Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([OH:18])=O.C(N(CC)CC)C.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([NH:32][CH3:33])=[CH:30][CH:29]=1.S(Cl)(Cl)=O>ClCCl>[CH3:33][N:32]([C:31]1[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=1)[C:16]([C:3]1[C:4](=[O:15])[N:5]([CH3:14])[C:6]2[C:11]([C:2]=1[OH:1])=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: CNc1ccc(C(F)(F)F)cc1
Reactant: COc1cccc2c1c(O)c(C(=O)O)c(=O)n2C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(O)c(C(=O)N(C)c1ccc(C(F)(F)F)cc1)c(=O)n2C
Temperature: 0 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To an ice-cold solution of 1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid (8 g, 0.032 mol), triethylamine (15.5 ml, 0.11 mol) and 4-trifluoromethyl-N-methylaniline (6.1 g, 0.035 mol) in 150 ml of dichloromethane, a solution of thionyl chloride (3.0 ml, 0.042 mol) in 10 ml of dichloromethane was added dropwise during 0.5 hours. The stirring was continued at 4° C. for 4 hours. The solution was diluted with 10 ml of dichloromethane, washed with cold 1 M sulfuric acid and then extracted with 1 M sodium hydroxide. The pH of the aqueous phase was adjusted to 8-8.5, and the aqueous solution was clarified by filtration and then acidified with hydrochloric acid to pH 4. On standing a crystalline precipitate was formed which was filtered off, washed with water and dried to give the title compound (8.5 g), yield 65%.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[CH:12][C:13]([N+:26]([O-])=O)=[C:14]([CH:25]=1)[C:15]([NH:17][CH2:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:16])[CH2:3][CH2:2]2.[H][H]>CO.[Pd]>[NH2:26][C:13]1[CH:12]=[CH:11][C:10]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[CH:25][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:16]
Reactant: [H][H]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Yield: 98.9 %

Procedure:
5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (Intermediate 4A) (7.0 g, 18.0 mmol) was dissolved in methanol (120 mL) and palladium on carbon (0.7 g) added. The resulting solution was hydrogenated at room temperature under 4 bar pressure of hydrogen overnight. The reaction mixture was filtered through a celite pad, washed with methanol and dichloromethane, and concentrated to afford 2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)benzamide (6.4 g, 17.8 mmol).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(O)[CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:14]\[CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(O)(CCN2CCCC2)c2ccccn2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(/C(=C\CN2CCCC2)c2ccccn2)cc1
Temperature: 20 °C
Yield: 109.2 %

Procedure:
15 ml of demineralized water is charged into a round-bottomed flask kept at 25° to 30° C. and then slowly 243 ml of 90% Conc. H2SO4 is added and the temperature is raised to 10° C.-20° C. under stirring. Slowly 50 g of 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol is charged and the temperature is maintained at 20° C. under stirring. The reaction mass is heated to 100-105° C. and the temperature is maintained for 4 hours under stirring. After completion of the reaction, the reaction mass is cooled to 25°-30° C., and then poured into ice cold water (1 litre) at 5-10° C. under stirring over a period of an hour. 50% NaOH solution (w/w) is added slowly to the reaction mixture by maintaining the temperature at 5° to 20° C. over a period of 2 hours and the contents are stirred for an hour at 25° to 30° C. The reaction mixture is filtered under suction to obtain 51.3 g of wet triprolidine base comprising >92% E-isomer along with <8% Z-isomer. 500 ml of demineralized water and 51.3 g of wet triprolidine base are charged into a round-bottom flask at 25° to 30° C. and the contents are stirred for 3 hours by maintaining the same temperature. The contents are filtered and dried under suction for 2 hours. The process is repeated thrice to obtain 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidino prop-1-ene (38 g, 81.2%) consisting of >98% E isomer along with <2% Z-isomer.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](OC)([O:14]C)[CH:10]([O:18][CH3:19])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([O:18][CH3:19])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC1CN(Cc2ccccc2)CCC1(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COC1CN(Cc2ccccc2)CCC1=O
Yield: 90.6 %

