Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.[Cl-].[NH4+].[N-:12]=[N+:13]=[N-:14].[Na+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:12]=[N:13][NH:14][N:9]=2)[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cncc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1cncc(-c2nn[nH]n2)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To the solution of 5-bromo-3-cyanopyridine (3.0 g, 15.9 mmol, 1 eq) in anhydrous dimethylformamide (40 mL) was added ammonium chloride (1.45 g, 1.7 eq) and sodium azide (1.76 g, 1.7 eq). The resulting reaction mixture was heated at 100° C. under nitrogen for 20 hours. After the reaction mixture was cooled to room temperature, it was poured into ice-water and the pH of the mixture was adjusted to ˜3.5 using aqueous hydrochloric acid (2 N). The aqueous was first extracted with ethyl acetate three times, followed by an extraction with i-PrOH—CHCl3 (1:4). All organics were combined and dried with anhydrous sodium sulfate. The upper clear liquor was decanted, concentrated under reduced pressure, and the resulting oily residue was placed under high vacuum for 20 hours. Upon treatment with EtOAc-Hex (1:1) and filtration, 3-bromo-5-(2H-tetrazol-5-yl)pyridine was obtained as a white solid in the amount of 3.241 g.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:13]=3)=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30](OC(OCC)OCC)[CH3:31]>>[CH2:20]([N:19]1[C:14]2[CH:13]=[C:12]([C:11]3[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=[N:9][C:10]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:17]=[CH:16][C:15]=2[N:18]=[C:30]1[CH3:31])[CH:21]([CH3:23])[CH3:22]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)CNc1cc(-c2c(-c3ccccc3)ncn2C2CCCCC2)ccc1N
Product: Cc1nc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc2n1CC(C)C
Temperature: 25 °C
Yield: 45 %

Procedure:
Heat a mixture of 1-(cyclohexyl)-4-phenyl-5-(3-(isobutylamino)-4-aminophenyl)-1H-imidazole (103 mg, 0.26 mmol) and 3 mL triethylorthoformate at 120° C. for 3 hours. Cool to room temperature and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 2:1 ethyl acetate:hexanes to provide the title compound (45%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][CH:29]([CH3:33])[C:30](Cl)=[O:31]>ClCCl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:30](=[O:31])[CH:29]([CH3:33])[CH3:28])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) and pyridine (0.09 ml) in dichloromethane (3 ml) was added 2-methylpropanoyl chloride (0.1 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, and washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate), and the obtained product was washed with diisopropyl ether to give the title compound as a pale-yellow powder (0.21 g, 60%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:29])=[C:5]([F:30])[CH:4]=1)#[N:2].O=C1C=C(OC2CCN(C(OC(C)(C)C)=O)CC2)C=CN1C1C=NC=CC=1.ClC1[N:64]=[CH:63][C:62]([CH2:65][CH2:66][CH3:67])=[CH:61][N:60]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:65]1([C:62]2[CH:61]=[N:60][C:22]([N:19]3[CH2:18][CH2:17][CH:16]([O:15][C:12]4[CH:13]=[CH:14][N:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[F:30])[C:10](=[O:29])[CH:11]=4)[CH2:21][CH2:20]3)=[N:64][CH:63]=2)[CH2:67][CH2:66]1
