Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][S:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][S:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1)[C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)O
Reactant: N#CCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)OCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
Bromoacetonitrile (76 μl, 1.124 mmol) and N,N-diisopropylethylamine (196 μl, 1.124 mmol) were added to a solution of ((S)-2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoic acid (Compound tk87) (150 mg, 0.375 mmol) in acetonitrile (6 ml), and the reaction solution was stirred at room temperature for 5 hours. Bromoacetonitrile (49 μl, 0.413 mmol) was further added and the mixture was stirred at room temperature for 1 hour to complete the reaction. The reaction mixture was concentrated under reduced pressure using an evaporator, and the residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoate (Compound tk88) (152 mg, 92%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[O:5][C:4]([CH3:21])([CH3:20])[CH2:3]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH3:21])([CH3:20])[CH2:3][CH:2]2[NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(N)c2cc(OCc3ccccc3)ccc2O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Reaction time: 0.5 h

Procedure:
4.0 g (14 mmol) of 4-amino-6-benzyloxy-2,2-dimethylchroman were treated with 4.2 ml (30 mmol) of triethylamine at RT in 80 ml of THF and the mixture was stirred for 30 min, then treated with 1.95 g (1.3 ml, 17 mmol) of methanesulfonyl chloride, the temperature rising to 40° C. The mixture was then heated to reflux for 2 h, allowed to stand overnight at RT, concentrated in vac. and the residue was treated with water; 4.9 g of product, m.p. 162-165° C.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]([F:26])([F:25])[O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)=[O:19])[CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[CH2:34]([O:41][C:42]([C:44]1[N:52]2[C:47]([CH:48]=[CH:49][CH:50]=[CH:51]2)=[C:46]([N:53]=[C:54]=[O:55])[CH:45]=1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>C1COCC1>[CH2:34]([O:41][C:42]([C:44]1[N:52]2[C:47]([CH:48]=[CH:49][CH:50]=[CH:51]2)=[C:46]([NH:53][C:54]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:18](=[O:19])[NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]([F:25])([F:8])[F:26])[CH:12]=2)=[O:55])[CH:45]=1)=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CCCN1
Reactant: O=C=Nc1cc(C(=O)OCc2ccccc2)n2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)c1cc(NC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccn12
Temperature: 25 °C

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide TFA salt (328 mg, 0.845 mmol) and triethylamine (353 μl, 2.54 mmol) in THF (10 mL) was added the crude 1-isocyanato-indolizine-3-carboxylic acid benzyl ester (247 mg, 0.845 mmol, prepared as described in Scheme A6). The resulting mixture was stirred at RT under nitrogen over the week-end then poured into HCl 1N and extracted with EtOAc (×3). The combined organic extracts were washed with an aqueous saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The crude mixture was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to c-hexane/EtOAc 3:7) to afford the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.3; MS (LC/MS): 567.3 [M+H]+ 565.2 [M−H]−; tR (HPLC conditions a): 4.16 min.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=2)[CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH:25][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:3]=3)[CH:21]=2)[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 23 °C
Reaction time: 6 h
Yield: 45.6 %

Procedure:
To a suspension of 4-chloro-5-nitro-2-phenylpyrimidine (800 mg, 3.40 mmol, 1.0 eq) in CHCl3 (20 mL) was added 5-cyclopropyl-1H-pyrazol-3-amine (832 mg, 6.80 mmol, 2.0 eq). The reaction mixture was stirred for 6 hours at 23° C. The precipitate was filtered and recrystallized to give the desired product N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitro-2-phenylpyrimidin-4-amine (Compound 6) (500 mg, 45.7%). LC-MS (m/z): 323.0 [M+H]+. 1H-NMR (300 MHz, DMSO-d6): δ 0.73-0.78 (m, 2H), 0.96-1.01 (m, 2H), 1.96-2.01 (m, 1H), 6.53 (s, 1H), 7.55-7.63 (m, 3H), 8.35-8.38 (m, 2H), 9.33 (s, 1H), 10.26 (s, 1H), 12.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20]O)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][Cl:24])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCC(CO)CC2)ccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(O)c1cc(S(=O)(=O)N2CCC(CCl)CC2)ccc1Cl

