Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([C:10]2[C:11](=[O:22])[N:12]([CH3:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:9]=1)=[C:2]=[S:3].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCO>[C:24]([NH:32][NH:33][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([C:10]2[C:11](=[O:22])[N:12]([CH3:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:9]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N=C=S)ccc1C)c(=O)n2C
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=S)NNC(=O)c3ccccc3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 19 (50 mg, 0.16 mmol) in EtOH (1.0 mL), benzohydrazide (26 mg, 0.19 mmol) was added and stirred at rt for 2 h. The solvent was removed under vacuum to yield crude 2-benzoyl-N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)hydrazinecarbothioamide, which was used without purification. MS m/z 458.2 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@@H:20]([NH:45]C(OC(C)(C)C)=O)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(NCC2C3C(=CC=CC=3)N(CCCOC)C=2)CC1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@@H:20]([NH2:45])[CH2:19]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Agent: COCCCn1cc(CNC2CC2)c2ccccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred, ice-cooled solution of (3R*,5S*)-3-tert-butoxycarbonylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (prepared from cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amine analogously as described in Example 59A) (1.2 g, 1.7 mmol) in CH2Cl2 (8 ml), 2,6-lutidine (0.79 mL, 6.8 mmol) is added followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (0.92 mL, 5.1 mmol). The cooling bath is removed, and the mixture is stirred at RT for 2.5 h. The reaction mixture is diluted with CH2Cl2 and washed with saturated NH4Cl solution. The organic layer is dried over Na2SO4 and evaporated in vacuo to afford the title compound as a brownish solid, which is used without further purification for the next steps. MS: 607.5 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 6.05 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=O)[CH2:3]1.CC([O-])=O.[Na+].BrBr.[NH2:18][C:19]([NH2:21])=[S:20]>CC(O)=O>[NH2:21][C:19]1[S:20][C:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]=2[N:18]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: NC(N)=S
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2sc(N)nc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
5,5-Dimethyl-cyclohexane-1,3-dione (201 g, 1.43 mol) and NaOAc (176 g, 2.14 mol) are suspended in AcOH (2 L) and Br2 (229 g, 1.43 mol) is added in dropwise while maintaining the reaction temperature between 15 and 20° C. After complete addition, the reaction is stirred at RT overnight. Thiourea (109 g, 1.43 mol) is added in portions and the reaction mixture is heated at 100° C. for 1 h. After cooling to RT, the AcOH is removed in vacuo and the resulting crude product is diluted with water (1 L) and neutralized with an aqueous saturated NaHCO3 solution. The resulting mixture is extracted with ethyl acetate (4×500 mL). The organic layer is washed with brine (500 mL), dried over anhydrous Na2SO4 and the solvent is evaporated in vacuo to give crude product. The crude product is washed with water (1.5 L) to yield 2-amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (211 g, 75% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[N:15]/[CH:12]2[CH2:14][CH2:13]2)=[CH:2]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: NC1CC1
Solvent: CCO
Product: C(=N/C1CC1)\c1c[nH]c2ncccc12
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a suspension of 1H-pyrrolo[2,3-b]pyridin-3-carbaldehyde (1.46 g) in ethanol (30 mL) was added cyclopropylamine (1.41 mL), and the mixture was stirred at 50° C. for 19 hours. The reaction solution was concentrated under reduced pressure, and then treated azeotropically with toluene. The resulting residue was triturated with isopropyl ether/n-hexane (3:1) to give N-[(1E)-1H-Pyrrolo[2,3-b]pyridin-3-ylmethylene]cyclopropylamine [REx(28-1)] (1.75 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:5]=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:5]=[C:24]1[S:20][C:21](=[O:26])[NH:22][C:23]1=[O:25]
Reactant: COc1ccc(Oc2c(Cl)cc(C=O)cc2Cl)cc1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1ccc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)cc1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a solution of the title compound of Step B (284 mg, 0.96 mmol) in toluene (16 ml) was added 2,4-thiazolidinedione (140 mg, 1.2 mmol), a catalytic amount of piperidinium acetate which was generated from piperidine (five drops) and acetic acid (five drops) and 4 Å molecular sieves. The mixture was stirred under reflux for about four hours, cooled to room temperature, filtered and concentrated. The product was purified by preparative TLC (4% methanol in dichloromethane) to afford the title compound (153 mg). MS (APCI−) Calc: 395.0, Found: 394.0 (M−1).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23](O)=[O:24])[CH:13]=2)[CH2:3][CH2:2]1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:23]([C:14]2[CH:13]=[C:12]([O:11][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[O:1][CH2:2][CH2:3]3)[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=2)=[O:24])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2cc(OC3CCOc4ccccc43)c3nc(C)n(C)c3c2)CC1
Yield: 38 %

