Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:40]>C(OCC)(=O)C>[ClH:40].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:18]2[CH:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=[N:16][CH:17]=2)[CH2:21][C:22]([C:33]([F:39])([F:38])[C:34]([F:35])([F:36])[F:37])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(N3CCNCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[3-(4-BOC-piperazin-1-yl)-pyridin-5-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (220.0 mg, 0.4 mmol) prepared in Example 169 was added to a saturated solution of hydrochloric acid in ethyl acetate (2.0 mL). The reaction mixture was stirred at room temperature 2 hours and then concentrated under reduced pressure to give 210.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: COC(=O)CBr
Reactant: CCOC(=O)CCC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCC1CCCN1CC(=O)OC

Procedure:
A solution of ethyl 3-(pyrrolidin-2-yl)propanoate (3 g, 17.5 mmol), methyl 2-bromoacetate (3 g, 18 mmol) and K2CO3 (3 g, 21.7 mmol) in CH3CN was stirred at 80° C. overnight. The completion of the reaction was monitored by TLC. After the suspension was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL), the combined organic layers were concentrated to give the crude product, which was directly used for the next step without further purification. MS (ESI): 244 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[N:23]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[N:22]=1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:29]1[C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[N:23]1[C:24]([CH3:26])=[CH:25][C:21]([CH3:20])=[N:22]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: Cc1cc(C)n(-c2ccccc2C=O)n1
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Reaction time: 3 h
Yield: 45.7 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (64 mg, 0.25 mmol) in DMF (3 mL) is added 2-(3,5-dimethyl-pyrazol-1-yl)-benzaldehyde (50 mg, 0.25 mmol) at room temperature. Oxone (150 mg, 0.25 mmol) in H2O (1 mL) is added and the solution is stirred at the same temperature for 3 hours. The reaction is poured into water (25 mL) and sodium thiosulfate (sat., 50 mL). The product is extracted into EtOAc (2×) and the combined organics are then dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (4 g silica gel, 0-6% MeOH/CH2Cl2) affords the title compound (50 mg, 46%). LCMS (ESMS): m/z 438.20 (M++1)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]2)=[CH:4][C:3]=1[O:16][CH3:17].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27]Br>C(#N)C>[Br:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH2:13]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: BrCCCBr
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Yield: 13.2 %

Procedure:
A mixture of 1-(4hydroxy-3-methoxyphenyl)phenyl-methanone (14 g, 61.4 mmol), K2CO3 (13 g, 92.1 mmol), and 1,3-dibromopropane (28 g, 86 mmol) in acetonitrile (400 ml) was heated at reflux for 4 hours. The reaction was followed by thin layer chromatography. At the end of the reaction, the inorganics were filtered off and the solvent was removed on a rotary evaporator. The residue was purified on a flash chromatographic column (SiO2, 140 g, eluted with 4:1 hexane:dichloromethane, 1.2 l) to give a partially solidified material: 15.44 g (72%). Recrystallization twice from ethanol gave 2.84 g of 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone as white crystals, m.p.=88°-89° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][O:17][C:18]2[C:19]([C:24]([NH2:26])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:10])[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][N:79]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[N:79]1[CH:80]=[CH:81][CH:82]=[CH:83][C:78]=1[NH:26][C:24](=[O:25])[C:19]1[C:18]([O:17][CH2:16][C@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:2]([F:1])([F:27])[F:28])[CH2:4][CH2:5]2)=[O:10])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Brc1ccccn1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccccn1)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
To a stirred mixture of 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide (30 mg, 0.08 mmol, EXAMPLE 75 Step 1), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (3.47 mg, 6.00 micromol), cesium carbonate (0.10 g, 0.30 mmol), and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (1.56 mg, 1.50 micromol) in 1,4-dioxane (2 mL) was added 2-bromopyridine (14 mg, 0.09 mmol) at room temperature. After being stirred at 120° C. for 12 h under microwave irradiation, water was added to the mixture. The mixture was extracted with ethyl acetate twice. The extracts were combined and dried over magnesium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by preparative HPLC.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO.[Na]>O.C(O)(C)C.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 12.7 g.), conc. hydrochloric acid (9.6 ml.), methanol (9.5 ml.) and tetrahydrofuran (9.5 ml.) was stirred at room temperature for 3 hours. The resultant solution was concentrated in vacuo, and the residue was suspended in water. The suspension was adjusted to pH 3.5 with sodium bicarbonate under ice cooling, and stirred at same temperature for 30 minutes. The precipitates were collected by filtration and dried over magnesium sulfate to give the powder (10 g.). The powder was suspended in water (300 ml.) and adjusted to pH 7.0 with sodium bicarbonte. The solution was adjusted to pH 6.0 with 10% hydrochloric acid and subjected to column chromatography on nonionic adsorption resin (Diaion HP-20: trademark, manufactured by Mitsubishi Chemical Industries Ltd.) (300 ml.) with 10% aqueous solution of isopropyl alcohol. The eluate was adjusted to pH 3.5 with 10% hydrochloric acid under ice cooling, and the precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 7.2 g.