/e (%): 506 (M+H+, 100).