Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br-].[CH2:25]([Zn+])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1.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>[C:26]1([CH2:25]/[CH:2]=[CH:3]/[C@@H:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CCOC(=O)C[C@@H](/C=C/I)c1ccc(OC2CCCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](/C=C/Cc1ccccc1)c1ccc(OC2CCCCO2)cc1

Procedure:
To a stirred solution of 84.4 (321.9 mg, 0.748 mmol, 1 eq., MW 430.29) in THF (19 mL) at 23° C. was added Pd(PPh3)4 (86.8 mg, 0.075 mmol, 0.1 eq., MW 1155.58) followed by dropwise addition of benzyl zinc bromide solution (1.8 mL, 0.90 mmol, 1.2 eq., 0.5 M) After 3 hours, water (10 mL) was added to quench the reaction. The mixture was extracted with EtOAc (2×50 mL), dried with MgSO4, and filtered. The organic layer was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated providing the product as a colorless oil that was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([NH2:26])[CH:21]=[N:22][C:23]=1[O:24][CH3:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:16][C:5]1[CH:6]=[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[C:2]([NH:26][C:20]2[CH:21]=[N:22][C:23]([O:24][CH3:25])=[C:18]([F:17])[CH:19]=2)=[N:3][CH:4]=1
Reactant: Cc1nc(N)nc(-c2cc(F)cnc2Cl)n1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(F)cc2-c2nc(C)nc(N)n2)cc1F
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
A solution of 4-(2-chloro-5-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (100 mg, 0.417 mmol) and 5-fluoro-6-methoxypyridin-3-amine (120 mg, 0.844 mmol) (Anichem, NJ, USA) in THF (2.0 mL) was cooled in an ice bath under nitrogen. A THF solution of LiHMDS (1 M in THF, 2500 μL, 2.500 mmol) was added dropwise. After 5 min, the cooling bath was removed. After a total of 22 min, HCl (5 N, 0.5 mL) was added. After 5 min, EtOAc (10 mL) and saturated NH4Cl (10 mL) were added. The organic layer was washed with water (2×5 mL). The combined aqueous layers were extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was suspended in MeOH (5 mL) and filtered. The solid was washed with MeOH (2×2 mL), DCM (3×3 mL) and EtOAc (3×3 mL) to give the first batch of product as a brown solid. The combined washings were concentrated and purified on silica using 0-3% MeOH in DCM. The dark blue fraction contained the desired product (m/z 346) as a second batch. The combined product batches was suspended in ether (4 mL) and filtered to give the final product as a green solid (60 mg). LCMS (ES, pos.): calcd for C15H13F2N7O: 345.1. found: 346.2 (M+H)−. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (s, 1H); 8.56 (dd, J=9.78, 2.93 Hz, 1H); 8.38 (br. s., 2H); 8.28 (dd, J=12.81, 1.86 Hz, 1H); 7.97 (br. s., 1H); 7.84 (br. s., 1H); 3.93 (s, 3H); 2.44 (s, 3H). 19F NMR (377 MHz, d6-DMSO) δ −140.84 (s, 1 F); −139.70 (s, 1 F).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[F:32])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14][CH2:15]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:28])=[CH:25][C:24]=4[F:32])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(N)CC1
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CCC3)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluorobenzoic acid (Intermediate 10) (100 mg, 0.23 mmol, 1 eq), DIPEA (80 μl, 0.46 mmol, 2 eq) and TBTU (80 mg, 0.25 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution stirred at rt for 10 min before the addition of 1-amino-4-methylpiperazine (33 μL, 0.27 mmol, 1.2 eq). The RM was then stirred at rt for 1 hour before splitting into two equal batches and purifying by preparative RP-HPLC-MS (Preparative—3) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluoro-N-(4-methylpiperazin-1-yl)benzamide (0.05 g, 41%).
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH:30]=[CH2:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[CH:28][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:19][C:20]=1[CH3:21])[CH3:31]
Reactant: [H][H]
Reactant: C=Cc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Yield: 63.6 %