Procedure:
The title compound was prepared as a white solid in 38% yield (35 mg) from 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2 in Example 11) and 1-acetylpiperazine (53 mg, 0.42 mmol) by the same manner in STEP 3 in Example 11: 1H NMR (CDCl3) δ: 7.31-7.23 (m, 2H), 7.21 (s, 1H), 6.89-6.77 (m, 3H), 6.50-6.00 (m, 1H), 4.50-4.40 (m, 1H), 4.27-4.32 (m, 1H), 3.75 (s, 3H), 3.80-3.36 (m, 8H), 2.64 (s, 3H), 2.40-2.19 (m, 2H), 2.13 (s, 3H) ppm;
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4CCNCC4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[N:23]1([C:29]([C@@H:31]2[CH2:36][CH2:35][C@H](O)[CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C@H:17]4[CH2:35][CH2:36][C@H:31]([C:29]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[O:30])[CH2:32][CH2:33]4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C([C@H]1CC[C@@H](O)CC1)N1CCOCC1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Product: O=C([C@H]1CC[C@H](Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1)N1CCOCC1

Procedure:
Example 287 (E287) was prepared from 3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and cis-4-(4-morpholinylcarbonyl)-cyclohexanol (D55) using the method described for Example 5a (E5a); MS (ES+) m/e 413 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccccc3C(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of methyl 4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylate (248) (0.108 g, 0.24 mmol) in a mixture of EtOH (6 mL) and THF (4 mL) was added an aqueous solution of 1N NaOH (10 mL). The mixture was stirred at 60° C. overnight. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Concentration gave a white residue, which was triturated with hot hexanes containing 1% MeOH to yield the title compound (249) as white solid (92.8 mg, 89%). mp 230-231° C. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (s, 6H), 0.89 (s, 6H), 1.25 (s, 2H), 1.91 (s, 4H), 6.67 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.34-7.44 (m, 2H), 7.50-7.55 (m, 1H), 7.65 (d, J=7.7 Hz, 1H), 9.27 (s, 1H), 12.72 (s, 1H). LCMS (ESI): m/z 441 (M+H)+, 439 (M−H)−.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[N:14]=[C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(O)C>C(Cl)Cl>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[N:14]=[C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cn3cccnc3n2)c2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: Oc1ccc(-c2cn3cccnc3n2)c2ccccc12
Temperature: -40 °C
Yield: 48 %

Procedure:
1.38 g (5 mmol) of 2-(1-methoxy-naphth-4-yl)-imidazo[1,2-a]pyrimidine are suspended in 50 ml of methylene chloride, cooled to -40° C. and 1.15 ml (12 mmol) of boron tribromide are added dropwise with stirring. The mixture is then stirred for 14 hours at ambient temperature, 30 ml of ethanol are added and the mixture is stirred for a further 30 minutes. It is then concentrated to dryness in vacuo and the crude product thus obtained in purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([C:13](=[O:51])[CH2:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18](=[O:32])[CH:17]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36](C(OC(C)(C)C)=O)[N:35]=4)[C:16]3=[O:50])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:52]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([CH2:33][CH:17]2[C:16](=[O:50])[N:15]([CH2:14][C:13]([N:12]3[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:52][C:7]=4[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:51])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]2=[O:32])=[N:35]1
Reactant: COc1ccc2c(c1)CCCCN2C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCCCN2C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 0.75 h
Yield: 29.8 %

