Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[CH2:9][CH2:10][CH:11]1[CH2:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[C:14]2=[C:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33]C)=[O:32])=[CH:29][C:30]=3[N:13]2[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([N:8]([CH3:41])[CH2:9][CH2:10][CH:11]1[CH2:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[C:14]2=[C:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:25]3[CH:26]=[CH:27][C:28]([C:31]([OH:33])=[O:32])=[CH:29][C:30]=3[N:13]2[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCN(C)C(=O)OC(C)(C)C)Cc1cc(OC)ccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CC(CCN(C)C(=O)OC(C)(C)C)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 70 °C

Procedure:
To a 0.05M solution of methyl 6-{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}-13-cyclohexyl-3-methoxy-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate in dioxane, 1M aqueous KOH solution (10 eq) was added and the mixture was heated to 70° C. After 2 h the mixture was neutralised with 1N HCl and then all volatiles were removed in vacuo. The residue was taken up with DCM and filtered to remove salts. The crude material was used without purification in the next step. (ES+) m/z 547 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:33]2[CH:34]=[CH:35][C:30]([C:29]([O:28][CH3:27])=[O:37])=[CH:31][CH:32]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(O)cc2)cccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
The product from Example 65B (0.4618 g, 1.33 mmoles), methyl-4-bromobenzoate (0.5707 g, 2.65 mmoles), K3PO4 (0.5634 g, 2.65 mmoles), Pd(OAc)2 (0.0238 g, 0.106 mmoles), and 2-(di-tert-butylphosphino)biphenyl (0.0475 g, 0.159 mmoles) was treated with toluene (3.9 mL) under a nitrogen atmosphere. The resulting red solution was degassed, stirred for 10 min, and heated to 100° C. overnight. The black solution was diluted with diethyl ether, extracted with sat. NH4Cl and sat. NaCl, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (10:1 to 4:1 hexane:ethyl acetate) on silica gel to provide the title compound (0.5904 g, 92%) as a yellow oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])C>O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:7]([C:8]([C:10]([F:11])([F:12])[F:13])=[CH2:9])[C:6]([OH:21])=[O:5])=[CH:19][CH:18]=1
Reactant: C=C(C(C(=O)OCC)c1ccc(Cl)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C(C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
15% Aqueous sodium hydroxide (3 ml) is added to a stirred solution of ethyl-2-(4-chlorophenyl)-3(trifluoromethyl)-but-3-enoate (0.3 g) and the mixture refluxed for 3 hours, cooled to room temperature, diluted with water (10 ml) and extracted with ether. The aqueous phase is acidified with 2N aqueous hydrochloric acid extracted with ether (×3), dried and the solvent evaporated under reduced pressure. Yield 0.25 g nD 1.4898.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Cc1ccc2cccc(N)c2n1
Product: Cc1ccc2cccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])c2n1
Yield: 46.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 2-methyl-quinolin-8-ylamine (Intermediate 22) (417 mg, 2.64 mmol) and 2-nitrobenzensulfonyl chloride (643 mg, 2.64 mmol) gave the title compound (423 mg, 47%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][O:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[Si]([O:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1)(C(C)(C)C)(C)C>>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:20][CH2:21][O:22][CH3:23])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([C:35]3[CH:34]=[C:33]([CH2:32][OH:31])[CH:38]=[N:37][CH:36]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(B(O)O)c1
Reactant: COCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: COCCc1nc2c(N)nc3cc(-c4cncc(CO)c4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3-boronic acid according to the method described in Examples 118-121. The reaction was heated at reflux for 2.25 hours, and the work-up procedure described in Part F of Examples 125-131 was followed. The crude product was purified and deprotected according to the procedure described in Example 144. The resulting solid was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 55:45) followed by recrystallization from acetonitrile to provide {5-[4-amino-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl}methanol as white needles, mp 202-204° C.
Reaction SMILES: C(C([C:14]1[N:22]2[C:17]([C:18](=[O:34])[NH:19][C:20](CC3C=CC(OC)=C(OC)C=3)=[N:21]2)=[C:16]([CH3:35])[N:15]=1)C/C=C/C1C=CC=CC=1)(=O)C.[BH4-].[Na+]>>[CH3:35][C:16]1[N:15]=[CH:14][N:22]2[C:17]=1[C:18](=[O:34])[NH:19][CH:20]=[N:21]2
Reactant: COc1ccc(Cc2nn3c(C(C/C=C/c4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ncn2nc[nH]c(=O)c12