Procedure:
A solution of 4-[2-(4-benzyloxy-2-vinylphenoxy)ethyl]-5-methyl-2-phenyloxazole (1.30 g, 3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid (0.65 g, 64%): 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J=8.3 Hz, 2.0 Hz, 2H), 7.45-7.38 (m, 3H), 6.63 (d, J=2.4 Hz, 1H), 6.50-6.41 (m, 2H), 5.98 (br s, 1H), 4.10 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.85-2.51 (m, 2H), 2.39 (s, 3H), 1.08 (t, J=7 Hz, 3H); HRMS: Calc'd=324.1599; Found=324.1597.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)=[N+:2]=[N-:3].[C:11](OC=C)(=O)[CH3:12]>>[N:1]1([C:4]2[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=2)[CH:12]=[CH:11][N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccc(F)nc1
Reactant: C=COC(C)=O
Product: Fc1ccc(-n2ccnn2)cn1
Temperature: 100 °C

Procedure:
5-Azido-2-fluoropyridine (262 mg, 1.9 mmol) and vinyl acetate (4.0 mL, 43 mmol) were mixed in a flame dried high pressure sealable vessel. The reaction vessel was evacuated and charged with nitrogen, sealed, and heated to 100° C. for 15 hours. The reaction was cooled to room temperature and TLC indicated that the reaction was complete. Minimal dichloromethane was added to the reaction (just enough to dissolve solids that formed upon cooling) and the solution directly chromatographed on silica gel (Biotage size 40S column), eluting with 20-50% ethyl acetate/heptane to give the title compound as a white solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:15]1[C:14](=[C:23]3[C:18](=[CH:17][CH:16]=1)[CH:19]=[CH:20][CH:21]=[N:22]3)[NH:13][S:10]2(=[O:11])=[O:12]
Reactant: COc1ccc(N)c(S(=O)(=O)Nc2cccc3cccnc23)c1
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)S(=O)(=O)Nc1c-2ccc2cccnc12
Yield: 4.5 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-5-methoxy-N-quinolin-8-yl-benzenesulfonamide (Intermediate 293) (450 mg, 1.36 mmol), t-butyl nitrite (0.24 ml, 2.04 mmol), AcOH (4.5 ml) and THF (4.5 ml) gave the title compound (19 mg, 4%) after purification by column chromatography with DCM/MeOH (99.7:0.3) as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=C)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])=[O:15].[Na+].[Na+].O>C(O)(C)(C)C>[C:1]([O:5][C:6]1[N:7]=[C:8]([CH:12]=[O:15])[CH:9]=[N:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1cncc(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
After adding 7.20 g of AD-mix-5 to 60 ml of 50% aqueous tert-butanol, a solution of 1.00 g of 2-tert-butoxy-6-vinylpyrazine in tert-butanol (5 ml) was added and the mixture was stirred overnight at room temperature. Next, 8.40 g of sodium sulfite was added to the reaction solution, the mixture was stirred at room temperature for 1 hour, and then water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of methanol, an aqueous solution of 2.35 g of sodium periodate (20 ml) was added while stirring on ice, and stirring was continued at room temperature for 40 minutes. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (954 mg, 96% yield).
Reaction SMILES: [CH2:1]1[CH2:6][CH:5]([C:7]2([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26](NC4NN=NN=4)[CH:25]=3)=[O:22])[N:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH3:18])[C:8]2=[O:19])[CH2:4][CH2:3][CH2:2]1.[NH:36]1[C:40]([NH:41][CH2:42]C2C=C(C=CC=2)N)=[N:39][N:38]=[N:37]1>C(#N)C>[CH2:3]1[CH2:4][CH:5]([C@@:7]2([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:42][NH:41][C:40]4[NH:39][N:38]=[N:37][N:36]=4)[CH:25]=3)=[O:22])[N:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH3:18])[C:8]2=[O:19])[CH2:6][CH2:1][CH2:2]1
Reactant: CN1C(=O)C(NC(=O)Nc2cccc(Nc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Reactant: Nc1cccc(CNc2nnn[nH]2)c1
Solvent: CC#N
Product: CN1C(=O)[C@@](NC(=O)Nc2cccc(CNc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21

