Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([NH2:13])=[N:9][C:10]([NH2:12])=[N:11][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>CC(O)C.O>[CH3:1][C:2]1[C:7]2[C:8]([NH2:13])=[N:9][C:10]([NH2:12])=[N:11][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[F:28][C:29]([F:34])([F:33])[C:30]([O-:32])=[O:31]
Reactant: O=C(O)C(F)(F)F
Agent: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
Solvent: O
Solvent: CC(C)O
Product: O=C([O-])C(F)(F)F

Procedure:
To a suspension of 5 g of trimetrexate hydrate in 30 ml of 2-propanol and 15 ml of water was added 2.10 g of trifluoroacetic acid (approximately a 40% excess). The solid partly dissolved, but new crystals came out before it was completely gone. The mixture was heated to near reflux to give a clear dark yellow-green solution. To this was added 100 ml of 2-propanol. The product crystallized rapidly, and was collected after ice-cooling for 1 hour, washed with ice-cold 2-propanol and dried in air at 50% relative humidity to give 5.95 g of greenish-yellow crystals.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CC[O:30]CC.[H-].[OH-].[Na+].OO>O1CCCC1.O>[CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:10][CH2:11][CH2:12][OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: OCCCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a mixture of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentene (2.86 g., 10 mmoles), sodium borohydride (0.47 g., 12.5 mmoles), and tetrahydrofuran (25 ml.) is added dropwise a solution of boron fluoride etherate (2.1 ml., 16.7 mmoles) in tetrahydrofuran (5 ml.) at ice-bath temperatures under a nitrogen atmosphere. The resulting mixture is further stirred at room temperature overnight (ca.15 hours). The reaction flask is chilled in an ice bath and water (2 ml.) is very cautiously added to destory the excess hydride, followed by the additions of sodium hydroxide (5N, 4 ml.) and hydrogen peroxide (30%, 8 ml.). The final mixture is stirred at room temperature for 1/2 hour, diluted with cold water and then extracted with chloroform three times. The combined extracts are washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo leaving the title compound as a viscous oil (3.00 g., 10 mmoles, 100%). ir (neat) 2.97, 3.30, 3.41, 6.22, 6.68, 6.90, 8.03, 8.30, 9.16, 9.44, 12.10, 13.20, 13.60, 14.40μ; pmr (CCl4) δ 1.4-1.9 (4H, m), 3.2-4.2 (6H, m), 4.58 (2H, broad s), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:28]([OH:33])(=[O:32])[CH:29]([CH3:31])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:29]([C:28]([OH:33])=[O:32])[CH3:31])=[O:5]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)O)c(F)c1

Procedure:
A flask containing 10.0 g 2-fluoro-4-(hexadecylamino)-benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 2-fluoro-4-(hexadecylamino)benzoate separates as off-white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:29]2[CH2:30][CH2:31][CH:27]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH2:28]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)C2CCNC2)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(S(=O)(=O)c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methylphenylsulfonyl)pyrrolidine hydrochloride (15.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (12.1 mg). Calcd for C22H22N2O4S: 410.1300, found 410.1303.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])/[C:3](/[NH2:10])=[CH:4]/[C:5]([O:7]CC)=O.[Cl:13][C:14]1[C:25]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])=[CH:24][C:17]([NH:18][C:19](=O)[O:20]CC)=[C:16]([F:32])[CH:15]=1>>[CH:28]([NH:27][C:26](=[O:31])[C:25]1[CH:24]=[C:17]([N:18]2[C:5](=[O:7])[CH:4]=[C:3]([C:2]([F:1])([F:11])[F:12])[NH:10][C:19]2=[O:20])[C:16]([F:32])=[CH:15][C:14]=1[Cl:13])([CH3:30])[CH3:29]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1cc(C(=O)NC(C)C)c(Cl)cc1F
Product: CC(C)NC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl

