Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][C:20]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]>C(OC(=O)C)(=O)C>[ClH:1].[CH2:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:28][C:26](=[O:27])[C:20]4([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[N:19]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)[CH2:3][CH3:4]
Reactant: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)O)CCCCC3)cc2)CC1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCCN1CCN(c2ccc(C3=NC4(CCCCC4)C(=O)O3)cc2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
After a suspension of 631 mg (1.54 mmol) of 1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid hydrochloride in 18 ml of acetic anhydride was stirred at 100° C. for 1 hour, the reaction solution was concentrated under reduced pressure. The operation for adding toluene to the obtained residue and distilling off it under reduced pressure was carried out three times, and acetic anhydride was removed by azeotropic distillation to obtain 500 mg (83%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:27]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)=[O:34])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Reaction time: 8 h

Procedure:
To a mixture of 0.45 g (1.75 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.707 g (6.99 mmol) of triethylamine and 5 ml of dimethylformamide at ice-water bath temperature is added dropwise a solution of 0.247 g (1.75 mmol) of isonicotinoyl chloride hydrochloride and 1 ml of dimethylformamide. The reaction mixture is allowed to stir overnight while slowly reaching room temperature. A white precipitate is formed which is collected by filtration, washed with water and dried to yield 0.320 (50%) of the title compound as a white solid: m.p.>250° C.; m/e 362.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[NH3:38].CO>>[NH2:38][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=3[F:36])(=[O:29])=[O:28])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: N
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Solvent: CO
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (156 mg, 0.267 mmol) and ammonia in methanol (10 mL, 70 mmol), the title compound was obtained as a yellow solid (53 mg, 33% yield). MS (ESI): 564 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH2:9][CH:10]([O:19][C:20](=[O:22])C)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3]C(OCC)=O.[OH-].[Na+].C(OCC)(=O)C>CO>[OH:1][C:2]1([CH3:3])[CH2:9][CH:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:19][C:20](=[O:22])[CH2:23]1
Reactant: CCOC(=O)CC(C)(O)CC(CCc1ccccc1)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
Using 1.48 g of 4-acetoxy-6-phenylhexan-2one, 1 ml of ethyl bromoacetate and 0.62 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.03 g of ethyl 3-hydroxy-3-methyl-5-acetoxy-7-phenylheptanoate. The ester (0.90 g) thus obtained was dissolved in 5 ml of methanol and 2 ml of 4 N sodium hydroxide was added thereto. The mixture was stirred for 4 hours at room temperature, acidified by the addition of 4 N hydrocholoric acid, 5 ml of ethyl acetate was added and the mixture was stirred for 3 days. The usual treatment of the organic solvent layer afforded 400 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-])=O.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH2:10]
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1cc(C)ccc1N