Procedure:
2-Chloro-5-(4-hydroxymethylpiperidinosulfonyl)benzoic acid (5.0 g.) is refluxed overnight with 50 ml. of thionyl chloride. After evaporation to dryness, the residue is dissolved in 70 ml. of acetone, 30 ml. of water added and the mixture is allowed to stand at room temperature for a half hour. The solution is then filtered and concentrated to half volume. On the addition of 20 ml. of water a precipitated oil is obtained which crystallizes on stirring. Recrystallization from acetone-benzene yields the product, m.p. 175°-177° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(CBr)ccc1Cl
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a solution of 5-methyl-2-chlorobenzonitrile (200 mg, 1.32 mmol) in carbon tetrachloride (12 mL) was added N-bromosuccinimide (235 mg, 1.32 mmol) and benzoyl peroxide (32 mg, 0.132 mmol). The mixture was heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate and evaporated to give an orange oil. The oil was purified by silica gel chromatography eluting with 50% heptanes in DCM to afford the title compound (192 mg) as a 2:1:1 mixture with 5-methyl-2-chlorobenzonitrile and 2-chloro-5-(dibromomethyl)benzonitrile respectively, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[CH3:22][N:23]([CH:25]=[N:19][C:17]([C:16]1[CH:15]=[N:14][N:13]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:9][CH:10]=[N:11][C:12]=12)=[O:18])[CH3:24]
Reactant: Cc1cccc(-c2ccnc3c(C(N)=O)cnn23)c1
Reactant: COC(OC)N(C)C
Product: Cc1cccc(-c2ccnc3c(C(=O)N=CN(C)C)cnn23)c1

Procedure:
A mixture of 6.0 g of 7-(3-methylphenyl) pyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 13) and 15 ml of N,N-dimethylformamide dimethyl acetal is heated on a steam bath for 4 hours to give a solution. The solution is evaporated in vacuo to give a solid. The solid is recrystallized twice from dichloromethane-hexane to give 4.70 g of the desired product as colorless crystals, mp 165°-166° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:44])[N:20]([C:39]2[CH:43]=[CH:42][O:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:44])[N:20]([C:39]2[CH:43]=[CH:42][O:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccoc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccoc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.31 g), sodium hydrogen carbonate (0.50 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-furyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.13 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.073 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.067 g, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:16][CH:12]([F:17])[O:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Cc1cc(O)cnc1C#N
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OC(F)F)cnc1C#N