Procedure:
70 mg (0.14 mmol) of 7-[(3E)-1-acetyl-4-phenyl-3-butenyl]-2-(3,4-dimethoxy-benzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one are reacted analogously to Example 12 with 5 mg (0.14 mmol) of sodium borohydride to give 2-(3,4-dimethoxybenzyl)-7-[(3E)-1-1-hydroxyethyl)-4-phenyl-3-butenyl]-5-methylimidazo-[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 2-amino-5-nitropyridine (4.0 g, 28.8 mmol) in dichloromethane (15 ml) were added 176 mg (31.6 mmol) of 4-N,N'-dimethylaminopyridine (DMAP), 4.41 ml of triethylamine (31.6 mmol) and 2.16 ml (31.6 mmol) of acetyl chloride in turn, and the mixture was stirred at room temperature for 1 hour. A 1 M aqueous solution of potassium carbonate was added to the mixed suspension to neutralize it. Extraction with chloroform was repeated three times, and the extract was dried over magnesium sulfate. The solvent was removed, and the residue was subjected to silica gel column chromatography (eluent: chloroform). Recrystallization from chloroform-hexane gave 2.14 g of the intended product as a flesh-colored powder (yield: 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[CH3:34][N:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36](Cl)=[O:37]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:36]([N:35]([CH3:34])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(OC(=O)N(C)c2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 25.4 mg, 0.0564 mmol) and N-methyl-N-phenylcarbamoyl chloride (20.4 mg, 0.120 mmol) was dissolved in pyridine (1 mL), and stirred for 2 hours at 100° C. The reaction mixture was concentrated, and then the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.7 mg) as a pale yellow amorphous product. (Yield 87%)
Reaction SMILES: CC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([OH:20])[CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19].N1C=CC=CC=1.CC1C=CC(S(OCCC#CCCCC)(=O)=O)=CC=1.[O:46]=[CH:47][C:48]1[CH:56]=[CH:55][C:53](O)=[C:50]([O:51][CH3:52])[CH:49]=1>C(Cl)Cl>[CH3:52][O:51][C:50]1[CH:49]=[C:48]([CH:56]=[CH:55][C:53]=1[O:20][CH2:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:47]=[O:46]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCCCC#CCCO
Agent: CCCCC#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC#CCCOc1ccc(C=O)cc1OC
Yield: 16.2 %

Procedure:
4-Methylbenzenesulfonyl chloride (5.70 g, 30 mmol), 3-octyn-1-ol (1.52 mL, 20 mmol) and pyridine (3.24 mL, 40 mmol) in CH2Cl2 (20 mL) were treated according to Procedure 4 giving oct-3-ynyl 4-methylbenzenesulfonate (5.21 g, 93%) as a colourless oil. Vanillin (0.90 g, 5.94 mmol) was alkylated with oct-3-ynyl 4-methylbenzenesulfonate (2.50 g, 8.92 mmol) according to Procedure 4 and the crude product was recrystallised from purified by flash chromatography with 10% EtOAc/petrol as eluent to give 3-methoxy-4-(oct-3-ynyloxy)benzaldehyde (0.25 g, 16%) as a colourless crystalline solid; mp 64.5-65.5° C.; δH (400 MHz, CDCl3) 0.86 (t, J=7.2 Hz, 3H, CH3), 1.32-1.44 (m, 4H, CH3CH2CH2), 2.12 (t, J=7.2 Hz, 2H, CH2), 2.69 (t, J=7.2 Hz, 2H, CH2CH2O), 3.88 (s, 3H, OCH3), 4.15 (t, J=7.2 Hz, 2H, OCH2), 6.96 (d, J5,6=8.0 Hz, 1H, H5), 7.37 (s, 1H, H2), 7.39 (d, J5,6=8.0 Hz, 1H, H6), 9.80 (s, 1H, CHO); δC (100 MHz, CDCl3) 13.5, 18.3, 19.5, 21.8, 30.8, 55.9, 67.5, 74.8, 82.5, 109.4, 111.7, 126.4, 130.2, 149.7, 153.4, 190.7; vmax 1020, 1132, 1262, 1508, 1584, 1684, 2931 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[OH:28][CH2:27][C:26]1[CH:31]=[CH:32][C:23]([C:21]([NH:20][C:10]2[CH:11]=[C:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Methyl 4-[({2-[(tert-butoxycarbonyl)amino]-5-thien-2-ylphenyl}amino)carbonyl]benzoate (1.7 g, 3.76 mmol) was made 0.1 M in anhydrous THF and cooled to 0° C. To this stirring suspension was added LiBH4 (0.55 g, 25.20 mmol), 2M in anhydrous THF. The resulting solution was slowly warmed to ambient temperature stirred for 14 hours. The reaction was then cooled to 0° C. and carefully quenched with saturated aqueous NH4Cl. The mixture was diluted with water and extracted with ethyl acetate two times. The combined organic layers were washed with brine then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was diluted with DCM and purified by MPLC to give tert-butyl 2-{[4-(hydroxymethyl)benzoyl]amino}-4-thien-2-ylphenylcarbamate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12](B(O)O)=[C:11]([F:19])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br[C:21]1[S:22][C:23]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:25]=1>>[F:19][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:14]=[C:13]([F:15])[C:12]=1[C:21]1[S:22][C:23]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:25]=1
Reactant: CCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
Reactant: CCCc1ccc(Br)s1
Product: CCCc1ccc(-c2c(F)cc(-c3ccc(CC)cc3)cc2F)s1