Procedure:
Analogously to the procedure described in Example 1, starting from ethyl 4,4,4-trifluoro-3-aminocrotonate and ethyl 4-chloro-2-fluoro-5-(N-isopropylcarbamoyl)-carbanilate there is obtained N-isopropyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, m.p. 234°-239° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1CCCCC1.[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[N:35][C:36]=1[CH:37]([O:40][CH3:41])[O:38][CH3:39])[N:33]([C:42](OC1C=CC=CC=1)=[O:43])[CH2:32][CH2:31][CH2:30]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[NH2:51][C:52]1[CH:59]=[C:58]([O:60][CH:61]2[CH:66]3[CH2:67][CH2:68][N:63]([CH2:64][CH2:65]3)[CH2:62]2)[C:55]([C:56]#[N:57])=[CH:54][N:53]=1.[NH4+].[Cl-]>C1COCC1>[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[N:35][C:36]=1[CH:37]([O:38][CH3:39])[O:40][CH3:41])[N:33]([C:42]([NH:51][C:52]1[CH:59]=[C:58]([O:60][CH:61]3[CH:66]4[CH2:67][CH2:68][N:63]([CH2:64][CH2:65]4)[CH2:62]3)[C:55]([C:56]#[N:57])=[CH:54][N:53]=1)=[O:43])[CH2:32][CH2:31][CH2:30]2)([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Reactant: N#Cc1cnc(N)cc1OC1CN2CCC1CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC1CCCCC1
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(OC2CN3CCC2CC3)c(C#N)cn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of LHMDS in methylcyclohexane (0.9 M, 0.70 ml, 0.630 mmol) was added drop wise over 5 minutes to a mixture of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 135 mg, 0.287 mmol) and racemic 6-amino-4-(quinuclidin-3-yloxy)nicotinonitrile (intermediate 79, 70.0 mg, 287 mmol) in THF (2.9 ml) cooled at −78° C. The reaction mixture was stirred at −78° C. for a further 10 minutes then allowed to warm to 0° C. and aqueous NH4Cl (1 M) added. The mixture was extracted with DCM (3×), dried over Na2SO4 and evaporated. The residue was applied to a 4 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an off-white solid. (UPLC-MS 6) tR 1.27; ESI-MS 623.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[O:12][C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:14][N:15]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:3]=[C:4]([C:8]([NH:10][C:11]4[O:12][C:13]([C:16]5[O:17][CH:18]=[CH:19][CH:20]=5)=[N:14][N:15]=4)=[O:9])[CH:5]=[N:6][CH:7]=3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH3:22]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cncc(Br)c1
Product: CCc1ccc(-c2ccc(-c3cncc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 5-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-3-pyridinecarboxamide prepared in Reference Example 8 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13]([OH:15])=O)([CH2:5]3)[CH2:3]1)[CH2:9]2.S(Cl)([Cl:18])=O>>[Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13]([Cl:18])=[O:15])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: O=C(O)CC12CC3CC(CC(Cl)(C3)C1)C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC12CC3CC(CC(Cl)(C3)C1)C2
Yield: 98.3 %

Procedure:
(3-Chloroadamantan-1-yl)acetic acid (607.5 mg, 2.66 mmol) was dissolved in thionyl chloride (5 mL, 68.5 mmol). The reaction mixture was heated at reflux for 5 hours. The reaction mixture was cooled and then concentrated in vacuo to provide the title compound as a white solid (646.4 mg, 98%) that was used without additional purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]2[OH:15])=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)nc1Cl
Yield: 76 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl trans(±)-4-amino-3-hydroxypiperidine-1-carboxylate obtained in Example (77a) (510 mg, 2.36 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (440 mg, 2.14 mmol), WSC hydrochloride (1.2 g, 6.26 mmol) and HOBT (284 mg, 2.10 mmol), to obtain 604.1 mg of the title compound as a white solid (76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:18]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:7][C:6]=2[CH:18]=1
Reactant: CN1c2ccc(Cl)cc2NC(=S)c2ccccc21
Reactant: NCc1cccnc1
Solvent: CCOCCO
Product: CN1c2ccc(Cl)cc2N=C(NCc2cccnc2)c2ccccc21
Yield: 38.2 %

Procedure:
A solution of 329 mg (1.2 mmol) of 8-chloro-5-methyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL of 2-ethoxyethanol was treated with 0.3 mL (2.4 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product as an oil. Chromatography on silica gel, eluting with CHCl3 /MeOH (98/2) gave 160 mg (38.4% yield) of the product as a golden solid foam. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =349.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([SH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([S:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)S
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82.7 %