Procedure:
To a solution of 2-methoxy-4-methyl-1-nitrobenzene (5 g; 29.9 mmol) in methanol (200 mL) was added Tin(II) chloride dihydrate (33.7 g; 150 mmol) and the mixture was heated to reflux for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. A saturated solution of sodium hydrogen carbonate was added until pH 8. A suspension formed and the mixture was filtered on a plug of celite. The organic phase was separated, washed with a saturated solution of sodium hydrogen carbonate solution and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was used as such in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (2) (4.18 g, 25 mmol) was dissolved in anhydrous DMF (100 mL). To this solution was added benzyl bromide (3.27 mL, 27.5 mmol) and potassium carbonate (3.8 g, 27.5 mmol). The reaction mixture was stirred at room temperature for 18 h, filtered and evaporated. The residue was taken up into ethyl acetate (250 mL) and water (250 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and evaporated leaving 3-benzyloxy-4-nitro-benzaldehyde (3) as an orange solid (6.31 g, 98% yield): 1HNMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.45 (m, 5H), 5.40 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 192.4, 151.2, 143.5, 139.9, 135.9, 128.9, 128.6, 127.9, 125.9, 122.7, 115.5, 71.1. To a suspension of sodium hydride (0.29 g, 12 mmol) in anhydrous THF (25 mL) at 0° C. was added via dropping funnel diethyl cyanomethylphosphonate (4) (1.94 mL, 12 mmol) in anhydrous THF (5 mL) followed by 3-benzyloxy-4-nitro-benzaldehyde (3) (2.6 g, 10 mmol) in anhydrous THF (30 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solvent was evaporated and the residue was taken up into ethyl acetate (50 mL) and water (25 mL). The organic phase was washed with brine (25 mL), dried over MgSO4, filtered and evaporated leaving 3-(3-benzyloxy-4-nitro-phenyl)-acrylonitrile (5) as an orange-red solid (0.28 g, 100% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.04 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J=16.6 Hz, 1H), 7.45 (m, 6H), 6.72 (d, J=16.6 Hz, 1H), 5.33 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 151.4, 148.9, 140.8, 139.5, 136.0, 128.9, 128.6, 128.0, 126.0, 120.7, 118.5, 114.5, 101.3, 71.1; MS calculated for C16H12N2O3 (M)+: 280. found 280. 3-(3-Benzyloxy-4-nitro-phenyl)-(5) (0.28 g, 1.0 mmol) was dissolved in anhydrous methanol (20 mL). To this solution was added 10% palladium on carbon (56 mg, 20% wt) under a blanket of carbon dioxide. The hydrogenation was carried out under 60 psi of hydrogen at room temperature for 4 h, filtered through a pad of Celite and evaporated to yield an orange oil. This oil was stirred in hexane, decanted and vacuum dried leaving 3-(4-amino-3-hydroxy-phenyl)-propionitrile (1) as an orange solid (0.58 g, 100% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.81 (bs, 1H), 6.31 (m, 3H), 4.30 (bs 2H), 3.18 (s, 2H), 2.35 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 144.3, 135.5, 127.1, 120.8, 119.6, 114.9, 30.5, 19.2; MS calculated for C9H10N2O (M)+: 162. found 162.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(C1(N[C:34]([CH:36](NC(N2CCOCC2)=O)CC(C)(C)C)=[O:35])CC(C2C=CC=CC=2)NC(C2C=CC=CC=2)C1)#N>C(O)(=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:34](=[O:35])[CH3:36])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CC(c2ccccc2)NC(c2ccccc2)C1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC(C)=O)cc1

Procedure:
Methyl-4-(acetylamino-methyl)-benzoate was prepared from acetic acid and methyl 4-(aminomethyl)benzoate using a method analogous to that of Example 1-part (d). The crude N-acyl ester was saponified using a method analogous to that of Example 1-part (c). The crude product was used without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=2)[N:19]=[CH:18][N:17]=1.C(O)(=O)C>CN1C(=O)CCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]3=[O:3])[CH:24]=2)[N:19]=[CH:18][N:17]=1
Reactant: Oc1ccccn1
Reactant: Fc1ccc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=c1ccccn1-c1ccc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
Sodium hydride (0.24 g) was added to a solution of 2-hydroxypyridine (0.95 g) in NMP (10 ml) and the mixture was stirred at ambient temperature for 30 minutes. A mixture of a portion (3 ml) of the resultant solution and 4-(3,4-dichloroanilino)-6-fluoroquinazoline hydrochloride (0.172 g) was heated at 215° C. for 10 hours. The reaction mixture was acidified with glacial acetic acid and evaporated at 90° C. under high vacuum. The residue was chromatographed on silica using a mixture of methylene chloride and methanol, increasing in polarity from pure methylene chloride to a 19:1 mixture of methylene chloride: methanol as eluent. The product so obtained was triturated with a 1:1 mixture of isopropanol and ethyl acetate. The solid was filtered off, washed with ethyl acetate and dried under high vacuum to give 4-(3,4-dichloroanilino)-6-(2-oxo-1,2-dihydropyridin-1-yl)quinazoline (0.099 g); NMR Spectrum: (CD3SOCD3) 6.44 (m, 1H), 6.57 (m, 1H), 7.55-7.66 (m, 1H), 7.68 (d, 1H), 7.75-8.00 (m, 4H), 8.34 (d, 1H), 8.65 (s, 1H), 8.78 (s, 1H), 9.78 (s, 1H);
Reaction SMILES: FC1C=CC([C:8]2([C:12]3C4C(=CC=C(OCCN)C=4)CC[N:13]=3)CCC2)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([C:37]3[C:46]4[C:41](=[CH:42][C:43]([OH:47])=[CH:44][CH:45]=4)[CH2:40][CH2:39][N:38]=3)[CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2([C:37]3[C:46]4[C:41](=[CH:42][C:43]([O:47][CH2:8][CH2:12][NH2:13])=[CH:44][CH:45]=4)[CH2:40][CH2:39][N:38]=3)[CH2:36][CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Reactant: Oc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Product: NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-yl}oxy)ethanamine was prepared analogously to 2-({1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine using 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-ol in place of 1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (cf. example 65).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1)[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCC=O
Product: CCCCNc1ccc(C(=O)OC)cc1
Yield: 87.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-aminobenzoic acid methyl ester (Aldrich, 500 mg, 3.31 mmol) and butyraldehyde (300 μL, 3.31 mmol) were converted to the title compound (600 mg, 82%). 1H NMR (CDCl3) δ 7.91-7.80 (m, 2H), 6.59-6.46 (m, 2H), 3.86 (s, 3H), 3.18 (t, J=7.0 Hz, 2H), 1.67-1.58 (m, 2H), 1.48-1.37 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 208.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][CH2:22]Br>CN(C=O)C>[F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([O:8][CH2:20][O:21][CH3:22])=[N:6][CH:7]=1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: COCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1ncc(F)c(N=CN(C)C)n1
Yield: 18.5 %