Reactant: CCCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(C#N)cc3F)c(=O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3cccnc3)c(=O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#Cc1ccc(-n2ccc(OC3CCN(c4ncc(C5CC5)cn4)CC3)cc2=O)c(F)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Example 190 was prepared according to procedures described in Example 132 substituting tert-butyl 4-(1-(4-cyano-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (Example 176) for tert-butyl 4-(2-oxo-1-(pyridin-3-yl)-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step C and substituting 2-chloro-5-cyclopropylpyrimidine (prepared according to the procedure described in Step A of Example 159) for 2-chloro-5-propylpyrimidine and substituting potassium carbonate for cesium carbonate in Step D except that reaction was stirred at 100° C. for 7 h. The crude solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2). 1H NMR (500 MHz, CDCl3) δ ppm 8.14 (s, 2 H), 7.51-7.62 (m, 3 H), 7.11 (d, J=7.70 Hz, 1 H), 6.06 (dd, J=7.70, 2.75 Hz, 1 H), 6.01 (d, J=2.75 Hz, 1H), 4.52-4.62 (m, 1 H), 4.15-4.26 (m, 2 H), 3.58-3.68 (m, 2 H), 1.96-2.14 (m, 2 H), 1.79-1.96 (m, 2 H), 1.69-1.77 (m, 1 H), 0.88-0.96 (m, 2 H), 0.57-0.64 (m, 2 H). MS (ESI) 432 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][CH:17]([O:19][CH2:20][CH3:21])[CH3:18])=O)[CH:3]=1.CO.Cl.[CH3:25][O:26][NH2:27].C[O-].[Na+].CO>[Cl-].[Na+].O>[CH3:25][O:26][N:27]=[C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][CH:17]([O:19][CH2:20][CH3:21])[CH3:18]
Reactant: CON
Reactant: CCOC(C)OCc1ccccc1C(=O)c1cc(C)on1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CCOC(C)OCc1ccccc1C(=NOC)c1cc(C)on1
Yield: 90.5 %

Procedure:
2-(1-Ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone (4.34 g, 0.015 mol) was added to a mixture of methanol (30 ml), methoxyamine hydrochloride (2.51 g, 0.03 mol) and 28% sodium methylate/methanol solution (7.23 g, 0.0375 mol), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, half-saturated brine (200 ml) was added, and the mixture was extracted with dichloromethane (100 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (4.32 g, yield: 90.5%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[C:21]([C:23]([OH:27])([C:25]#[CH:26])[CH3:24])[CH:20]=[N:19]1>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:26]#[C:25][C:23]([C:21]4[CH:22]=[N:18][NH:19][CH:20]=4)([OH:27])[CH3:24])[CH:10]=3)[CH:6]=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1cn[nH]c1
Reactant: Nc1nccc(-n2ncc3ccc(Br)cc32)n1
Product: CC(O)(C#Cc1ccc2cnn(-c3ccnc(N)n3)c2c1)c1cn[nH]c1
Reaction time: 1 h

Procedure:
The title compound was prepared by the procedure described in Example 2 (Step 2-b) by reacting 4-(6-bromo-1H-indazol-1-yl)pyrimidin-2-amine with 2-(1H-pyrazol-4-yl)but-3-yn-2-ol. The reaction was carried out at 75° C. for 1 hr: 1H NMR (500 MHz, DMSO) delta 1.81 (3H, s), 5.95 (1 H, br. s.), 6.93-7.17 (3H, m), 7.38 (1H, d, J=9.30 Hz), 7.70 (2H, br. s.), 7.88 (1H, d, J=8.35 Hz), 8.31 (1H, d, J=5.52 Hz), 8.49 (1H, s), 8.91 (1H, s), 12.71 (1H, br. s.); LC-MS: m/z=+346.50 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][N:21]=2)(=[O:19])=[O:18])[C:3]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37].O.[NH2:39][NH2:40].C(O)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH:39][NH2:40])=[NH:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][N:21]=2)(=[O:19])=[O:18])[C:3]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37]
Reactant: NN
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C(=N)NN)c2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Temperature: 15 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
122 g (233 mmol) of 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-(2-cyano-pyridine-4-yl)-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide was suspended in 450 ml of N,N-dimethyl formamide and the mixture was cooled down to 15° C. At this temperature, 35 ml of hydrazine hydrate were added dropwise within 1 hr. The resulting solution was stirred at 15° C. to 20° C. for 16 hr and thereafter diluted with 600 ml of de-ionized water. Then 50 ml of glacial acetic acid were added dropwise at 0° C. to 5° C. until pH=5.5. 600 g of ice were added and the suspension was stirred for 1 hr. The solid was filtered off under suction, washed with 3000 ml of water and dried at 40° C., 2000 Pa for 24 hr. There were obtained 126 g (97% of theory) of 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-[2-(hydrazino-imino-methyl)-pyridine-4-yl]-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide with a HPLC purity of 91.8% (w/w).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:19][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Reactant: F[B-](F)(F)F