Procedure:
1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b, 2.22g, 8.36 mmol) from Example 2 and p-toluenesulfonic acid (3.15 g, 16.6 mmol) was heated to reflux in acetone (100ml) for three hours. After being cooled, the reaction solution was concentrated under vacuum, then slurried in 40ml of 10% sodium hydroxide solution. The aqueous mixture was extracted with 2×60 ml of ether, the combined organic layers were dried over magnesium sulfate, then concentrated under vacuum. The crude residue was purified by chromatography (silica gel; ethyl acetate/hexane; 1:1) to provide the intermediate 1-phenylmethyl-3-methoxy-4-piperidone (5b, 1.66 g, 90%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6]3=[C:7]([CH:13]=[CH:14][N:5]3[CH2:4]1)[CH:8]=[CH:9][CH:10]=2.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Si:15]([O:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6]3=[C:7]([CH:13]=[CH:14][N:5]3[CH2:4]1)[CH:8]=[CH:9][CH:10]=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: OCC1Cc2cccc3ccn(c23)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1Cc2cccc3ccn(c23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(hydroxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (47 mmol) in dichloromethane (143 mL) at 0° C. was added tert-butyldimethylsilyl chloride (7.63 g, 49.4 mmol), followed by triethylamine (7.92 mL, 56.4 mmol) and dimethylaminopyridine (0.58 g, 4.7 mmol). The reaction was allowed to warm to room temperature and stirred 2 hours. The reaction was quenched with water, extracted with dichloromethane and the combined organics dried over sodium sulfate. The organic phase was concentrated under reduced pressure to provide 5-(tert-butyldimethylsilyloxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline. This material was treated essentially as described in Preparation II to provide the title compounds.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13]C(=O)OCC3C=CC=CC=3)[C:11](=[O:24])[NH:10]2)[N:4]=1>CCO.[Pd]>[NH2:13][C@H:12]1[C@@H:9]([CH2:8][N:5]2[N:4]=[C:3]([CH2:2][OH:1])[CH:7]=[N:6]2)[NH:10][C:11]1=[O:24]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (1.54 g, 4.65 mmol) in EtOH (50 mL) and EtOH (25 mL) was added Pd/C (10%, 0.51 g, 4.65 mmol). After stirring at rt for 4 h, the reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to afford the title compound (assume quantitive). The crude was used as such in the following step. LCMS: Rt=0.12 min, m/z=198.0 (M+1) Method 2m_acidic.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([OH:13])(=[O:12])=[O:11].Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:10]([OH:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1cc(F)ccc1O
Reaction time: 0.5 h

Procedure:
200 g (1.78 mol) of 4-fluorophenol are dissolved under a nitrogen atmosphere in 1300 ml of CHCl3 (distilled, dried over CaCl2). Added dropwise to this solution, over a period of 1 hour at room temperature with stirring, are 131 ml(229 g=1.96 mol) of chlorosulfonic acid, a vigorous release of HCl being observed initially, which dies down 30 min after completion and ceases entirely after a further 3 hours. After a reaction time of 24 hours, the precipitated product is filtered off with suction at room temperature under inert gas, washed twice with 200 ml of CHCl3 each time, and dried in vacuo at 1333 Pa and room temperature for 3 hours.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H][H]>CCOC(C)=O.CCO.O=[Pt]=O>[Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C#Cc2ccccc2)c(Br)c(=O)n1Cc1cccc(F)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(CCc2ccccc2)c(Br)c(=O)n1Cc1cccc(F)c1