Procedure:
N′-(5-Fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and bromomethyl methyl ether (75 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was placed directly onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-80% gradient) to isolate 23 mg, 0.1 mmol (19%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 5.46 (s, 2H), 3.53 (s, 3H), 3.17 (s, 3H), 3.16 (s, 3H); HPLC-MS (ESI) m/z 229 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23.B(Br)(Br)[Br:30].CO.[BrH:35]>ClC(Cl)C>[BrH:30].[BrH:35].[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23
Reactant: BrB(Br)Br
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(OC)ccc1-2
Agent: Br
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(O)ccc1-2
Temperature: 78 °C
Yield: 96 %

Procedure:
A 25° C. suspension of 75 g (0:17 mol) of 5-amino-N,N-diethyl-8-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine, dihydrochloride (1) in 1.35 L of dichloroethane was treated dropwise with 213 g (0.85 mol) of boron tribromide. The mixture was heated at 78° C. for 16 hr, treated cautiously with 1.5 L of methanol, then heated at reflux for 6 hr. After cooling to 25° C., then chilling at -5° C. overnight, the precipitated solids were collected by filtration, washed with cold methanol, and dried at 2 mm/48° C./24 hr to give 84.3 g (96%) of 7 as a salt with 2.0 equivalents of hydrogen bromide, mp 318° C. (dec), 98.3% pure by HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]([CH3:40])[C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:33][CH:32]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N(C)C)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 13 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (49 mg, 0.292 mmol). The final product was collected as a white solid (49 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H) 8.57-8.65 (m, 2H) 8.35 (s, 1H) 8.01-8.06 (m, 2H) 7.83 (s, 1H) 6.76 (d, J=8.84 Hz, 1H) 5.92 (s, 1H) 5.13 (dt, J=13.14, 6.57 Hz, 1H) 4.42 (br. s., 1H) 4.41 (br. s., 1H) 3.09 (s, 6H) 2.54 (m, 2H) 2.14 (s, 3H) 1.51-1.58 (m, 2H) 1.50 (s, 3H) 1.49 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=487.4 [M+H]+
Reaction SMILES: Br.C(O)(=O)C.CS(O)(=O)=O.C(OC([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][C:31]=1[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:28])=O)C1C=CC=CC=1>C(OCC)C>[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:37])[NH2:38])=[CH:32][C:31]=1[C:39](=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:28]
Reactant: N=C(N)c1ccc(OC(=O)CCCCCNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2)c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: N=C(N)c1ccc(OC(=O)CCCCCN)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To 8.0 ml of a 30% hydrogen bromide-acetic acid mixture, was added 1.7 g of 4-amidino-2-benzoylphenyl 6-benzyloxycarbonylaminocaproate methanesulfonate. The mixture was stirred for one hour at room temperature, whereby the crystals dissolved in 4 to 5 minutes, forming a uniform solution. Upon addition of anhydrous ethyl ether to the solution, an oily substance separated out. The supernatant was removed and the oily substance was washed a few times with ethyl ether. The oily substance was dissolved with heating in a small volume of water, admixed with acetone, and stirred while cooling in ice, to obtain 0.9 g of a colorless powder of 4-amidino-2-benzoylphenyl 6-aminocaproate dihydrobromide.
Reaction SMILES: [H-].[Na+].CC1C=CC(S(O[CH2:14][C@@H:15]2[O:17][CH2:16]2)(=O)=O)=CC=1.[F:18][C:19]1[CH:34]=[CH:33][C:22]2[C:23]([C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)=[N:24][O:25][C:21]=2[CH:20]=1>CN(C)C=O.O>[F:18][C:19]1[CH:34]=[CH:33][C:22]2[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:14][C@H:15]4[CH2:16][O:17]4)[CH:27]=3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1cccc(-c2noc3cc(F)ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Yield: 75 %