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:32]([F:56])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O.[C:58](OC(=O)C)(=[O:60])[CH3:59].N1C=CC=CC=1>C1COCC1>[C:58]([NH:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:32]([F:56])[CH:31]=2)[CH2:25]1)(=[O:60])[CH3:59]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Triphenylphosphine (2.82 g, 10.8 mmol) was added portionwise to a solution of 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]-oxazolidine-2-one (5.00 g, 9.79 mmol) in THF (40 mL), and the mixture stirred for 2 h at room temperature. Water (1.41 mL, 78.3 mmol) was added, and the mixture heated at 40° C. overnight. Solvent was removed under vacuum, and the oily residue dissolved in dichloromethane (50 mL). Acetic anhydride (4.62 ml, 49.0 mmol) and pyridine (7.92 ml, 97.9 mmol) were added, and the mixture stirred for 8 h at r.t. Solvent was removed under vacuum and the crude product purified by silica gel flash column chromatography (eluent: 30% ethyl acetate in hexanes) to give the product as a foam (4.98 g, 97%); MS: 527 [M+H]+. 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To 720 g of polyphosphoric acid (116.5%) heated at 89° C. were added 120 g of 2,5-di(4-chloroanilino)terephthalic acid over a period of approximately 45 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The reaction mixture was held at 113° C. for five hours and then cooled to 95° C. To this mixture was added 89.4 g of phosphoric acid (75%) dropwise over a period of 20 minutes. The resultant melt was allowed to stir for 15 minutes at 92° C. and then poured slowly into 1240 g of methanol, the temperature being maintained below reflux by adjustment of the addition rate. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 102 g of 2,9-dichloroquinacridone as a magenta pigment.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]([C@H:19]([OH:21])[CH3:20])[CH2:17][OH:18].C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]([C@H:19]([OH:21])[CH3:20])[CH2:17][OH:18])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](O)[C@H](N)CO
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](O)[C@@H](CO)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 125 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (686 mg, 2.5 mmol), (2R,3R)-2-aminobutane-1,3-diol (394 mg, 3.75 mmol) and diisopropylethylamine (0.873 mL, 5.00 mmol) in DMA (10 mL) was heated to 125° C. for 3 hr. After cooling to rt, the volatiles were removed under high vacuum to afford a red oil that was treated with ˜25 ml of water. A gummy solid formed and the mixture was stirred at rt overnight. A few crystals of pure title compound from a previous batch were added at the beginning of the stirring. The suspension was filtered and dried to afford a yellow solid that was washed with 25 ml of Et2O:EtOAc, 1:1. Drying afforded 6-bromo-4-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (670 mg, 1.952 mmol, 78% yield) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 4.21 (dd, J=6.4, 2.6 Hz, 1H), 4.15-4.06 (m, 1H), 3.90-3.74 (m, 2H), 1.23 (d, J=6.4 Hz, 3H); (ES+) m/z: 343.1, 345.1 (M+H); LC retention time: 1.957 min (analytical HPLC Method P).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[O:29][C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:31][CH:32]=2)[CH2:23][CH2:22]1.O1CCOCC1>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:30]3[O:29][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:32][CH:31]=3)[S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CN2CCN(C)CC2)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)o2)CC1
Temperature: 90 °C
Yield: 63.3 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 0.600 g, 1.55 mmol), 1-methyl-4-((5-(tributylstannyl)furan-2-yl)methyl)piperazine (0.802 g, 1.71 mmol), PdCl2(PPh3)2 (0.050 g, 0.075 mmol), and dioxane (8 mL). The reaction mixture was heated to 90° C. for 18 hours under nitrogen and then cooled to room temperature. The reaction mixture was diluted with brine (100 mL) and extracted with EtOAc (100 mL). The combined organic layers were dried over sodium sulfate, filter and concentrated. The residue was purified by Biotage 40S eluting with CHCl3/MeOH saturated NH3. (95:5) to provide 430 mg (60%) of the product as a light green solid. 1H NMR (CDCl3, 400 MHz). δ 8.43 (d, J=5.5 Hz, 1H), 7.62 (s, 1H), 7.03 (t, J=8.6 Hz, 1H), 6.69 (d, J=3.5 Hz, 1H), 6.48 (m, 3H), 6.34 (d, J=3.1 Hz, 1H), 3.88 (s, 2H), 3.66 (s, 2H), 2.61 (m, 8H), 2.29 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3](=[O:29])[NH:4][C:5](=[O:28])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C:15]3([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[C:13]([CH3:27])([CH2:14]3)[CH2:12]2)[N:7]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>COCCOC.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.COCCOC>[F:30][C:31]1[C:36]([C:2]2[C:3](=[O:29])[NH:4][C:5](=[O:28])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C:15]4([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=5)[C:13]([CH3:27])([CH2:14]4)[CH2:12]3)[N:7]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC12CN(CCCn3nc(Br)c(=O)[nH]c3=O)CC1(c1ccc(C(F)(F)F)cc1)C2
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: O
Solvent: COCCOC
Product: CC12CN(CCCn3nc(-c4cccnc4F)c(=O)[nH]c3=O)CC1(c1ccc(C(F)(F)F)cc1)C2
Temperature: 90 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