Procedure:
A solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CAS registry 228867-86-5) (228 mg, 1.70 mmol), sodium chlorodifluoroacetate (CAS registry 1895-39-2) (518 mg, 3.40 mmol) and K2CO3 (705 mg, 5.10 mmol) in DMF (7 ml) was stirred for 0.5 h at 100° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl soln. and brine. The aqueous layers were reextracted with EtOAc, the combined organic layers dried over Na2SO4, filtrated and the filtrate was concentrated. The title compound was obtained as a colourless oil after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 95:5, 3-35 min 95:5 to 60:40).
Reaction SMILES: [CH3:1][C:2]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([CH3:5])[C:3]#[CH:4].C([Li])CCC.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][C@@H:25]1[C@@:55]2([CH3:56])[C:29](=[CH:30][CH2:31][C@@H:32]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:57])[C@H:33]3[CH2:34][CH2:35][C@@H:36]2[C@H:37]([CH3:50])[CH2:38]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][C@@H:27]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][O:60]2)[CH2:26]1.N1C=CC=CC=1>O1CCOCC1.CCCCCC>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][C@@H:25]1[C@@:55]2([CH3:56])[C:29](=[CH:30][CH2:31][C@@H:32]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:57])[C@H:33]3[CH2:34][CH2:35][C@@H:36]2[C@H:37]([CH3:50])[CH2:38][C:4]#[C:3][C:2]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)([CH3:1])[CH3:5])[CH2:28][C@@H:27]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][O:60]2)[CH2:26]1
Reactant: C#CC(C)(C)OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)[C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](OC6CCCCO6)C[C@H](OC6CCCCO6)[C@]5(C)[C@H]4CC[C@]23C)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C[C@H](CC#CC(C)(C)OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
In a 1.5 l 4-neck flask equipped with stirrer, 100 ml dropping funnel with pressure equalizer, 30-cm Dimroth condenser, thermometer and argon-supply, a solution of 16.85 g (0.1 mol) of 3-methyl-3[(tetrahydro-2H-pyran-2-yl)oxy]-but-1-yne (prepared from 3-hydroxy-3-methylbut-1-yne and 3,4-dihydro-2H-pyran) in 300 ml of dioxane with constant stirring and under argon for 30 min. at 9°, was added drop by drop 50 ml (approximately 0.1 ml) of approximately 2 M n-butyl lithium in hexane. The solution was stirred for 2 hr. at 9° and for a further 2 hr. at room temperature. To the light yellow mixture was then added, in one portion, a solution of 22.4 g of crude (20S)-1α,3β-bis[(tetrahydro-2H-pyran-2-yl)oxy]-20-methyl-21-p-toluenesulfonyloxypregn-5-ene (corresponding to approximately 0.033 mol), in 40 ml of dioxane and stirred for 64 hr. at 105° under argon. The mixture, which became dark yellow and cloudy, was cooled to room temperature, poured onto 500 g of ice, and the emulsion was extracted 3 times with 200 ml of ether. The ether extracts were washed successively 2 times with 200 ml of water, combined, dried over sodium sulfate and concentrated under vacuum at 40°. The residue was dissolved in 200 ml of toluene and concentrated under vacuum at 40°. The residue was treated twice more in the same way to remove dioxane and excess 3-methyl-3[(tetrahydro-2H-pyran-2-yl)oxy]-but-1-yne). After drying for 1 hr. under vacuum at room temperature, the remaining light brown oil, 34.1 g (which contained some 3-methyl-3[(tetrahydro-2H-pyran-2-yl)oxy]-but-1-yne and ditetrahydropyranyloxytosylate), was dissolved in ether and added to a column prepared with hexane--ether (9:1), containing 4 ml of pyridine/1, and 1 kg of silica gel. Elution with hexane--ether (4:1) mixtures (without the addition of pyridine) yielded 19.6 g (88%) of 1α,3β,25-tris[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-en-23-yne.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].ClCCl>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CC3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4,5-dihydropyridazin-3(2H)-one -6-yl)pyridinium bromide (300 mg, 0.74 mmol) was dissolved in methanol (5 ml), gradually added with sodium borohydride (280 mg, 7.4 mmol) under ice cooling and then stirred at room temperature overnight. The :solvent was removed under reduced pressure. The residue obtained was added with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (145 mg) as colorless crystals.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:34][CH2:33]1
Reactant: CC1CCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CC1CCN(CCc2cc3cc(-c4ccc(C(=O)N5CCOCC5)cn4)ccc3o2)CC1

Procedure:
The product from Example 44E and 4-methylpiperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.97 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-3.8 (m, 14H), 3.05 (m, 2H), 1.95 (m, 2H), 1.75 (m, 1H), 1.5 (m, 2H), 1.05 (d, J=6.6 Hz, 3H); MS (DCI) m/z 434 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](C(C)C)=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:15]=[N:16][N:17]([CH3:18])[C:3]=12.[CH:19](C1C2C(=O)C3N(C)N=CC=3NC=2C=CC=1)([CH3:21])[CH3:20].ClC1C2C=CC(F)=CC=2N=C2C=NN(C)C=12.C(C1C=CC2C(=O)C3N(C)N=CC=3NC=2C=1)(C)C>>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][C:8]([CH:19]([CH3:21])[CH3:20])=[CH:7][C:6]=2[N:5]=[C:4]2[CH:15]=[N:16][N:17]([CH3:18])[C:3]=12
Reactant: CC(C)c1cccc2nc3cnn(C)c3c(Cl)c12
Reactant: CC(C)c1cccc2[nH]c3cnn(C)c3c(=O)c12
Agent: CC(C)c1ccc2c(=O)c3c(cnn3C)[nH]c2c1
Agent: Cn1ncc2nc3cc(F)ccc3c(Cl)c21
Product: CC(C)c1ccc2c(Cl)c3c(cnn3C)nc2c1