Procedure:
The title compound is prepared from a mixture of sodium hydride in dimethylformamide, 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol in dimethylformamide and (2R)-(−)-glycidyl tosylate in dimethylformamide essentially as described above except that the reaction mixture is diluted with water, extracted with ethyl acetate, washed with water (twice), dried (MgSO4), concentrated and purified by column (silica) chromatography eluting with a graded solvent mixtures of toluene to 1% ether in toluene to give the title compound as a white solid (9.29 g, 75% Yield). NMR and microanalysis (C, H, N) are consistent with the final, desired compound. Chiral HPLC, 16.92 minutes, [Chiralcel OD (250×4.6 mm), 98:2 heptane/ethanol @ 0.8 mL/min, UV @ 285 nm, 18.14] shows the title compound as 95.5% e.e. mp=84-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:6]Cl.[C-:17]#[N:18].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:17]#[N:18])[CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: [C-]#N
Reactant: CCCOc1c(OC)cc(CCl)cc1SC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1c(OC)cc(CC#N)cc1SC
Reaction time: 48 h
Yield: 94 %

Procedure:
To 16 g of 3-methoxy-5-methylthio-4-propoxybenzyl chloride in 100 ml of dry DMF was added 5 g (0.10 mole) sodium cyanide. The mixture was stirred for about 48 hours at rom temperature under N2. The solution was filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography to yield 14.5 g of 3-methoxy-5-methylthio-4-propoxyphenyl acetonitrile as an oil. (95% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25](Cl)[N:26]=[C:27]=[O:28])=[C:21]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:20]=1>ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[NH:26][C:27](=[O:28])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=3)[C:10]3[CH2:14][CH2:13][C:12](=[O:15])[C:11]2=3)=[C:21]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:20]=1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(Cl)N=C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2

Procedure:
3-(3-(Trifluoromethyl)phenylamino)cyclopent-2-enone (234 mg, 0.97 mmol) is added to a solution of 4-bromo-1-(chloro(isocyanato)methyl)-2-(methylsulfonyl)benzene (Step 1, 945 mg, 2.91 mmol) in dichloromethane (10 mL). The mixture is heated at reflux over night and then concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Agilent ZORBAX™ SB—C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 110 mg; ESI mass spectrum: ESI mass spectrum: [(79Br)-M+H]+=529, [(81Br)-M+H]+=531; Retention time HPLC: 1.21 min (Z017_S04).
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:8][NH:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[NH:21][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[C:6]([OH:42])=[O:5])=[O:31])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCCNc2nc3ccccc3[nH]2)cc1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(OCCCNc2nc3ccccc3[nH]2)cc1

Procedure:
A CH2Cl2 solution (20 mL) of 36-7 (580 mg, 0.97 mmol) and TFA (5 mL) was stirred under ambient conditions for 2 h and at 50° C. for 2 h. Concentration and flash chromatography (silica, 9:0.5:0.5 EtOH/H2O/NH4OH) gave 36-8 as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(Cl)c(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-chloro-2,4-difluorobenzene (0.829 g, 5.58 mmol) in concd H2SO4 (8.0 mL) at 0° C., KNO3 (0.565 g, 5.59 mmol) was added in one portion. The resulting solution was allowed to warn to room temperature and stirred overnight at room temperature. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 1.007 g (93%) pure (1H NMR) title compound as a light red oil; 1H NMR (CDCl3) δ 7.17 (dd, 1H, J1=9.9 Hz, J2=8.4 Hz), 8.24 (t, 1H, J=7.5 Hz).