Procedure:
The title compound was prepared from Intermediate 3 and 3-[(tetrazol-5-yl)aminomethyl]aniline using a similar method to that described for Example 4, except that anhydrous acetonitrile was used instead of tetrahydrofuran; the crude product was purified by flash chromatography (silica gel, dichloromethane-methanol, 95:5 to 90:10) and recrystallized from a mixture of methanol and ethyl acetate; mp 175°-178° C.; [α]D24 +17.4° (c=0.50, dimethylformamide); the spectroscopic properties of this material (1 H-NMR and MS spectra) were identical to those described for its racemate (Example 1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C)C=O>[F:16][C:2]([F:1])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]([CH:24]([CH3:26])[CH3:25])[CH:6]=1)=[O:4]
Reactant: Cc1ccc2c(C(=O)C(F)(F)F)c[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-methyl-1H-indol-3-yl)-ethanone (1.5 g, 6.60 mmol) in N,N-dimethylformamide (15 mL) at 25° C. was treated with potassium carbonate (2.28 g, 16.51 mmol). The resulting mixture was stirred at 25° C. for 15 min and then treated with 2-iodopropane (0.99 mL, 9.90 mmol). The reaction was heated at 65° C. for 3 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was then washed with a 1N aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(1-isopropyl-6-methyl-1H-indol-3-yl)-ethanone (1.61 g, 90.6%) as a pink solid: mp 65-68° C.; EI-HRMS m/e calcd for C14H14F3NO (M+) 269.1027, found 269.1037.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.Br[CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:10][C:11]([C:15]#[N:16])=[C:12]([O:14][CH2:25][CH2:26][N:27]2[C:28](=[O:37])[C:29]3[C:30](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:32])[N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCCN1C(=O)c2ccccc2C1=O

Procedure:
Using the procedure described in Example 25, 6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile from Step C of Example 129 was reacted with N-(2-bromoethyl)phthalimide to afford the title compound. MS (electrospray) m/e 513.9 MH+ (Rt=4.2 min LC/MS).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11]C(C)C)=[O:10])[CH:2]=[CH2:3].O.[OH-].[Li+]>C1COCC1.O.O>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of isopropyl 5-allyloxy-2(S)-(tert-butoxycarbonylamino)pentanoate (product of step 26D, 16.1 g, 51.1 mmol) and lithium hydroxide hydrate (4.19 g, 102 mmol) in THF/water (100 mL/20 mL) was stirred at room temperature under nitrogen for 16 hours. The reaction was diluted with water, washed with ether, pH of aqueous fraction adjusted to ˜4, extracted with ether, combined organic fractions washed with saturated NaCl, dried (MgSO4) and evaporated giving 5-allyloxy-2(S)-(tert-butoxycarbonylamino)pentanoic acid as a light yellow syrup: 1H NMR (300 MHz, Chloroform-D) δ 5.89 (ddt, 1H, J=17.4, 10.4, 5.5), 5.25 (dd, 1H, J=17.4, 1.6 Hz), 5.17 (dd, 1H, J=10.4, 1.6 Hz), 4.30 (br d, 1H, J=6.2), 3.96 (dt, 2H, J=5.9, 1.5 Hz), 3.46 (t, 2H, J=5.9 Hz), 1.96-1.86 (m, 1H), 1.85-1.77 (m, 1H), 1.75-1.64 (m, 2H), 1.43 (s, 9H). LCMS m/z 274 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[CH3:30])=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:11][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:25]=[C:24]2[CH3:30])=[O:20]
Reactant: COC(=O)c1ccc2[nH]nc(C)c2c1
Reactant: CC(C)Cn1ncc2cc(Br)cc(CO)c21
Product: COC(=O)c1ccc2c(c1)c(C)nn2Cc1cc(Br)cc2cnn(CC(C)C)c12
Yield: 76 %