Procedure:
To a solution of 3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one (0.55 g, 0.0014 mol) in EtOAc (10.0 mL) and EtOH (10.0 mL) was added PtO2 (0.05 g) and stirred in an atmosphere of hydrogen gas at 15 psi for 30 min. The catalyst was removed by filtration, the filtrate was concentrated and the residue was purified by silica gel flash chromatography using 25% EtOAc in hexane as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:27]([OH:29])=O)=[N:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)=[O:4].[CH2:30]([N:32](CC)CC)C.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:27](=[O:29])[NH:32][CH3:30])=[N:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccccc1Nc1ccc2c(C(=O)O)nn(C3CCCCO3)c2c1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1nn(C2CCCCO2)c2cc(Nc3ccccc3C(=O)OC)ccc12
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a solution of 6-(2-Methoxycarbonyl-phenylamino)-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboxylic acid (0.50 g, 1.27 mmol) in DMF was added triethylamine (0.42 mL, 3.04 mmol), methylamine (1.9 mL, 3.81 mmol), and HATU (0.578 g, 1.52 mmol). The reaction was stirred for 3 hours and then concentrated by rotary evaporation. The crude oil was chromatographed (50 g silica gel, 25–50% EtOAc/hexanes) to yield the desired product (214 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=[O:7].C(O)(=O)C.C(O[Cl:22])(C)(C)C>ClCCl.C(OCC)(=O)C>[Cl:22][C:3]1[C:2]([F:1])=[C:10]([F:11])[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:12]
Reactant: CC(C)(C)OCl
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1c(C(=O)O)cc(F)c(F)c1Cl
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To a solution of 4,5-difluoroanthranilic acid (2.45 g, 14.2 mmol) in dichloromethane (25 mL) is added acetic acid (10 mL) and hypochlorous acid tert-butyl ester (1.75 mL, 15.6 mmol). After 2 hours, the reaction mixture is diluted with ethyl acetate and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The resulting residue is purified via flash column chromatography (5% isopropyl alcohol/1% formic acid/94% dichloromethane) to afford 3-chloro-4,5-difluoroanthranilic acid as an oil (2.97 g). MS CI: m/z 206 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7C(OC(C)(C)C)=O)[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH3:60][O:61][C:62]([NH:64][C@@H:65]([C@@H:69]([CH3:72])[CH2:70][CH3:71])[C:66](O)=[O:67])=[O:63].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:7]([CH3:8])[CH2:9][CH3:10])[C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:66](=[O:67])[CH:65]([NH:64][C:62](=[O:63])[O:61][CH3:60])[C@H:69]([CH3:72])[CH2:70][CH3:71])[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CN1CCOCC1
Product: CC[C@@H](C)C(NC(=O)OC)C(=O)N1C[C@@H](COC)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)[C@@H](NC(=O)OC)[C@H](C)CC)[nH]2)ccc1-4
Reaction time: 3 h
Yield: 86 %

Procedure:
tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,35)-2-(methoxycarbonylamino)-3-methylpentanoic acid (34 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(3R)-1-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate (98 mg, 86%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)=[O:4].NC1C=CC([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][Br:27])=CC=1>>[Br:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])=[CH:7][CH:8]=1)=[O:28]
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Reactant: Nc1ccc(C(=O)CCCCBr)cc1
Product: O=C(CCCCBr)c1ccc(NC(=O)C(F)(F)F)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 32, using Intermediate 43 as a substrate. ES/MS calcd. for C13H14BrF3NO2+ 352.0. Found m/z=352.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC.[NH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>C(#N)C>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: Nc1cnc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCOc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Yield: 84 %