Agent: *CC(*)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])cc1-c1c(F)cnn1C
Temperature: 80 °C
Yield: 33.3 %

Procedure:
5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (300.0 mg, 1.29 mmol) was dissolved in ACN (15 ml) in a polypropylene 20 mL scintillation vial. To this solution, Selectfluor (913.9 mg, 2.58 mmol) was added and the mixture was degassed with argon and heated to 80° C. for 6 hours. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL EtOAc and 30 mL 3N HCl. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was then purified by flash chromatography (Biotage SiO2, Hexanes (0.01% TEA)/EtOAc gradient elution) to afford 108 mg (33%) of 4-fluoro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole as a white solid. LCMS m/z (%)=252 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J=9.2 Hz, 1H), 8.22 (s, 1H), 7.44 (d, JH,F=4.4 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H) 3.98 (s, 3H), 3.77 (s, 3H). 19F NMR (376 MHz, CDCl3) δ: −175.50 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[NH:36]1[C:32]([C:31]2[CH:30]=[CH:29][C:28]([C:13]3[N:9]4[N:10]=[CH:11][CH:12]=[C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:8]4=[N:15][C:14]=3/[CH:16]=[CH:17]/[C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:35][CH:34]=2)=[N:33][N:38]=[N:37]1
Reactant: N#Cc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C(=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(-c2nnn[nH]2)cc1)\c1ccc2ccccc2n1
Temperature: 130 °C

Procedure:
A mixture of compound 13a (95 mg, 0.21 mmol), sodium azide (20 mg, 0.31 mmol) and ammonium chloride (16 mg, 0.31 mmol) in DMF (3 mL) was heated at 130° C. overnight. The reaction mixture was cooled to rt and water (20 mL) was added. The mixture was extracted with DCM/MeOH (9:1 v/v, 2×100 mL). The combined organic layers were washed with brine, and dried over Na2SO4. The mixture was filtered and concentrated to obtain a residue, which was washed with MeOH (2×2 mL). The resulting solid was purified by flash column chromatography on silica gel (0-20% MeOH/DCM) to give compound 13b as an orange solid. 1H-NMR (400 MHz, CDCl3+CD3OD) δ (ppm): 8.27 (d, J=8.3 Hz, 2H), 8.09-8.14 (m, 1H), 8.02-8.07 (m, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.84-7.92 (m, 3H), 7.73-7.80 (m, 2H), 7.65-7.72 (m, 2H), 7.46-7.53 (m, 1H), 6.12 (d, J=5.6 Hz, 1H), 4.04-4.11 (m, 4H), 3.96-4.02 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H23N9O: 502.2 (M+H). Found 502.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:39])[CH2:12][CH2:13][CH2:14][C:15]([NH:17][CH2:18][C:19]2[C:20]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:21]3[CH:29]=[N:28][N:27]([CH2:30][CH3:31])[C:22]3=[N:23][C:24]=2[CH2:25][CH3:26])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8].[CH:40]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)=[O:41].C([O-])([O-])=O.[Na+].[Na+].N#N>O1CCOCC1.O.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.O>[CH2:30]([N:27]1[C:22]2=[N:23][C:24]([CH2:25][CH3:26])=[C:19]([CH2:18][NH:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]([NH:10][CH2:9][C:4]3[CH:3]=[C:2]([C:46]4[CH:45]=[CH:44][CH:43]=[C:42]([CH:40]=[O:41])[CH:47]=4)[C:7]([F:8])=[CH:6][CH:5]=3)=[O:39])[C:20]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:21]2[CH:29]=[N:28]1)[CH3:31]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1ccc(F)c(-c2cccc(C=O)c2)c1
