Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][NH:9][C:10](=[O:59])[CH2:11][C@H:12]1[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH2:26][C@@H:27]([CH3:31])[CH2:28][O:29][CH3:30])=[CH:20][CH:19]=2)[C@@H:15]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][N:39]([CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]=3[CH:48]=2)[CH2:14][N:13]1[S:49]([C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:30][O:29][CH2:28][C@H:27]([CH3:31])[CH2:26][O:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:16]2[C@@H:15]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][CH2:40][N:39]([CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]=4[CH:48]=3)[CH2:14][N:13]([S:49]([C:52]3[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=3)(=[O:50])=[O:51])[C@@H:12]([CH2:11][C:10]([NH:9][NH2:8])=[O:59])[CH2:17]2)=[CH:23][CH:22]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)NNC(=O)OC(C)(C)C)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)NN)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1 mmol of N′-{2-[(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetyl}-hydrazinecarboxylic acid tert-butyl ester in 13 ml of CH2Cl2 is treated at 0° C. with 3.3 ml of trifluoroacetic acid. The reaction mixture is stirred at 0° C. for 1 h, then at RT for 3 h and diluted with CH2Cl2, basified with saturated aqueous NaHCO3. The aqueous layer is extracted with CH2Cl2 (2×), the combined organic extracts are washed with H2O, then with brine, dried over Na2SO4, and concentrated under reduced pressure, affording the title compound as an orange oil. Rf=0.45 (CH2Cl2/MeOH/25% conc. NH3 200:20:1); Rt=4.57 (gradient I).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[N:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36](=[O:38])[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[N:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36]6([CH2:8][O:38]6)[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4nc3CCCC2C1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1ccc(-n2ncc3cc4c(nc32)CCCC2CC3(CCC42Cc2ccccn2)CO3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
Sodium hydride (60 wt % in oil, 0.454 g, 11.35 mmol) and DMSO (25 mL) were heated to about 65° C. for about 30 min then cooled to rt. THF (50 mL) was added then the mixture was cooled to about 0° C. Trimethylsulfoxonium iodide (2.56 g, 11.63 mmol) was added then after about 30 min rac-(4aR,12bR)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3 (2H)-one (118, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (2.5 g, 5.68 mmol) was added. The mixture was allowed to warm to rt and stir for about 12 h. The mixture was concentrated under reduced pressure then the material was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (25 mL) then the organic solutions were combined and washed with water (75 mL) then brine (30 mL), dried over MgSO4 then filtered. The filtrate was concentrated under reduced pressure and the material was purified on silica gel (120 g) using a gradient from 0-10% MeOH in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(2′R,4aS,12bS)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine-3,2′-oxirane] (119, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (1.865 g, 72.3%); LC/MS, method 3, Rt=2.65 min, MS m/z 455 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.42-8.34 (m, 2H), 8.32-8.28 (m, 1H), 8.20 (s, 1H), 7.75-7.72 (m, 1H), 7.49-7.37 (m, 3H), 7.06 (ddd, J=5.2, 4.5, 0.9 Hz, 1H), 6.72-6.67 (m, 1H), 3.73 (d, J=12.8 Hz, 1H), 3.59-3.47 (m, 1H), 3.42-3.33 (m, 1H), 3.02 (d, J=12.9 Hz, 1H), 2.70-2.56 (m, 1H), 2.44-2.34 (m, 2H), 2.13-2.00 (m, 1H), 1.96-1.81 (m, 2H), 1.79-1.58 (m, 3H), 1.35-1.21 (m, 3H), 1.21-1.10 (m, 1H).
Reaction SMILES: C(OC(=O)C(OC1C=C(O)C=CC=1CCCC)(C)C)C.C(=O)([O-])[O-].[K+].[K+].C([O:29][C:30](=[O:66])[C:31]([O:34][C:35]1[CH:40]=[C:39]([O:41][CH2:42][CH2:43][C:44]2[N:45]=[C:46]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:52][CH:51]=3)[O:47][C:48]=2[CH3:49])[CH:38]=[CH:37][C:36]=1[CH2:62][CH2:63][CH2:64][CH3:65])([CH3:33])[CH3:32])C.[OH-].[Na+]>C(O)C>[C:53]1([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:52]=[CH:51][C:50]([C:46]2[O:47][C:48]([CH3:49])=[C:44]([CH2:43][CH2:42][O:41][C:39]3[CH:38]=[CH:37][C:36]([CH2:62][CH2:63][CH2:64][CH3:65])=[C:35]([CH:40]=3)[O:34][C:31]([CH3:32])([CH3:33])[C:30]([OH:66])=[O:29])[N:45]=2)=[CH:55][CH:54]=1
Reactant: CCCCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1OC(C)(C)C(=O)OCC
Agent: CCCCc1ccc(O)cc1OC(C)(C)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1OC(C)(C)C(=O)O
Temperature: 55 °C