Procedure:
A mixture of 9-chloro-8-isopropyl-1-methyl-1H-pyrazolo[4,3-b]quinoline and 9-chloro-6-isopropyl-1-methyl-1H-pyrazolo[4,3-b]quinoline (EXAMPLE 10, step 2) was treated according to the procedure of step 3 in EXAMPLE 3 instead of 9-chloro-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]quinoline. The title compound and 6-isopropyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one were separable by column chromatography on silica gel eluting with methanol/dichloromethane (1:30).
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[C:19]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([S:27](Cl)(=[O:29])=[O:28])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[O:5]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][S:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:8][CH2:7]2)[O:2][CH2:3][CH2:4]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1N1CCC2(CC1)OCCO2
Agent: Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared from 2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine hydrochloride (which was obtained in Example 220) and N-acetylsulfanilyl chloride according to the procedure of Example 215 as a crystalline solid; 1H NMR (300 MHz, DMSO-d6) δ 1.73 (t, J=5.4 Hz, 4 H), 2.73 (t, J=5.4 Hz, 4 H), 3.33 (s, 4 H), 3.89 (s, 3 H), 7.00–7.10 (m, 2 H), 7.10–7.20 (m, 1 H), 7.30–7.40 (m, 1 H), 7.67 (d, J=9.3 Hz, 2 H), 7.71 (d, J=9.3 Hz, 2 H), 8.79 (s, 1 H), 10.29 (s, 1 H); MS (ES) m/z: 432.2 (MH+); HRMS Calcd. for C21H26N3O5S (MH+): 432.1593. Found: 432.1597. Anal. Calcd. for C21N25N3O5S: C, 58.45; H, 5.84; N, 9.74. Found: C, 58.41; H, 5.83; N, 9.72.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([S:14](=[O:27])(=[O:26])[NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:10]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[NH:38])=[CH:36][C:30]=4[N:29]=3)[C:9]=2[OH:40])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[O-:48][C:49]#[N:50].[K+]>CO.O>[OH:40][C:9]1[C:10]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[NH:38])=[CH:36][C:30]=3[N:29]=2)=[CH:11][C:12]([S:14](=[O:27])(=[O:26])[NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:49]([NH2:50])=[O:48])[CH:3]=1
Reactant: N#C[O-]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCc4cccnc4)cc(-c4cccc(N)c4)c3O)nc2c1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCc4cccnc4)cc(-c4cccc(NC(N)=O)c4)c3O)nc2c1
Yield: 72.6 %

Procedure:
2-[3′-Amino-2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.015 g, 0.023 mmol), prepared as in Example 10, was dissolved in a mixture of methanol and water and then triethylamine was added to bring the solution to pH 9. The mixture was heated with potassium cyanate (0.018 g, 0.23 mmol) for 12 hour at 40° C., concentrated by evaporation under reduced pressure and the crude product was purified by reversed phase HPLC (acetonitrile gradient) to give 2-[2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-3′-ureido-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.01 g). MS: found (M+H+) 599.5, (M−H+) 597.7, calc. 598.17.
Reaction SMILES: O1C2C=CC(C[C:11](Cl)=[O:12])=CC=2OC1.CO[C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:17]=1[C:24]1[S:28][C:27]([NH:29][C:30](=[O:39])[C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:26][C:25]=1[CH3:40].[Br:41]Br>>[Br:41][C:21]1[C:20]2[O:12][CH2:11][O:22][C:19]=2[CH:18]=[C:17]([C:24]2[S:28][C:27]([NH:29][C:30](=[O:39])[C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])=[N:26][C:25]=2[CH3:40])[CH:16]=1
Reactant: COc1ccc(OC)c(-c2sc(NC(=O)c3c(F)cccc3F)nc2C)c1
Reactant: O=C(Cl)Cc1ccc2c(c1)OCO2
Reactant: BrBr
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cc(Br)c2c(c1)OCO2

Procedure:
Compound 56 was prepared from 2-(benzo[d][1,3]dioxol-5-yl)acetyl chloride in the similar manner as described for the preparation of Compound 55 with the exception that 2 equivalents of bromine was used.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([NH:20][C@H:21]([CH:26]=O)[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]1([CH2:11][NH:12][CH2:26][C@@H:21]([NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C@@H:22]([CH3:23])[CH2:24][CH3:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccc2ccccc12
Reactant: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](CNCc1cccc2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 1-naphthylmethylamine (5.84 g, 37.2 mmol), crushed 3A molecular sieves (10 g), and N-t-butoxycarbonyl-isoleucinal (8.0 g, 37.2 mmol) in 1,2-dichloroethane (50 ml) was added sodium triacetoxyborohydride (15.8 g, 74.3 mmol) at 0° C. The reaction was allowed to warm slowly to RT and stirred for 48 hrs. The reaction was cooled to 0° C. and quenched with sat. aq. NaHCO3 and stirred for 30 min. The organic layer was separated, washed with saturated brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to provide the title compound as an oil.