Procedure:
A solution of tert-butyl 3-({1-[2-(7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) -2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}methyl) -1H-indazole-1-carboxylate (47 mg) in methylene chloride (10 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 45 minutes then concentrated to dryness. The residue was chromatographed on silica gel (Hexane:Ethyl Acetate) to yield a foamy oil. The foam was triturated with Ethyl Ether and filtered to yield the title compound as a white solid (12 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>>[ClH:25].[CH3:24][CH:22]([S:19]([C:16]1[S:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:18][CH:17]=1)(=[O:20])=[O:21])[CH3:23]
Reactant: CC(C)S(=O)(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Product: CC(C)S(=O)(=O)c1cnc(N2CCNCC2)s1
Yield: 97 %

Procedure:
Prepared in analogy to example 4 (d) from 4-[5-(propane-2-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and hydrogen chloride solution. The crude material was purified by recrystallisation from ether to afford the title compound as a white crystalline solid (yield 97%). MS (m/e): 276.4 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=[C:10]([C:19]2([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20]2)[O:11][Si](CC)(CC)CC)[CH2:4][CH2:3]1.[Br:27]Br>ClCCl>[Br:27][CH:9]([CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:26])([F:1])[CH2:3][CH2:4]1)[C:10]([C:19]1([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20]1)=[O:11]
Reactant: BrBr
Reactant: CC[Si](CC)(CC)OC(=CCC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Solvent: ClCCl
Product: O=C(C(Br)CC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
{3-(4,4-Difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)prop-1-enyloxy}triethylsilane (3.00 g, 7.53 mmol) obtained in step 4 was dissolved in dichloromethane (30 mL). Under ice-cooled condition, a dichloromethane solution (10 mL) of bromine (1.32 g, 8.28 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with hexane after adding a saturated sodium hydrogen carbonate aqueous solution, and a sodium thiosulfate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 2-bromo-3-(4,4-difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)propan-1-one (2.69 g, yield 98%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22](Br)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Br)c1
Reactant: OB(O)c1ccccc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(-c2ccccc2)c1
Yield: 76.2 %