6-bromo-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (P16, 48 mg, 0.101 mmol) was suspended in a degassed mixture of 1,2-Dimethoxyethane (DME) (1.725 mL)/Water (0.345 mL). Then (2-fluoro-3-pyridinyl)boronic acid (42.9 mg, 0.304 mmol), sodium carbonate (32.2 mg, 0.304 mmol), Tetrakis (23.44 mg, 0.020 mmol) and 2-biphenylyl(dicyclohexyl)phosphane (7.11 mg, 0.020 mmol) were added and the mixture was heated to 90° C. and stirred at that temperature for 3 hours. The mixture was cooled down to room temperature, diluted with 1.3 mL of a mixture of DME/Water (5:1) then 2-biphenylyl(dicyclohexyl)phosphane (7.11 mg, 0.020 mmol), (2-fluoro-3-pyridinyl)boronic acid (42.9 mg, 0.304 mmol), Tetrakis (23.44 mg, 0.020 mmol) and sodium carbonate (32.2 mg, 0.304 mmol) were added again. The reaction mixture was then heated to 90° C. and left stirring at that temperature for 40 minutes. The reaction mixture was cooled down to room temperature and evaporated under reduced pressure. The residue was partitioned between AcOEt and water and extracted. Organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude product was purified by Preparative HPLC then further purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) affording 6-(2-fluoro-3-pyridinyl)-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (Enantiomer 2) (E11, 14 mg, 0.029 mmol, 28.2% yield).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27](/[CH:31]=[C:32](\[CH3:38])/[C:33]([O:35]CC)=O)=[CH:26][C:25]=2[F:39])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[N+:2]=[N-:3].[NH2:42][C:43]([NH2:45])=[NH:44].NCCOCCOCCOCCNS(C1C=CC(OC2C(F)=CC(/C=C(\C)/C(N=C(N)N)=O)=CC=2F)=CC=1)(=O)=O>O>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27](/[CH:31]=[C:32](\[CH3:38])/[C:33]([N:42]=[C:43]([NH2:45])[NH2:44])=[O:35])=[CH:26][C:25]=2[F:39])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[N+:2]=[N-:3]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1
Reactant: N=C(N)N
Agent: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)c(F)c1)C(=O)N=C(N)N
Solvent: O
Product: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1)C(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (E)-ethyl 3-(4-(4-(N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylate (250 mg, 0.42 mmol) was added 4.4 M guanidine in methanol (as prepared in example 45) (1.0 mL, 4.4 mmol) and the reaction was stirred at RT. After 30 minutes, water (10 mL) was added, and the mixture was extracted with DCM (4×25 mL). The aqueous phase was adjusted to pH 7, and extracted with DCM (2×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound (245 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=[C:20]([Br:24])[Br:21])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of triphenylphosphine (119.6 g) in methylene chloride (420 mL) at 0° C. was added a solution of carbon tetrabromide (75.72 g) in methylene chloride (90 mL). After completion of the addition, the mixture was stirred for 10 min. Then a solution of 3-(benzyloxy)benzaldehyde (J.A.C.S., 93, 2571 (1977)) (40 g) in methylene chloride (150 ml) was added. The mixture was stirred for 16 hrs at -5° C. After warming to room temperature, the organic layer was washed with saturated sodium bicarbonate (2×150 ml) and brine (1×150 ml), then dried over magnesium sulfate, filtered and the mixture was concentrated. Ether (300 ml) was added, causing the formation of a precipitate which was filtered. The filtrate was concentrated and the process repeated 2 times. Finally, the filtrate was concentrated and chromatographed using 10% ethyl acetate in hexane, affording the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)(O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-(4-chloro-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one (from Example 7a supra) was suspended in a mixture of triethylsilane (5 mL, 31.3 mmol) (Aldrich) and trifluoroacetic acid (12.5 mL) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate (100 mL) and treated with solid sodium carbonate (10.5 g). After stirring for 30 minutes, mixture was extracted with water (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ethyl acetate (100 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from ethyl acetate-hexanes to give rac-6-chloro-3-(4-chloro-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 2.20 g, 79.1% over two steps).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[CH2:23][CH2:24][CH2:25][N:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:27][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:27][N:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:25][CH2:24][CH2:23][N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: CS(=O)(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)N1CCCn2c(nc3c(N)nc4cc(O)ccc4c32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
3-(Benzyloxy)-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine, (6.37 g, 14.56 mmol) prepared as described in Example 369, was dissolved in methanol (150 mL) and transferred to a hydrogenation vessel charged with 10% palladium on carbon (12.4 g, 116 mmol). The vessel was purged with nitrogen gas and placed under hydrogen pressure (50 psi, 3.45×105 Pa) and shaken for 3 days at ambient temperature. The catalyst was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue crystallized from isopropanol. The material was purified by column chromatography on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 47-minute gradient from 5:95 to 50:50) and crystallized from isopropanol to provide 1.15 g of 6-amino-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-3-ol.