Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:25]([OH:34])=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:23][C:24]1[C:25]([OH:34])=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=4[OH:22])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: Cc1ccc(B(O)O)c(O)c1C
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4ccc(C)c(C)c4O)n3)n2)c1O
Yield: 11 %

Procedure:
6-(3,4-Dimethyl-2-hydroxyphenyl)-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 3,4-dimethyl-2-hydroxyphenylboronic acid in 11% yield using method F; δH [2H6]-DMSO 13.32,(1H, s), 8.38-8.22,(4H, m), 8.14,(1H, d), 8.10,(1H, d), 7.88,(1H, d), 7.72,(1H, d), 7.10,(1H, d), 6.94,(1H, t), 6.82,(1H, d), 3.84,(3H, s), 2.31,(3H, s), 2.20,(3H, s); MS 339 (MH)+; HPLC retention time (system 1) 4.39 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CBr

Procedure:
A mixture of 5-fluoro-N,N,2-trimethylbenzenesulfonamide (5.20 g, 24.0 mmol) and N-bromosuccinimide (4.69 g, 26.4 mmol) in dry CCl4 (100 mL) was refluxed overnight under nitrogen. Cooled the reaction and filtered off the succinimide salts by vacuum filtration, washing with CCl4. The concentrated filtrate was dissolved in a minimal amount of ethyl acetate and purified on an Isco column (110 g silica) running a 0 to 20% EtOAc/Hexane gradient over 40 minutes. The collected fractions were concentrated in vacuo to afford the desired material as a yellow oil in a ratio of 3.5:1 with the starting material.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33]([C:35]1[N:36]=[CH:37][N:38]([CH3:40])[CH:39]=1)=[CH2:34]>CN(C=O)C.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>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[S:10][C:9]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:8]=3[C:7]=2[O:6][C:5]2[CH:24]=[CH:25][C:2](/[CH:34]=[CH:33]/[C:35]3[N:36]=[CH:37][N:38]([CH3:40])[CH:39]=3)=[CH:3][CH:4]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=Cc1cn(C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(/C=C/c2ccc(Oc3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)c1
Temperature: 150 °C
Yield: 57.9 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (50 mg, 0.121 mmol) was dissolved in DMF (2 ml) and triethyl amine (0.506 ml, 3.63 mmol). To the solution was added the 4-vinyl-1-methyl imidazole (39.2 mg, 0.363 mmol) and Pd(PPh3)2Cl2 (8.49 mg, 0.012 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1-100% CH3CN/H2O) to afford (E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-imidazol-4-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (31 mg, 0.070 mmol, 58.2% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.82 (s, 3 H) 6.57-6.74 (m, 3 H) 6.75-6.93 (m, 3 H) 6.98-7.14 (m, 3 H) 7.32-7.54 (m, 5 H) 8.73 (s, 1 H), LC/MS (m/z, MH+): 441.3.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.C[NH:17][C:18](=[NH:20])S.OS(O)(=O)=O>>[NH2:20][C:18]1[O:14][C:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:5][C:4](=[O:3])[N:17]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CNC(=N)S
Agent: O=S(=O)(O)O
Product: Nc1nc(=O)cc(-c2ccc(Cl)cc2)o1

Procedure:
The title compound was prepared from ethyl(4-chloro)benzoylacetate (5.0 g, 22 mmol) (obtained in preparation 2) and methylthiopseudourea.H2SO4 (3.31 g, 12 mmol) by following the procedure described in preparation 4, (0.573 g, 11.6%). MS m/z: 223 (M+).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:11][CH:10]([NH:26]C(OCC2C=CC=CC=2)=O)[C:9]1=[O:37])=[O:6])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:11][CH:10]([NH2:26])[C:9]1=[O:37])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)CN(c2ccccc2F)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)CN1C(=O)C(N)CN(c2ccccc2F)c2ccccc21
Yield: 99.7 %