Yield: 137.8 %

Procedure:
A mixture of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}pentanediamide (0.92 g, 1.5 mmol), (3-formylphenyl)boronic acid (292.5 mg crude, 1.95 mmol), Na2CO3 (477 mg, 4.5 mmol) in dioxane/water (3:1, 16 mL) was swept with N2 for about 5 min before Pd(PPh3)4 (87 mg, 0.075 mmol) was added. The tube was sealed and irradiated with a microwave reactor for 30 min at 150° C. The same reaction was then repeated at the same scale. The combined mixture was mixed with water (50 mL), washed with EtOAc/Diethyl Ether (1:1, 50 mL, 2×). Purification via a CombiFlash system (EtAc/MeOH/DCM) then provided the desired product (1.3 g in total from two trials). LC-MS m/z 630 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]3[CH2:12][CH2:11][CH2:10][C:9](=O)[C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[C:1]1([CH:7]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC2=C1C(c1ccccc1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1CCCC2=C1C(c1ccccc1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 9-phenyl-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g), sodium borohydride (6.5 g), ethanol (150 mL) and pyridine (50 mL) was heated at 70° C. overnight and cooled to room temperature. The solvent was removed, the residue partitioned between water and ethyl acetate, the organic layer was dried and the solvent removed. Chromatography (methylene chloride/methanol; 98/2) provided the title compound (3.0g) as a white solid. Recrystallization from ethanol/hexane returned analytically pure title compound, mp 252°-254° C., NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.03-2.13 (m,4, CH2), 2.38-2.44 (m,2, CH2), 4.14 (s,1, CH), 7.04-7.21 (m,5, Ar) 8.34 (s,1, NH); (CI, CH4) MS: m/z=280(M+1). Analysis for C19H21NO.0.2H2O: Calculated: C, 80.64; H, 7.62; N, 4.95; Found: C, 80.84; H, 7.62; N, 4.80.
Reaction SMILES: [Na].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9](O)=[C:8](CC(C)C)[C:7]=1[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:3](C)[CH3:4].[CH2:21]1[O:23][CH2:22]1.[O-]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].C([O:40][CH2:41][CH3:42])(=O)C=C.C([O-])(=O)C(CC([O-])=O)=C.[Na+].[Na+].OCNC(=O)C(C)=C.C(N)(=O)C(C)=C>O>[CH2:11]([C:6]1[CH:2]=[CH:3][CH:4]=[CH:22][C:21]=1[OH:23])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:17][CH:18]([CH3:19])[CH3:20].[CH2:41]1[O:40][CH2:42]1
Reactant: C=CC(=O)OCC
Reactant: CC(C)Cc1ccc(O)c(CC(C)C)c1CC(C)C
Agent: C=C(C)C(=O)NCO
Agent: C=C(C)C(N)=O
Agent: C=C(CC(=O)[O-])C(=O)[O-]
Solvent: O
Solvent: C1CO1
Product: CC(C)CCCCCCc1ccccc1O

Procedure:
0.2 part by weight of the sodium salt of a sulfated addition product of triisobutylphenol and 7 mols of ethylene oxide (emulsifier A) and 0.02 part by weight of potassium peroxodisulfate are dissolved in 61.5 parts by weight of completely desalted water at 80° C. in a polymerization vessel provided with a reflux condenser, stirrer, thermometer, and feed vessel. An emulsion, earlier prepared from 83 parts by weight of ethyl acrylate, 10 parts by weight of methoxy polyethyleneglycol methacrylate [formula (I), n=15], 5 parts by weight of disodium itaconate, 1.2 parts by weight of N-hydroxymethyl methacrylamide, 0.8 part by weight of methacrylamide, 2.3 parts by weight of emulsifier A, 1 part by weight of the addition product formed between isononylphenol and 100 mols of ethylene oxide (emulsifier B), 0.18 part by weight of potassium peroxodisulfate, and 94 parts by weight of desalted water, is added dropwise to this solution at 80° C. over a period of 4 hours. After addition is complete, the reaction temperature is kept for one further hour at 80° C. and subsequently the mixture is cooled to room temperature. A coagulate-free dispersion having a solids content of about 40% is obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]2[CH:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][CH:17]([OH:18])[CH:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][CH:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1CCC2OC2CN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCC(N=[N+]=[N-])C(O)CN1C(=O)OCc1ccccc1