Procedure:
The following example exemplifies the general procedure for the parallel synthesis of analogs utilizing the DynaVac carousel. To a 50 mL glass tube with screw cap and nitrogen inlet were charged 2-(2-butyl-5-hydroxyphenoxy)-2-methylpropionic acid ethyl ester, (0.050 g, 0.178 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-bipheny-4-yl-loxazol-4-yl)ethyl ester (0.187 mmol) (see Ex. 1, part F), and powdered potassium carbonate (0.050 g, 0.36 mmol) in 1 mL of absolute ethanol. The mixture was heated to reflux for 18 h. MS analysis of the reaction indicated that 2-{5-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-butylphenoxy}-2-methylpropionic acid ethyl ester, MS (ES) m/e 542 (M+1). had formed. Next 0.4 mL of 5 N sodium hydoxide was added and the reaction was heated for 3 h at 55° C. The ethanol was removed in vacuo and the residue was treated with 1 mL of 5N hydrochloric acid and 1 mL of dichloromethane and poured into a 3 mL ChemElute column to remove the aqueous layer. The column was eluted with additional dichloromethane until nothing UV active remained on the column. The solvent was removed in vacuo. The crude residue was purified by mass-directed reverse phase HPLC to provide 2-{5-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-butylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ8.06 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.47 (t, J=7.6 Hz, 2H), 7.39 (t, J=7.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.53 (dd, J=8.3, 2.4 Hz, 1H), 4.20 (t, J=7.6 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H), 2.38 (s, 3H), 1.64 (s, 6H), 1.55 (quintet, J=7.7 Hz, 2H), 1.35 (sextet, J=7.5 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H), MS (ES) m/e 514 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH:30][CH3:31])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25].N1C=CC=CC=1.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:29]=[C:28]([N:30]([CH3:31])[C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)C(C)(C)C)cc3Cl)c2n1
Reaction time: 48 h
Yield: 89.6 %

Procedure:
To a suspension of 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (188 mg) in dichloromethane (1.9 ml) were added pyridine (58 mg) and pivaloyl chloride (65 mg) at room temperature and the mixture was stirred for 2 days. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and ethanol was added to the residue to give crude crystals. Ethanol was evaporated, and the residue was recrystallized from acetone-water to give 3-(2-chloro-4-(methyl(pivaloyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (199 mg) as a white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[O:12][C:13]3[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17]([C:23]#[N:24])=[CH:16][C:14]=3[N:15]=2)=[N:9][CH:10]=1)=[O:4].[OH-].[Li+]>O1CCCC1>[C:23]([C:17]1[CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[C:13]2[O:12][C:11]([C:8]3[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=3)=[N:15][C:14]=2[CH:16]=1)#[N:24]
Reactant: COC(=O)c1cnc(-c2nc3cc(C#N)cc(C(C)C)c3o2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ncc(C(=O)O)cn3)oc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a solution of methyl-2-(5-cyano-7-isopropyl-1,3-benzoxazol-2yl)pyrimidine-5-carboxylate (429 mg, 1.332 mmol) in tetrahydrofuran (30 ml) was added 1N lithium hydroxide (1.466 ml) dropwise at 60° C. The reaction mixture was stirred at room temperature for 4 h, and then the solution was concentrated and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified with 1N HCl to pH=4˜5. The white solid was filtered and dissolved in a mixture of dichloromethane and methanol (9:1). This solution was dried over magnesium sulfate and then concentrated to provide the title compound (74 mg) as a yellow solid. Mass spectrum (ESI) 308.8 (M+1). 1H NMR (500 MHz, DMSO) δ 9.45 (s, 2H), 8.42 (s, 1H), 7.92 (s, 1H), 3.20˜3.60 (m, 1H, overlapped with H2O peak), 1.41 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]#[CH:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:22]([C@H:25]1[C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][C:29]=2[CH2:28][CH2:27][CH2:26]1)[CH2:36][N:35]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH2:34][CH2:33]3)=[N+:23]=[N-:24].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O1CCOCC1.CC(O)(C)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:24]=[N:23][N:22]([C@H:25]3[C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][C:29]=4[CH2:28][CH2:27][CH2:26]3)[CH2:36][N:35]([C:39](=[O:44])[C:40]([F:41])([F:43])[F:42])[CH2:34][CH2:33]5)[CH:21]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc3c(cc21)CCN(C(=O)C(F)(F)F)C3
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: O
Product: O=C1NC=CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)[C@@H]1Cc1cn([C@@H]2CCCc3cc4c(cc32)CCN(C(=O)C(F)(F)F)C4)nn1
Temperature: 25 °C