Procedure:
1-tert-Butylcarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (205 mg) was dissolved in methanol (10 ml), 10% palladium carbon (30 mg) was added, under hydrogen atmosphere the filtration, the filtrate was concentrated under reduced pressure, to thereby obtain 150 mg of the titled compound (Yield: 100%).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4](Cl)([O:6][CH2:7][CH:8]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5]>C(Cl)Cl.O>[OH:3][NH:2][C:4](=[O:5])[O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: NO
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NO)OCC1c2ccccc2-c2ccccc21
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
hydroxylamine hydrochloride (6.0 g, 86 mmol) in CH2Cl2 (250 mL) and water (100 mL) at 0° C. After 10 mins, solid FmocCl (21 g, 81 mmol) is added portionwise with vigorous stirring. After 1 h a white precipitate forms and more CH2Cl2 (100 mL) is added. The solution is allowed to warm to 20° C. and left to stir for 3 d. The white solid that remains is filtered away, re-dissolved in ethyl acetate (300 mL), washed with brine and dried over MgSO4 to yield (9H-fluoren-9-yl)methyl hydroxycarbamate (Mellor, S. L.; McGuire, C.; Chan, W. C.; Tet. Lett., 1997, 38, 3311-3314) as a white solid (15 g, 68%). Furthermore, the mother-liquor is concentrated and purified by column chromatography (silica gel, ethyl acetate/CH2Cl2 1:1 to 1:0) to yield the title compound (by-product) as a white solid (0.55 g, 1%).
Reaction SMILES: C[O:2][C:3]1[CH:51]=[CH:50][CH:49]=[CH:48][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[N:7]1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:51]=[CH:50][CH:49]=[CH:48][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[N:7]1
Reactant: COc1ccccc1Cn1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccn(Cc6ccccc6O)n5)c34)n(-c3ccccc3)c(=O)c12
Yield: 44.8 %

Procedure:
(S)-2-(1-((5-(1-(2-Methoxybenzyl)-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (53 mg, 0.08 mmol) was treated with boron tribromide (1M in dichloromethane, 750 μL, 0.75 mmol) in dichloromethane (1.0 mL) and then with a solution of ammonia (7N in methanol, 750 μl, 5.25 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (reverse phase, 0% to 100% water-methanol/acetonitrile 1:1) to obtain 20 mg (48% yield) of the title compound.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([N:24]([CH3:26])[CH3:25])=[CH:18][CH:19]=3)[N:14]=2)[CH:12]=1)=[O:7])C.C(OC(C1C=NN(C2NC(=O)C3C(=CC=CC=3N(C)C)N=2)C=1)=O)C.CN(C)C1C=CC=C2C=1C(=O)NC(N1C=C(C(O)=O)C=N1)=N2>C1COCC1>[CH3:25][N:24]([CH3:26])[C:17]1[CH:16]=[C:15]2[C:20]([C:21](=[O:23])[NH:22][C:13]([N:11]3[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N(C)C)ccc3c(=O)[nH]2)c1
Agent: CCOC(=O)c1cnn(-c2nc3cccc(N(C)C)c3c(=O)[nH]2)c1
Agent: CN(C)c1cccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c12
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)c1ccc2c(=O)[nH]c(-n3cc(C(=O)O)cn3)nc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous 1M KOH (3.8 mL, 3.8 mmol) was added to a 3:2 mixture of 1-(7-dimethylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester and 1-(5-dimethylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.415 g, 1.27 mmol) in THF (3.8 mL). The reaction mixture was allowed to stir at room temperature for 18 h and was then concentrated. The residue was re-dissolved in water (10 mL) and acidified with 1M aqueous HCl (3 mL). The resulting precipitate was collected by filtration to yield a mixture of the titled compound and 1-(5-dimethylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The collected precipitate was triturated from DMSO and rinsed with ethanol to yield pure 1-(7-dimethylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (0.113 mg, 29% yield). The filtrate was saved for further purification. MS (ESI/Cl): mass calcd. for C14H13N5O3, 299.1; m/z found, 300.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.97 (s, 1H), 12.21 (s, 1H), 8.92 (s, 1H), 8.22 (s, 1H), 7.90 (d, J=8.9 Hz, 1H), 6.93 (dd, J=9.0, 2.3 Hz, 1H), 6.72 (s, 1H), 3.07 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.CC1C2C=C3[C:34]4([C:42]5[C:37](=[CH:38]C=C[CH:41]=5)N[C:35]4=[O:43])COC3=CC=2ON=1.BrCC1CCOCC1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:41][CH:42]4[CH2:37][CH2:38][O:43][CH2:35][CH2:34]4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: COc1cc2c(cc1F)C1(CO2)C(=O)Nc2ccccc21
Agent: BrCC1CCOCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)tetrahydropyran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.16-7.00 (m, 2H), 6.89 (d, J=7.8 Hz, 1H), 6.59 (d, J=6.8 Hz, 1H), 6.38 (d, J=10.0 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 4.02-3.92 (m, 2H), 3.85 (s, 3H), 3.76-3.51 (m, 2H), 3.35 (t, J=11.5 Hz, 2H), 2.18-2.00 (m, 1H), 1.65-1.37 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.4, 157.3 (d, J=1.7 Hz), 149.3, 149.1, 149.0, 146.1, 142.7, 131.9, 129.1, 123.7 (d, J=49.0 Hz), 118.9 (d, J=6.4 Hz), 110.3 (d, J=21.7 Hz), 96.4, 80.7, 67.41, 67.39, 57.9, 56.4, 46.1, 33.9, 30.8, 30.7; MS (ES+) m/z 384.2 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:41])([CH3:40])[C:13]([NH:15][C:16]1[N:21]=[C:20]([F:22])[C:19]([CH:23]([OH:39])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:18][CH:17]=1)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:11][C:12]([CH3:41])([CH3:40])[C:13]([NH:15][C:16]1[N:21]=[C:20]([F:22])[C:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a solution of oxalyl chloride (0.11 ml, 1.25 mmol) in dichloromethane (10 ml) was added dropwise dimethylsulfoxide (0.18 ml, 2.51 mmol) at −78° C. After stirring for 10 min, a solution of 1,1-dimethylethyl 4-(3-{6-[(2,2-dimethylpropanoyl)amino]-2-fluoro-3-pyridinyl}-3-hydroxypropyl)-1-piperidinecarboxylate (step 1, 500 mg, 1.14 mmol) in dichloromethane (5 ml) was added to the mixture at −78° C. After 15 min, triethylamine (0.79 ml, 5.70 mmol) was added at the same temperature and the resulting mixture was allowed to warm up to room temperature and stirred for 18 h. The mixture was quenched with 1N aqueous hydrochloric acid (100 ml) and extracted with dichloromethane (150 ml). The organic layer was washed with water (50 ml) and dried over magnesium sulfate. Removal of solvent gave a pale yellow solid, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (4:1 ) to afford 362 mg (73%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]=[C:18]([NH2:20])[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[CH2:26](N)[CH2:27]N>O.C(O)CCCC>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]1[NH:20][CH2:26][CH2:27][N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: NC(N)=Nc1nc2ccccc2n1Cc1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCO
Solvent: O
Product: c1ccc(Cn2c(NC3=NCCN3)nc3ccccc32)cc1