Procedure:
The compound 2-(3,5-difluoro-4′-ethylbiphenyl-4-yl)-5-propylthiophene (PUS-2-3) is prepared analogously to Example 2 from 4′-ethyl-3,5-difluoro-4-biphenylboronic acid and 2-bromo-5-propylthiophene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>ClCCl>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N+:15]([O-:17])=[O:16])=[N:3][CH:4]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])nc1
Reaction time: 4 h
Yield: 52.3 %

Procedure:
To a stirring solution of 2-amino-5-methylpyridine (3.1 g, 29 mmol) and pyridine (7.3 mL, 90 mmol) in dichloromethane (200 mL) was added 2-nitrobenzoyl chloride (5.7 g, 30 mmol). After 4 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (250 mL). The organic phase was separated and washed again with water (250 mL) followed by brine (250 mL) and then dried with MgSO4, filtered and partially concentrated in vacuo, which resulted in the formation of a precipitate. After standing overnight, the solid was filtered and dried in vacuo to give 3.9 g (52%) of white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH:6]=1
Reactant: BrCC1CC1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnn(CC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.7 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (0.1 g, 0.68 mmol) in DMF (20 ml) were added K2CO3 (0.19 g, 1.36 mmol, 2 eq.) and (bromomethyl)cyclopropane (92 mg, 0.68 mmol, 1 eq.). The mixture was stirred at RT for 4 h. The mixture was quenched and extracted as in Intermediate Example 5(c). The solvent was distilled off to afford the crude product (0.15 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[C:12]([CH2:16][CH2:17][NH:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[C:24]=1[CH3:25])=[CH:11]2>ClCCl.ClCCl.CO>[F:5][C:6]1[C:14]2[N:13]([CH3:15])[C:12]3[CH2:16][CH2:17][N:18]([CH2:19][C:20]4[N:21]=[CH:22][N:23]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])[C:24]=4[CH3:25])[C:1](=[O:2])[C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1c(CNCCc2cc3cccc(F)c3n2C)ncn1S(=O)(=O)N(C)C
Reactant: O=C(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of phosgene (12.5% v/v in toluene; 4 ml) in dichloromethane (4 ml) was added a solution of 4-[[[2-(7-fluoro-1-methyl-1H-indol-2-yl)ethyl]amino]methyl]-N,N,5-trimethyl-1H-imidazole-1-sulphonamide (100 mg) in dichloromethane (4 ml), and the resulting mixture was stirred for 1 h. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (5 ml). Aluminium chloride (68 mg) was added, and the mixture was heated at reflux for 3 h. The cooled mixture was then poured into 2M sodium hydroxide solution (80 ml) and extracted with dichloromethane (2×50 ml). The combined, dried organic extracts were evaporated in vacuo to leave a solid which was dissolved in dichloromethane:methanol (1:1; 50 ml) and adsorbed onto silica. Purification by FCC eluting with System A (200:8:1) gave a solid (21 mg) which was triturated with ether to give the title compound (14 mg), m.p. 162°-166°.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][C:7]1[C:15]2[C:10](=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.O.[OH-].[Na+]>CN(C=O)C>[Cl:5][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:9][CH:8]=[C:7]([CH3:6])[C:15]=12
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c[nH]c2c1ccc[n+]2[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c[nH]c2nccc(Cl)c12
Temperature: 59 °C
Reaction time: 4 h