Procedure:
To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-mercapto-3-methylbutanoic acid (4.5 g, 18.05 mmol) in THF (60 mL) was added a solution of methyl 2-bromoacetate (3.04 g, 19.85 mmol) in THF (10 mL) followed by DIPEA (9.46 mL, 54.1 mmol). The resulting mixture was stirred at rt for 4.5 h. The reaction mixture was concentrated in vacuo to remove most of the solvent, and the residue was diluted with EtOAc and sat. aq. NaHCO3 solution. The aqueous layer was acidified with 1N HCl solution to adjust the pH to 2-3. The resulting aqueous layer was extracted with EtOAc (2×). The organic layers were combined and dried over MgSO4. The filtrate was concentrated in vacuo to give the title compound as solid (4.8 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 6.93 (d, J=9.0 Hz, 1H), 4.10 (d, J=9.5 Hz, 1H), 3.62 (s, 3H), 3.41 (s, 2H), 1.39 (s, 9H), 1.33 (s, 3H), 1.27 (s, 3H); MS (ESI+) m/z 266.0 (M-55)+.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(O)C>[C:1]([N:3]=[C:4]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[S:5][CH3:6])#[N:2]
Reactant: CSC(=NC#N)SC
Reactant: C1COCCN1
Solvent: CCO
Product: CSC(=NC#N)N1CCOCC1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A 3 L round bottom flask equipped with a mechanical stirrer was charged with dimethyl cyanodithioimidocarbonate (200 g, 1368 mmol). The solid material was taken up in Ethanol (2279 ml) and stirred until completely dissolved. Morpholine (119 ml, 1368 mmol) was then added to the flask by graduated cylinder and the mechanical stirrer set to a vigorous rate for overnight stirring of the resulting mixture at room temperature. The resulting white precipitate was collected and dried via suction filtration overnight to afford pure white solid methyl N-cyano-4-morpholinecarbimidothioate (212.5 g, 1147 mmol, 84% yield) as a white solid (1H NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 3.61-3.66 (m, 4H) 3.74-3.79 (m, 4H)).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([CH2:23][C:24]([O-:26])=[O:25])=[CH:18][CH:17]=4)=[C:9]([CH2:29][CH2:30][CH3:31])[CH:8]=2)=[CH:4][CH:3]=1>CO.[Li+].[OH-]>[F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=4)=[C:9]([CH2:29][CH2:30][CH3:31])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(F)cc2)ccc1OCCc1cc2cc(CC(=O)[O-])ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(Oc2ccc(F)cc2)ccc1OCCc1cc2cc(CC(=O)O)ccc2[nH]1

Procedure:
A solution of 2-(2-(4-(4-fluorophenoxy)-2-propylphenoxy)-ethyl)-indole-5-acetate (mg, mmol) in MeOH (mL) and LiOH (mL) was heated at reflux for 3 hours. The mixture was acidified to pH 6 with 1 N HCL and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:35]1[CH:60]=[CH:59][C:38]2[N:39]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:40]([C:42]3[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=3[N:50]3[CH:54]=[CH:53][CH:52]=[N:51]3)=[N:41][C:37]=2[CH:36]=1>O1CCOCC1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([C:35]2[CH:60]=[CH:59][C:38]3[N:39]([C:55]([CH3:56])([CH3:58])[CH3:57])[C:40]([C:42]4[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=4[N:50]4[CH:54]=[CH:53][CH:52]=[N:51]4)=[N:41][C:37]=3[CH:36]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1CO
Reactant: COc1ccc(-n2cccn2)c(-c2nc3cc(Br)ccc3n2C(C)(C)C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-n2cccn2)c(-c2nc3cc(-c4cnc(N)c(CO)c4)ccc3n2C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
To a high pressure vessel are added 2-amino-3-hyroxymethyl-5-bromopyridine (90 mg, 0.44 mmol), bis(pinacolato)diboron (135 mg, 0.53 mmol) and KOAc (131 mg, 1.33 mmol) in 10 mL of 1,4-dioxane. The solution is degassed with nitrogen for 10 minutes, followed by the addition of PdCl2(dppf) (36 mg, 0.04 mmol). The reaction mixture is warmed to 80° C. and stirred for 1 hour. After this time a solution of 5-bromo-1-tert-butyl-2-(5-methoxy-2-pyrazol-1-yl-phenyl)-1H-benzimidazole (226 mg, 0.53 mmol) and additional PdCl2(dppf) (16 mg, 0.02 mmol) in DMF (1 mL) and 2M Na2CO3 (0.1 mL) are added. The reaction is heated at 80° C. for 12 hours, then cooled to room temperature and poured into water. The mixture is extracted with EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-8% MeOH/CH2Cl2) and preparative TLC (0.5 mm silica gel, 8% MeOH/CH2Cl2) gives the title compound (15 mg, 7%). LCMS (ESMS): m/z 469.20 (M++1)
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[CH2:16][N:17]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]([NH:26][OH:27])=[NH:25])=[N:18]2)=[N:11][CH:12]=1.N1C=CC=CC=1.Cl[C:39](OCC)=[O:40]>CN(C=O)C>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[CH2:16][N:17]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]3[NH:25][C:39](=[O:40])[O:27][N:26]=3)=[N:18]2)=[N:11][CH:12]=1
Reactant: CN(C)CCCOc1cnc(-c2cccc(Cn3nc(C(=N)NO)ccc3=O)c2)nc1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN(C)CCCOc1cnc(-c2cccc(Cn3nc(-c4noc(=O)[nH]4)ccc3=O)c2)nc1