Procedure:
2-(1-Benzylbenzimidazolyl)guanidine (3.65g, 0.0143 mol) was dissolved in water (600 ml) containing 5N hydrochloric acid (5.5 ml). The solution was cooled to 0° to 5°C and treated portionwise with sodium nitrite (1.0g) each hour for 3 hours. After a further 4 hours the reaction mixture was filtered and the microcrystals so obtained were heated under reflux in amyl alcohol (15 ml) with ethylenediamine (3 ml) for 6 hours. The cooled reaction mixture was evaporated to dryness. The resulting semi-solid was crystallised from amyl alcohol was then recrystallised from ethanol to yield 2-(1-benzylbenzimidazolyl)amino-2-imidazoline (1.0g) as colourless microcrystals m.p. 165°-166°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[NH2:23][CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=1.C(N(CC)CC)C.O>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CCOC(=O)c1ccc(NCCN)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NCCNc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (740 mg, 2.39 mmol), ethyl 2-(2-aminoethylamino)pyridine-5-carboxylate (1.00 g, 4.78 mmol) and triethylamine (0.670 mL, 4.81 mmol) in anhydrous DMSO (7 mL) was stirred at 100° C. for 8 h. After cooling, the reaction mixture was poured into water (300 mL) and extracted with CH2Cl2 (2×100 mL). The organic layers were combined, washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc) to give 5-amino-1-cyclopropyl-7-[2-[(5-ethoxycarbonyl-2-pyridyl)amino]ethylamino]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (600 mg, 50%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[N:7]=1)=[O:5])[CH3:2].C([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])=[O:28])(C)(C)C.C1(C)C=CC=CC=1.CCO.C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=O>O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:27](=[O:29])(=[O:28])[NH2:26])=[CH:17][CH:16]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCCc1cc(C(=O)OCC)nn1Cc1ccc(Br)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 100 °C