Procedure:
Compound 37 was prepared following general method 3A, using compound 18 as a starting material and 3-methyl-1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 76%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CON(C)[C:16]([C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:22]=1)=[O:17].[Cl-].[NH4+]>C1COCC1>[C:25]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=[C:23]([N:21]2[CH:22]=[C:18]([C:16]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[O:17])[N:19]=[CH:20]2)[CH:24]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 28.8 %

Procedure:
A solution of 2-bromopyridine (1.0 g, 6.5 mmol) in THF (20 ml) was stirred at −78° C. in a nitrogen atmosphere. n-Butyllithium (8.1 ml 1.6M solution in hexanes, 13.0 mmol) was added and stirring at −78° C. was continued for 45 min. The resultant mixture was allowed to warm to 0° C. for two hours, in order to ensure completion of anion formation. The mixture was again cooled to −78° C. and compound 12a (0.5 g, 1.6 mmol) was added. After 30 min. the mixture was allowed to warm to 0° C. and saturated, aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel using a mixture of petroleum ether and ethyl acetate (9:1) as the eluent. This afforded the desired product (0.15 g, 22%) as a yellowish gum. HRMS (ESI+): m/z=326.1305 [M+H]
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([C:33](OC)=[O:34])=[CH:25][C:23]=3[N:24]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:19])[F:20])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:30])=[O:31])[C:26]([CH2:33][OH:34])=[CH:25][C:23]=3[N:24]=[C:5]12)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(OC)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)ncc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of (R)-methyl 1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (15 mg, 0.028 mmol) in CH2Cl2 (2 mL) was added DIBAL H (1M in toluene, 0.1 mL, 0.1 mmol) at −78° C. The mixture was stirred at −78° C. for 2 h and warmed to rt for 6 h. Sat. NH4Cl solution (1 mL) was added and the mixture was filtered. The filtrate was concentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-(1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol (3.50 mg, 24.6% yield) as a white solid. Analytical chiral HPLC: tR=6.598 min in 15 min chromatography, 94.60% ee (Method: OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 500.1 [M+H]+. 1H NMR (CDCl3 300 MHz): δ 8.31 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 6.02-5.98 (m, 1H), 5.43-5.38 (m, 1H), 5.04-4.98 (m, 2H), 4.32-4.28 (m, 1H), 4.16 (dt, J=5.1 and 12.0 Hz, 1H), 4.01 (s, 3H), 3.77-3.68 (m, 1H), 3.21 (s, 3H), 3.11-3.06 (m, 1H), 2.50-2.47 (m, 1H), 1.30 (d, J=6.6 Hz, 3H), 1.07 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[C:33](=[O:37])[CH2:32][CH2:31]4)=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[CH2:32][CH2:31]3)=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc4c(c3)CCC4=O)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc3c(c2)CCC3=O)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 56-4 (840 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (410 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH:31]=[O:32])[N:23]=[C:22]2[CH2:33][CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([Mg]Br)([CH3:39])([CH3:38])[CH3:37]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH:31]([OH:32])[C:36]([CH3:39])([CH3:38])[CH3:37])[N:23]=[C:22]2[CH2:33][CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Mg]Br
Reactant: CCCc1nc(C=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CCCc1nc(C(O)C(C)(C)C)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 59(b), 1.14 g of ethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-formyl-2-propylimidazole-5-carboxylate [prepared as described in step (c) above] was reacted with 2.4 ml of a 2M solution of t-butylmagnesium bromide in tetrahydrofuran, to afford 0.78 g of the title compound as a viscous oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)cc1
Reactant: NNc1ccccc1
Product: COc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 81 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methoxyl-phenyl)-1H-pyridazin-4-one (A-2) and phenylhydrazine according to the method described for Example 1 in 81% yield. MS: M=345.0 (M+H)+