Procedure:
To a solution of (R)-4-(3,4-dichlorophenylsulfonyl)-3-(prop-2-ynyl)-3,4-dihydropyrazin-2(1H)-one (345 mg, 1 mmol) and (R)-1-(6-azido-3,4,6,7,8,9-hexahydrobenzo[g]isoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (324 mg, 1 mmol) in dioxane (3 mL) and t-BuOH (4 mL) was added a solution of copper(2+) sulfate, pentahydrate (249 mg, 1 mmol) in water (0.5 mL), followed by a solution of (+)-sodium l-ascorbate (198 mg, 1 mmol) in water (0.5 mL). The resulting solution was stirred at room temperature for 16.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9]([NH:12][C@H:13]([C:21](O)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:11])[CH3:10].CN1CCOCC1>ClCCl>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:21](=[O:22])[C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:12][C:9](=[O:11])[CH3:10]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: -10 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
0.1 g of L-alanine methyl ester hydrochloride (0.7 mmol), 0.2 g of N-acetyl-L-phenylalanine (1 mmol) and 0.55 ml of N-methylmorpholine (5 mmol) are dissolved in 50 ml of dichloromethane and cooled to −10° C. 0.5 g of CPA from example 1 (50% in CH2Cl2; 0.8 mmol) is added slowly, and the mixture is stirred under cold conditions for 3 h and at room temperature for 72 h. The solution is concentrated by evaporation and extracted with ethyl acetate and 1N HCl solution, sat. NaHCO3, sat. NaCl and dist. water. The organic phase is dried over magnesium sulfate, filtered off and concentrated by evaporation. 0.18 g of the white N-acetyl-L-phenylalaninyl L-alanine methyl ester is obtained (88%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:12]2[O:13][CH2:14][C:15]3[S:19][C:18]([SH:20])=[N:17][C:16]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)C.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:30][S:20][C:18]2[S:19][C:15]3[CH2:14][O:13][C:12]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])=[CH:8][CH:9]=[CH:10][C:11]=4[C:16]=3[N:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1OCc1sc(S)nc1-2
Reactant: ICCC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1OCc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 45 %

Procedure:
Using ethyl[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 45%.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:12][C:13]1[CH:18]=[C:17]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]2[CH3:25])[CH:16]=[CH:15][C:14]=1[NH2:26])[CH2:6][C:7]([O:9][CH2:10]C)=[O:8])=O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:26][C:14]1[CH:15]=[CH:16][C:17]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]2[CH3:25])=[CH:18][C:13]=1[CH2:12][NH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(=O)CN(Cc1cc(-n2cc(C)nc2C)ccc1N)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CNCc1cc(-n2cc(C)nc2C)ccc1N
Yield: 40.5 %

Procedure:
A mixture of ethyl N-trifluoroacetyl-N-(2-amino-5-[2,4-dimethylimidazol-1-yl]benzyl)glycinate (1.4 g) and anhydrous sodium carbonate (0.74 g) in methanol (20 cm3) was heated under reflux for 3 hours. The cooled solution was evaporaed to dryness in vacuo and the residue was partitioned between chloroform (50 cm3) and water (10 cm3). The aqueous phase was re-extracted with chloroform (2×25 cm3) and the combined and dried (MgSO4) organic extracts were evaporated to give an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade mark]), eluting with ethyl acetate:methanol, 9:1. Combination and evaporation of the appropriate fractions afforded the title compound as an oil (0.41 g), used directly.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc2c(Cl)cccc2c1-c1ccc(O)cc1
Yield: 56.8 %

Procedure:
Prepared according to Method D step C from 7-chloro-3-(4-methoxyphenyl)-2-propyl-2H-indazole (0.013 g, 0.043 mmol), boron tribromide (0.05 mL, 0.5 mmol) and 0.2 mL of cyclohexene to give the product (0.007 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N+:13]([O-])=O)=[CH:5][CH:4]=1.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>>[NH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:2][P:19](=[O:23])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17])=[CH:4][CH:5]=1
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)c2ccccc12
Product: CCOP(=O)(Cc1ccc(N)c2ccccc12)OCC

Procedure:
1-Bromomethyl-4-nitronaphthalene and triethylphosphite ((C2H5 O)3P) were treated in the same manner as in Reference Example 43 to yield diethyl (4-amino-1-naphthyl)methylphosphonate, which was then recrystallized from ethyl acetate-hexane to yield yellow prisms having a melting point of 73°-74° C.
Reaction SMILES: C(O)C.[N:4]1([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=O)[CH2:14][CH2:13]3)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Cl-].[OH:21][NH3+:22].C(N(CC)CC)C>C(OCC)(=O)C.O>[N:4]1([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[N:22][OH:21])[CH2:14][CH2:13]3)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: [NH3+]O
Reactant: O=C1CCc2cc(N3CCOCC3)ccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: ON=C1CCc2cc(N3CCOCC3)ccc21
Yield: 96.9 %