Procedure:
1-(4-Bromobenzyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.2 g, 3.3 mmol) and N-t-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene sulfonamide (1.4 g, 4.0 mmol) were combined with toluene (70.9 mL, 666.0 mmol) and EtOH (18.5 mL, 316.7 mmol). Potassium carbonate (920 mg, 6.7 mmol) was dissolved in water (9.6 mL, 532.8 mmol) and added to the mixture, and stirred. Tetrakis(triphenyl-phosphine)palladium(0) (385 mg, 333 μmol) was added quickly and the mixture heated at 100° C. for 30 minutes in the microwave. EtOAc and water was added and organics were extracted and evaporated. The crude product was dissolved in neat TFA (20 mL, 300 mmol) and stirred at 50° C. for 1.5 hours. The product was dried under vacuum. DCM (20 mL) and saturated NaHCO3 (20 mL) were added, stirred and extracted, dried, and evaporated to yield the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]1.[Br:22]N1C(=O)CCC1=O>>[Br:22][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]([CH:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:12][CH2:11]3)[CH2:3][C:4]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(N1CCC(C2Cc3ccccc3O2)CC1)C(F)(F)F
Product: O=C(N1CCC(C2Cc3cc(Br)ccc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from 1-[4-(2,3-dihydro-benzofuran-2-yl)-piperidin-1-yl]-2,2,2-trifluoro-ethanone and N-bromo-succinimide following a procedure analogous to that described for Intermediate 1. LC (method 2): tR=1.47 min; Mass spectrum (ESI+): m/z=378 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:13])=[N+:5]([O-:12])[CH:6]=[CH:7][C:8]=1[N+]([O-])=O)[CH3:2].C([Cl:17])(=O)C>>[Cl:17][C:8]1[CH:7]=[CH:6][N+:5]([O-:12])=[C:4]([CH3:13])[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: CC(=O)Cl
Product: CCc1c(Cl)cc[n+]([O-])c1C
Temperature: -15 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
First, 3-ethyl-2-methyl-4-nitropyridine 1-oxide (3.37 g, 18.5 mmol) was added to acetyl chloride (20 ml, 281 mmol) in a nitrogen atmosphere at −30° C. The mixture was stirred at −30 to 0° C. for 3 hours. After the reaction mixture was concentrated, the residue was partitioned by chloroform and a saturated aqueous sodium hydrogen carbonate solution. After insoluble substance was removed by filtration, the aqueous layer was extracted twice with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 100 g, elution solvent: heptane, heptane/ethyl acetate=50/50) to obtain the title compound (2.10 g, yield: 66.1%) as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4](OC)[CH:3]=1.[CH3:27][CH:28]1[O:33][CH:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>CS(C)=O>[CH3:34][CH:32]1[O:33][CH:28]([CH3:27])[CH2:29][N:30]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:9][C:10]([C:13]4[C:14]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:15][O:16][C:17]=4[CH3:18])=[N:11][N:12]=3)=[CH:6][CH:7]=2)[CH2:31]1
Reactant: CC1CNCC(C)O1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Solvent: CS(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CC(C)OC(C)C3)cc2)o1
Temperature: 200 °C
Yield: 23.6 %

Procedure:
A suspension of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.62 mmol) in 2,6-dimethylmorpholine (2.00 mL, 16.0 mmol) was heated for 30 min at 200° C. (microwave) followed by stirring under gently reflux for 18 h at 160° C. After addition of DMSO (2 mL) and 2,6-dimethylmorpholine (0.50 mL, 4.00 mmol) the solution was stirred for another 24 h at 160° C. After cooling to ambient temperature the reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (61 mg, 24%) as a white solid. MS: m/e=417.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:12]=[C:13](I)[C:8]2=[CH:7][N:6]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([CH3:38])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCO.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>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:12]=[C:13]([C:32]3[CH:33]=[CH:34][C:29]([OH:28])=[CH:30][C:31]=3[CH3:38])[C:8]2=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cnc(Oc3ccc(F)cc3F)nc21
Reactant: Cc1cc(O)ccc1B(O)O
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: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1-c1nn(COCC[Si](C)(C)C)c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
6-(2,4-Difluoro-phenoxy)-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine from Example 11 (0.5 g, 0.99 mmol) was dissolved in 10 mL of dry dioxane, and the reaction mixture was degassed by treatment with vacuum and flushed with argon. Tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.1 mmol) was added, and the reaction mixture was stirred for 10 minutes. A solution of 4-hydroxy-2-methylphenyl boronic acid (0.311 g, 2.0 mmol) in 3 mL EtOH was added, and the reaction mixture was degassed, purged with argon, and stirred for 10 minutes. AA solution of potassium carbonate (0.411 g, 3.0 mmol) in 1 mL water was then added, and the reaction mixture was again degassed and flushed with argon. The reaction mixture was heated to 90° C. with stirring for 16 hours under argon. The reaction mixture was cooled, filtered, and the filtrate was partitioned between water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting residue was subject to flash chromatography (hexanes/EtOAc 1:0 to 2:1) to yield 0.308 g (0.64 mmol, 64%) of 4-[6-(2,4-difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-methyl-phenol.