Procedure:
At 50° C., 1.77 ml (22.81 mmol) of methanesulfonyl chloride are added dropwise to a solution of 1.30 g (8.77 mmol) of 3-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide in 7.5 ml of DMF such that the temperature increases to 59° C. The mixture is then stirred at 70° C. for 4 h. After cooling to room temperature, 30 ml of water are added slowly, at 5° C., the pH is adjusted to 10 by addition of 20% strength sodium hydroxide solution and the mixture is stirred for another hour. The precipitated solid is filtered off, washed with water and then dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:26])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:10](=[O:24])[C:9](Br)=[CH:8]2)=[O:4].[C:27]1([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O.Cl>CN(C=O)C.[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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:26])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:10](=[O:24])[C:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccc(C#N)cc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccc(C#N)cc2)c1O
Temperature: 120 °C
Yield: 40.5 %

Procedure:
A mixture of 3-bromo-1-(4-cyano-benzyl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.24 mmol), PhSnBu3 (0.1 mL, 0.29 mmol), and PdCl2(PPh3)2 (34 mg, 0.048 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (5 mL) and EtOAc (15 mL) were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-80% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound. MS: (+) m/z 412.26 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.Cl.[NH2:21][NH:22][C:23]([NH:25][OH:26])=[NH:24].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:21][NH:22][C:23](=[NH:24])[NH:25][OH:26])[CH2:8]1
Reactant: Cc1cnnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reactant: N=C(NN)NO
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)NO)CC(c1cc(Cl)sc1Cl)C2
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
To a mixture of 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (145 mg) and 1-amino-3-hydroxyguanidine hydrochloride (61 mg) were added ethanol (3 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 90° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol-acetone to give 7-(2,5-dichlorothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 155) (80 mg) as whitish gray crystals.
Reaction SMILES: CO[CH:3](C1C=CC=CC=1)[CH2:4][O:5][C:6]([C:8]1[CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7].[Na]>C(O)C>[CH:19]([O:18][C:16]([C:10]1[CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:8]([C:6]([O:5][CH2:4][CH3:3])=[O:7])=[C:13]([CH3:14])[NH:12][C:11]=1[CH3:15])=[O:17])([CH3:20])[CH3:21]
Reactant: COC(COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1

Procedure:
19 g (38 mmols) of (+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-carboxylic acid isopropyl 2-methoxy-2-phenylethyl ester (compound A) in a solution of 0.87 g (38 mmols) of sodium in 100 ml of ethanol are heated to the boiling point under nitrogen for 8 hours. The solvent is then distilled off in vacuo, the residue is taken up in water and the mixture is acidified with dilute hydrochloric acid and extracted several times with methylene chloride. The extracts are concentrated in vacuo, after drying over sodium sulphate. The residue crystallised completely and is filtered off and recrystallised from methanol (crude yield: 4.1 g (2,%), melting point: 143°-146° C.), and the product is purified by high performance liquid chromatography, as described under
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[CH2:25])[CH:21]=[C:20]([Cl:33])[CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:32])([F:31])[C:27]([F:28])([F:29])[F:30])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:33])[CH:19]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.1 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (378 mg, 1.58 mmol) and 1,3-dichloro-5-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene (506 mg, 1.74 mmol) in DMF (5 mL) at rt was added TEA (176 mg, 1.74 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the final desired title compound 5-(5-(3,5-dichlorophenyl)-5-(perfluoroethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (180 mg; 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.82 (s, 2H), 7.77-7.70 (m, 3H), 7.60 (s, 1H), 4.55 (d, J=18.4 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 1.48 (s,6 H) ppm; HPLC purity: 97.7% at 220 nm and 99.5% at 254 nm; MS: m/z=496.3 (M+, ESI+).