Yield: 80.1 %

Procedure:
Sodium azide (0.56 g, 8.62 mmol) was added to a solution of racemic (1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.75 g, 2.87 mmol) and ammonium chloride (0.46 g, 8.62 mmol) in MeOH (5 ml) and H2O (0.5 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexanes) to yield the title compound (0.7 g, 80%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m, 2H), 3.10 (1H, d), 1.85-1.53 (m, 4H), 1.09 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=305.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19](OC)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([Mg]Br)[CH3:33].CCOCC.C(=O)(O)[O-].[Na+]>C1COCC1.CC(=O)OCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:18]([N:13]2[C:14]3[C:10](=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)([C:19]2([OH:20])[CH2:33][CH2:32]2)[CH2:23][CH3:24])=[CH:26][CH:27]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NC(=O)OC(C)(C)C)cccc21)C1(O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-{4-[(tert-butoxycarbonyl)amino]-1H-indol-1-yl}-2-(4-chlorophenyl)butanoate (0.44 g, 1 mmol), as described in Example 3 step A, in THF (20 mL) was added titanium (IV) isopropoxide (0.3 g, 1 mmol) and the solution was cooled to 0° C. Ethylmagnesium bromide 3 N in ether (1.8 mL, 5 mmol) was then added via syringe pump over 1 hr period and the reaction was stirred for an additional 30 min at this temperature. The mixture was warmed into RT and stirred over night. The final mixture was diluted with EA, treated with saturated sodium bicarbonate solution, extracted with EA and DCM, dried over sodium sulfate and concentrated. The residue was purified by flash-chromatography over silica gel (eluted with hexanes/EA 95:5 to EA) to give the title compound. LC/MS m/z=441.0[M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[F:59][C:60]([F:72])([F:71])[CH:61]([OH:70])[CH2:62][CH2:63][C@@H:64]([C:66]([O:68][CH3:69])=[O:67])[NH2:65].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[F:59][C:60]([F:71])([F:72])[CH:61]([OH:70])[CH2:62][CH2:63][C@@H:64]([C:66]([O:68][CH3:69])=[O:67])[NH:65][C:22]([C:18]1[N:13]2[CH:14]=[C:15]([CH3:17])[CH:16]=[C:11]([O:10][CH2:9][C:4]3[C:3]([F:2])=[CH:8][CH:7]=[CH:6][N:5]=3)[C:12]2=[N:20][C:19]=1[CH3:21])=[O:23]
Reactant: COC(=O)[C@@H](N)CCC(O)C(F)(F)F
Reactant: Cc1cc(OCc2ncccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCC(O)C(F)(F)F)NC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(C)cn12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
250 mg (0.71 mmol) of 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid hydrochloride from Example 121A, 299 mg (0.79 mmol) of HATU and 0.50 ml (2.85 mmol) of N,N-diisopropylethylamine were initially charged in 2.5 ml of DMF, and the mixture was stirred at RT for 20 min. 216 mg (0.86 mmol) of methyl 6,6,6-trifluoro-5-hydroxynorleucinate hydrochloride (stereoisomer mixture) were added, and the mixture was stirred at RT overnight. Water and TFA were added to the reaction solution and the product was purified by preparative RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were concentrated, sodium bicarbonate solution was added to the residue and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off, concentrated and dried under high vacuum. This gave 265 mg (69% of theory) of the target compound.