Procedure:
500 mg (1.18 mmol) of 1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-benzyl}-N-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxamidine are dissolved in 15 ml of DMF, and 286 μl (3.54 mmol) of pyridine are added. 124 μl (1.30 mmol) of ethyl chloroformate are subsequently added with stirring, and the solution is stirred at 80° C. for 15 and subsequently at 100° C. for 72 h. The reaction mixture is evaporated, and the residue is purified by means of preparative HPLC; yield: 21.2 mg of “A227” trifluoroacetate; HPLC: Rt=2.07 min; LC-MS: 450 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[C:5]([CH3:19])=[N:4][C:3]=1I.N.[CH3:22][N:23]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[C:5]([CH3:19])=[N:4][C:3]=1[C:22]#[N:23]
Reactant: CN1CCCC1=O
Reactant: Cc1cc(-n2c(C)nc(I)c2Cl)cc2ccc(=O)[nH]c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Product: Cc1cc(-n2c(C)nc(C#N)c2Cl)cc2ccc(=O)[nH]c12

Procedure:
A mixture of 6-(5-chloro-4-iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)quinolone (1.0 g), cuprous cyanide (0.45 g) and palladium acetate (0.09 g) in 1-methyl-2-pyrrolidone (5 cm3) was stirred and heated at 160° for 4 hours. The cooled mixture was poured into aqueous ammonia solution (30 cm3 ; S.G. 0.880) and extracted with ethyl acetate (3×150 cm3). The combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:200 by volume. Combination and evaporation of the appropriate fractions afforded the title compound as a solid (0.54 g) which was characterised spectroscopically and used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.[C:43](Cl)(Cl)=[O:44]>C1(C)C=CC=CC=1.CCOC(C)=O.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:25]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:27][C@@H:26]3[O:34][C:43]2=[O:44])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H]3Cc4ccccc4[C@H]32)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To {2′-[((1R,2S)-2-hydroxy-indan-1-ylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester (0.178 g, 0.37 mmol) in toluene (3 mL) was added triethylamine (0.18 mL, 1.29 mmol), and the mixture was cooled to 0° C. Phosgene (1.9M in toluene; 0.23 mL, 0.44 mmol) was added, and the reaction was stirred for 20 minutes at 0° C. The mixture was diluted with EtOAc, H2O, and brine, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[C:48]([O:52][C:53]([NH:55][CH:56]([CH3:60])[C:57](O)=[O:58])=[O:54])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl.O>[C:48]([O:52][C:53](=[O:54])[NH:55][CH:56]([C:57](=[O:58])[NH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:60])([CH3:49])([CH3:50])[CH3:51]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)C(=O)NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 40 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (350 mg, 1.37 mmol, 1.0 eq.), EDCI (314.4 mg, 1.64 mmol, 1.2 eq.), HOBt (221.6 mg, 1.64 mmol, 1.2 eq.) and Et3N (0.46 mL mg, 3.29 mmol, 2.4 eq.) in DCM (15.0 mL) was added 2-tert-Butoxycarbonylamino-propionic acid (311.1 mg, 1.64 mmol, 1.2 eq.) drop wise. The mixture was stirred at room temperature overnight. The mixture was treated with H2O (10 mL) and the layers were separated. The aqueous was extracted with DCM (2×10 mL), combined organic phase was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give {1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester as a white solid. LCMS (m/z) 449 (M+23); 1H NMR (DMSO-d6) δ: 9.08 (s, 1H), 8.26 (t, J=5.7 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.22-7.31 (m, J=8.4 Hz, 2H), 6.96-7.01 (m, J=8.5 Hz, 2H), 6.88-6.95 (m, 3H), 4.89 (s, 2H), 4.21-4.30 (m, 2H), 3.88-4.02 (m, 1H), 1.35 (s, 9H), 1.18 (d, J=7.1 Hz, 3H).