Procedure:
Ethyl 1-benzyl-3-[(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (1.20 g), phenylboronic acid (0.37 g), tetrakis(triphenylphosphine)palladium (0.12 g), 2M aqueous sodium carbonate solution (3 mL), ethanol (5 mL) and toluene (20 mL) were stirred under an argon atmosphere while heating under reflux for 24 hrs. Ethyl acetate was added to the reaction mixture. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-phenylbenzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (0.91 g, 77%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(=O)OCC>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:16][CH2:17][N:12]([C:18]2[N:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:13][CH2:14]1
Reactant: ClCc1nc2cccnc2s1
Reactant: N#Cc1cccnc1N1CCNCC1
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 2-(1-piperazinyl)nicotinonitrile (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.75 (m, 4H) 3.68 (m, 4H) 4.07 (s, 2H) 6.94 (m, 1H) 7.56 (m, 1H) 8.08 (dd, J=7.80, 2.03 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H) 8.42 (dd, J=4.75, 1.70 Hz, 1H) 8.60 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 337 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[F:47][C:48]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:49]=1[O:50][CH:51]1[CH2:56][CH2:55][N:54]([C:57]2[N:58]=[C:59]3[CH2:70][CH2:69][NH:68][CH2:67][C:60]3=[N:61][C:62]=2[NH:63][CH:64]([CH3:66])[CH3:65])[CH2:53][CH2:52]1>CC(N(C)C)=O>[F:47][C:48]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:49]=1[O:50][CH:51]1[CH2:52][CH2:53][N:54]([C:57]2[N:58]=[C:59]3[CH2:70][CH2:69][N:68]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:67][C:60]3=[N:61][C:62]=2[NH:63][CH:64]([CH3:66])[CH3:65])[CH2:55][CH2:56]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)CC#N)C2
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-cyanoacetic acid (8.3 mg, 0.097 mmol) in DMA (0.3 mL) at room temperature was added DIPEA (33.9 μL, 0.194 mmol), followed by HATU (36.9 mg, 0.097 mmol). This mixture was stirred for 5 min, then was treated with a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (33.5 mg, 0.065 mmol) in DMA (0.35 mL). The reaction mixture was heated at 60° C. for 30 min. The reaction mixture was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (5.5 mg, 14%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.27 (m, 6H), 1.96 (m, 2H), 2.12 (m, 2H), 2.75 (t, J=5.9 Hz, 0.8H), 2.85 (m, 1.2H), 3.01 (m, 2H), 3.39 (m, 2H), 3.75 (t, J=5.8 Hz, 1.2H), 3.89 (t, J=5.9 Hz, 0.8H), 4.00 (m, 2H); 4.14 (m, 1H), 4.48 (m, 1H), 4.50 (s, 0.8H), 4.60 (s, 1.2H), 6.88 (m, 1H), 6.98 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 471.5.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)[C:10]([OH:12])=O)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].C(Cl)CCl.ON1C2N=CC=CC=2N=N1.[C:38]([NH:41][NH2:42])(=[O:40])[CH3:39]>CN(C=O)C>[C:38]([NH:41][NH:42][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=1)(=[O:40])[CH3:39]
Reactant: O=C(O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Reactant: CC(=O)NN
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A screw-cap vial was charged with 3-morpholino-5-nitrobenzoic acid (0.250 g, 0.991 mmol), sodium bicarbonate (0.250 g, 2.97 mmol), EDC (0.285 g, 1.487 mmol), 1-hydroxy-7-azabenzotriazole (0.202 g, 1.487 mmol), acetic hydrazide (0.088 g, 1.189 mmol), and DMF (2.0 mL). The orange solution was stirred at 23° C. for 18 h, then partitioned between EtOAc and water. The organic phase was washed with brine, dried over magnesium sulfate, and concd, affording N′-acetyl-3-morpholino-5-nitrobenzohydrazide as an orange oil. Mass Spectrum (ESI) m/e=309.2 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[C:16](C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=[CH:40][C:39]([C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[CH:38][CH:37]=1.C(OC(=O)C(NN1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)C>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[C:16]([C:44]1[O:43][C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:37][CH:38]=2)=[CH:46][CH:45]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(-c2ccc(-c3ccco3)cc2)cc1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: CCOC(=O)C(=O)NN1[C@@H](Cc2ccccc2)COC1(C)C
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 57 %

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)ethane-1,2-dione, 2-biphenyl-4-yl-furan was deprotonated and alkylated with N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-oxamic acid ethyl ester to give in 57% yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)ethane-1,2-dione as a pale yellow amorphous solid. 1H NMR: δ 7.91 (d, 2H, J=8.1 Hz), 7.69 (d, 2H, J=8.1 Hz), 7.64 (d, 2H, J=8.1 Hz), 7.49-7.36 (m, 4H), 7.25-7.10 (m, 5H), 6.85 (d, 1H, J=4.0 Hz), 4.624.57 (m, 1H), 3.91 (m, 2H), 3.00 (dd, 1H, J=5.0, 13.0 Hz), 3.82 (dd, 1H, J=10.1, 13.2 Hz), 1.86 (s, 3H), 1.68 (s, 3H). Anal. Calculated for C30H27NO4: C, 77.40; H, 5.85; N, 3.01. Found: C, 77.43; H, 5.88; N, 3.06.