Procedure:
4-Butoxy-benzoyl chloride (0.21 mL, 1.11 mmol), Et3N (0.16 mL, 1.15 mL) and 3-aminoquinoline (0.153 g, 1.06 mmol) were stirred together in 10 mL acetonitrile in a round bottom flask for 4 hours. The reaction mixture was then evaporated in vacuo and the residue was triturated with 5 mL acetonitrile. The resulting solid was collected by filtration, rinsed with acetonitrile and dried to yield the title product as a cream-colored powder (0.284 g, 0.89 mmol). 1H NMR (CDCl3): δ 8.91 (s, 2H), 8.20 (s, 1H), 8.08 (d, 1H), 7.94 (d, 2H), 7.84 (d, 1H), 7.67 (t, 1H), 7.57 (t, 1H), 7.01 (d, 2H), 4.05 (t, 2H), 1.83 (p, 2H), 1.52 (h, 2H), 1.01 (t, 3H); MS: m/z 321.0 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([OH:21])=O)[C:8]=3[CH:22]=2)[CH2:3][CH2:2]1.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>ClCCl.C(=O)(O)[O-].[Na+].CO.C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19]([NH:29][CH3:28])=[O:21])[C:8]=3[CH:22]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1C1CC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxylic acid (2.52 g, 6.47 mmol), HATU (2.95 g, 7.77 mmol) and triethylamine (1.984 mL, 14.24 mmol) in dry dichloromethane (100 mL) was stirred at room temperature for 1 hour, then treated with methylamine (16.18 mL, 32.4 mmol). The solution was stirred at room temperature under nitrogen for 4 hours, during which time a precipitate formed. The reaction was diluted with dichloromethane (300 mL) and sodium bicarbonate solution (200 mL) and stirred for 10 minutes. The layers were separated and the aqueous layer extracted with further dichloromethane (150 mL). The combined organics were washed with brine (200 mL), dried using a hydrophobic frit and evaporated to dryness to give an off-white solid. The crude product was purified by flash chromatography (eluting with 0-100% ethyl acetate/cyclohexane followed by 10% methanol/dichloromethane) to give a white solid. The solid was dissolved in hot methanol-chloroform (10% v/v), preabsorped onto silica gel and purified by flash chromatography (0-10% methanol/dichloromethane) to give the 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (br s, 1H) 8.42 (q, 1H) 7.88-7.98 (m, 2H) 7.60 (s, 1H) 7.37 (t, 2H) 7.16 (s, 1H) 3.06 (s, 3H) 2.83 (d, 3H) 2.23-2.36 (m, 1H) 0.93-1.05 (m, 2H) 0.65-0.74 (m, 2H). LCMS (m/z, ES+)=403 (M+H+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18](C)(C)C)=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[CH3:22][O-:23].[Na+].Cl>O1CCCC1.CO>[CH3:22][O:23][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(-c2ccc(-c3ccc(Br)s3)s2)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(-c3ccc(C)cc3)s2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
A solution of 1.5 grams (0.004 mole) of 5'-bromo-5-(4-methylphenyl) [2,2'-bithienyl] (prepared as in Example 64) in 25 ml of dry tetrahydrofuran was stirred, and 0.24 gram (0.0044 mole) of sodium methoxide in methanol was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for three hours, then was heated under reflux for 16 hours. The reaction mixture was cooled and 50 ml of aqueous 10% hydrochloric acid was added. The mixture was extracted with methylene chloride and the extract dried with sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with 25% methylene chloride in hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.6 gram of 5'-methoxy-5-(4-methylphenyl)[2,2'-bithienyl], m.p. 108°-111° C.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[N+:21]([C:17]1[CH:16]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)n1nc(-c2cccc([N+](=O)[O-])c2)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(-c3cccc([N+](=O)[O-])c3)c12

Procedure:
1-tert-butyl-3-(3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (23 mg, 0.055 mmol) was dissolved in a solution of formic acid (5 mL) and conc. HCl (0.1 mL) and heated to reflux for 2 hours. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 257.1, found 257.3.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[C:28]1([CH2:34][S:35](Cl)(=[O:37])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][N:23]([S:35]([CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:37])=[O:36])[CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Product: COc1cc(Nc2nc3c(s2)CN(S(=O)(=O)Cc2ccccc2)CC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 45 from 90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 39 mg (0.2 mmol) alpha-toluenesulphonylchloride yielding 18 mg (18%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(5-phenylmethanesulfonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine as a yellow solid. MS ISP (m/e): 496.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.36 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.38-7.35 (m, 6H), 7.30 (d, 1H), 7.25 (d, 1H), 7.02 (s, 1H), 4.50 (s, 2H), 4.29 (s, 2H), 3.78 (s, 3H), 3.48 (t, 2H), 2.64 (br t, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:26][N:14]3[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[N+](=[CH2:29])=[N-].C(#N)C>O1CCCC1.C(OCC)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:26][N:14]4[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:29][CH2:3]1
Reactant: C=[N+]=[N-]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(C(=O)OC(C)(C)C)CCN3C2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](Oc3cnc(C4(C)CC4)cn3)C[C@H]2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Example 202B (40 mg, 0.111 mmol) in anhydrous tetrahydrofuran (1 mL) was added a 0.67 M solution of diazomethane in diethyl ether. The yellow solution was cooled to 0° C., and palladium(II) acetate (1 mg, 4.45 μmol) was added resulting in rapid gas evolution. More diazomethane solution (1 mL) was added dropwise, and the mixture was stirred at 0° C. for 30 minutes. The addition of 1 mL diazomethane solution was repeated several more times at 0° C. while monitoring reaction progress by LCMS (C18 silica gel using a 3 minute gradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid)). The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel using a solvent gradient of 0-50% ethyl acetate in hexanes. The title compound was obtained as a colorless oil that crystallized on standing (30 mg, 72%).