Procedure:
An ethanol (5.0 mL) solution of 5-morpholin-4-yl-indan-1-one (2.20 g), hydroxyl ammonium chloride (1.05 g) and the triethylamine (4.22 mL) was refluxed for 3 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed with a saturated sodium chloride solution, and 2.28 g of the title compound was obtained by condensing under reduce pressure after drying over anhydrous magnesium sulfate. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12]4[CH:24]=[CH:23][CH:22]=[N:21][C:13]=4[NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:10]3=[N:9][C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([NH:35]C(=O)OC(C)(C)C)[CH2:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:43]>ClCCl.O1CCOCC1.CCOCC>[ClH:43].[C:1]1([C:7]2[N:11]3[C:12]4[CH:24]=[CH:23][CH:22]=[N:21][C:13]=4[NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:10]3=[N:9][C:8]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]3([NH2:35])[CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4n(c3-c3ccccc3)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4n(c3-c3ccccc3)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (1-(4-(3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.028 g) in dichloromethane (5 mL) was added 4.0 M HCl in dioxane (0.5 mL). The reaction was stirred at room temperature for 6 hours and then diluted with ether (20 mL). The product was removed by filtration under reduced pressure and dried to give 1-(4-(3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutanamine hydrochloride as a white solid (0.022 g, 77% based on tris HCl salt). M.p.: 252-258° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.78 (br. s, 3 H), 8.73 (br. s, 1H), 8.11 (dd, JA=4.8 Hz, JB=1.2 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.47-7.38 (m, 4H), 7.32 (d, J=8.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.77 (dd, JA=7.6 Hz, JB=4.8 Hz, 1H), 2.60-2.52 (m, 4H), 2.24-2.13 (m, 1H), 1.85-1.72 (m, 1H); LCMS: 456 [M+H]; Calc. for C30H25N5.3.86HCl.0.48 diethylether: C, 60.68; H, 5.37; N, 11.08. Found C, 60.68; H, 5.52; N 11.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[F:21][C:22]([F:27])([F:26])[CH2:23][CH2:24]I>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:24][CH2:23][C:22]([F:27])([F:26])[F:21])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: FC(F)(F)CCI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(CCC(F)(F)F)c3c(Cl)cccc23)cc1
Yield: 5.6 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.108 g, 0.4 mmol), sodium hydride (60% in oil, 0.016 g, 0.4 mmol) and 3,3,3-trifluoropropyliodide (0.047 mL, 0.4 mmol) to give the title compound (0.008 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]([OH:15])=[O:14])[O:11][C:10](=[O:16])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[CH3:19][Si](C=[N+]=[N-])(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]([O:15][CH3:19])=[O:14])[O:11][C:10](=[O:16])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](c2cccc(Br)c2)[C@@H](C(=O)O)O1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H]1OC(=O)N[C@@H]1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of (4R,5S)-4-(3-bromophenyl)-2-oxooxazolidine-5-carboxylic acid (20 mg, 0.070 mmol) in tetrahydrofuran (2 mL)/methanol (0.500 mL) was added trimethylsilyldiazomethane (0.063 mL, 0.126 mmol) dropwise at 0° C. After 3 h, the reaction was allowed to warm to ambient temperature and stirred for an additional 15 h, at which time it was concentrated in vacuo to provide (4R,5S)-methyl 4-(3-bromophenyl)-2-oxooxazolidine-5-carboxylate (18.2 mg, 0.058 mmol, 82% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78 (s, 3H) 4.98 (d, J=4.88 Hz, 1H) 5.01-5.04 (m, 1H) 7.37-7.45 (m, 2H) 7.56 (s, 1H) 7.57-7.61 (m, 1H) 8.60 (s, 1H). Mass spec.: 301.77 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O(C(C)(C)C)[K]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][N:13]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Clc1ccc(OCc2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OCc3ccccc3)cn2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 86.6 %

Procedure:
A stirred suspension of 5-benzyloxy-2-chloro-pyridine (12.4 g, 56.4 mmol, 1.0 equiv; prepared as described in WO 9728 128 A1 (Zeneca Ltd., UK)), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (11.31 g, 56.4 mmol, 1.0 equiv), palladium(II) acetate (0.51 g, 2.3 mmol, 0.04 equiv) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (1.44 g, 2.3 mmol, 0.04 equiv) in toluene (250 mL) was treated at rt with KOtert-Bu (6.71 g, 67.7 mmol, 1.2 equiv) and subsequently warmed to 70° C. After 7 h, the reaction mixture was poured into crashed ice and filtered over dicalite and extracted twice with toluene. The combined organic layers were dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 18.73 g (87%) of the title compound as a light yellow solid. MS (ISP): 384.1 [M+H]+.