Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:31]([O:33]C)=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1>Cl>[OH:1][C:2]1([C:31]([OH:33])=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1
Reactant: COC(=O)C1(O)CCC(n2c(Nc3c(F)cc(F)cc3F)nc3cnc(NC(C)C)nc32)CC1
Agent: Cl
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)O)CC3)c2n1
Temperature: 60 °C
Yield: 73 %

Procedure:
Methyl 1-hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}cyclohexanecarboxylate (1.858 g, 3.858 mmol) was dissolved in 27 mL of 4.0 N aqueous hydrochloric acid solution. The reaction mixture was heated to 60° C. for 24 h. The mixture was then concentrated under reduced pressure to an oil and purified by preparative HPLC (20-80% acetonitrile-water, 0.1% TFA). The product was isolated as a white solid by filtration after evaporating acetonitrile from the combined fractions and neutralizing with concentrated ammonium hydroxide. (1.325 g, 73% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[S:11][C:10]=1[C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C>ClCCl.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[S:11][C:10]=1[C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(OCc2ccccc2)c(C(=O)O)s1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CON(C)C(=O)c1sc(C(C)C)cc1OCc1ccccc1
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
860 mg of 3-benzyloxy-5-isopropyl-thiophene-2-carboxylic acid were dissolved in 30 ml of dichloromethane, and 560 mg of N,O-dimethylhydroxylamine hydrochloride and 2.3 of triethylamine were added. After 15 min at 22° C., 2.3 ml of a 50% strength 1-propanephosphonic anhydride solution in acetic acid were added, and the mixture was stirred at 22° C. for a further 18 h. The reaction mixture was washed twice with 20 ml of water each time and once with 70 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]([CH2:6][C@@H:7]([CH2:12][C:13]([O-:15])=O)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[Cl:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[NH:64]1[CH2:69][CH2:68][CH:67]([N:70]2[CH2:79][C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[NH:72][C:71]2=[O:80])[CH2:66][CH2:65]1>CN(C=O)C>[NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]([CH2:6][C@@H:7]([CH2:12][C:13](=[O:15])[N:64]2[CH2:65][CH2:66][CH:67]([N:70]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]3=[O:80])[CH2:68][CH2:69]2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[Cl:22]
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.0 g (8.83 mmol) 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and 3.05 g (9.5 mmol) TBTU, 1.28 g (9.47 mmol) HOBT in 1.7 mL (9.76 mmol) ethyldiisopropylamine and 1100 mL DMF was stirred for 1 h at RT. Then 2.2 g (9.51 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one were added and the reaction solution was stirred overnight at RT. The reaction mixture was evaporated down i.vac., the residue was taken up in DCM, washed with 10% citric acid solution and 15% K2CO3 solution and dried over Na2SO4. The desiccant was eliminated by filtering through activated charcoal; after elimination of the solvent the desired product was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].N1C=CC=CC=1.[CH3:24][C:25](OC(C)=O)=[O:26]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[C:25]([O:1][CH2:2][C:3]([CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])=[CH2:17])(=[O:26])[CH3:24]
Reactant: C=C(CO)COc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(COC(C)=O)COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a solution of 2-(2-(hydroxymethyl)allyloxy)-6-nitrobenzonitrile (Example 200d) (0.40 g, 1.73 mmol), 4-dimethylaminopyridine (0.21 g, 1.73 mmol) and pyridine (0.68 g, 8.64 mmol) in CH2Cl2 (10.0 mL) at 0° C., was added Ac2O (0.53 g, 5.19 mmol) under a nitrogen atmosphere. After being stirred at 0° C. for 10 min, the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with 1.5M HCl, saturated aqueous NaHCO3 and brine, and was dried over MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using the solvent gradient hexanes→hexanes/EtOAc (3:7), to furnish 0.40 g (84%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J=8.4 Hz, J=1.2 Hz, 1H), 7.91 (t, J=8.4 Hz, 1H), 7.74 (dd, J=8.4 Hz, J=1.2 Hz, 1H), 5.43-5.46 (m, 1H), 5.36-5.40 (m, 1H), 4.90 (s, 2H), 4.66 (s, 2H), 2.05 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([O:23]C)=[C:18]([O:21]C)[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.CO>ClCCl>[CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([OH:21])[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1Cc2cccc3c2C(C1)c1ccc(OC)c(OC)c1O3
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: C=CCN1Cc2cccc3c2C(C1)c1ccc(O)c(O)c1O3
Temperature: -78 °C
Reaction time: 8 h
Yield: 119.3 %

Procedure:
N-Allyl amine 10 (0.625 g; 1.93 mmol) was dissolved in 50 ml of dichloromethane. The solution was cooled to −78° C. and 10.0 ml of BBr3 solution (1.0 M in dichloromethane) was slowly added. The solution was stirred overnight, while the reaction slowly warmed to room temperature. After recooling the solution to 78° C., 50 ml of methanol was slowly added to quench the reaction. The reaction was then concentrated to dryness. Methanol was added and the solution was concentrated. This process was repeated three times. Recystallization of the brown solid from ethanol gave 0.68 g (61%) of a white solid: mp 251-253° C. dec; 1H NMR: (300 MHz, D2O): 10.55 (s, 1H); 10.16 (s, 1H); 8.61 (t, 1H, J=9 Hz); 8.42 (d, 1H, J=9 Hz); 8.31 (d, 1H, J=9 Hz); 7.87 (d, 1H, J=9 Hz); 7.82 (d, H, J=9 Hz); 7.36 (q, 1H, J=9 Hz); 6.89 (m, 2H); 6.85 (d, 1H, J=15 Hz); 5.58 (m, 3H); 5.28 (m, 2H); 3.76 (d, 1H, J=3 Hz). HRCIMS m/z: Calc'd: 295.1208; Found: 295.1214.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][C:30]=1[N+:31]([O-])=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCOC(C)=O>[NH2:31][C:30]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[CH:19][C:18]=1[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CN(CCc2ccccc2)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N)c(CN(CCc2ccccc2)C(=O)OC(C)(C)C)c1
Reaction time: 3 h
Yield: 91.4 %

Procedure:
A mixture of tert-butyl 3-[[N-(tert-butoxycarbonyl)-N-phenethylamino]methyl]-4-nitrobenzoate (2.7 g, 5.9 mmole), 10% Pd/C (0.6 g, 0.6 mmole Pd), and EtOAc (60 mL) was shaken under H2 (50 psi). After 3 hr, the mixture was filtered to remove the catalyst, and the filtrate was concentrated to dryness. Flash chromatography on silica gel (20% EtOAc/hexanes) gave the title compound (2.3 g, 91%) as a yellow foamy oil which slowly partially solidified: 1H NMR (250 MHz, CDCl3) δ 7.74 (dd, J=8.4, 2.0 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.05-7.40 (m, 5H), 6.57 (d, J=8.4 Hz, 1H), 5.00 (br s, 2H), 4.30 (s, 2H), 3.32 (app. t, 2H), 2.69 (app. t, 2H), 1.59 (s, 9H), 1.46 (s, 9H); MS (ES) m/e 449.2 (M+Na)+, 427.2 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH2:15][CH3:16])=[O:9])[N:4]=[CH:3]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CCO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1c[nH]cn1

Procedure:
1H-Imidazol-4-ylacetic acid hydrochloride (5.00 g) was dissolved in ethanol (100 mL). To the solution, thionyl chloride (2.46 mL) was added at room temperature, and the mixture was then heated to reflux for 3.5 hours. The reaction solvent was distilled off under reduced pressure. To the residue, a saturated aqueous solution of sodium bicarbonate was then added, and organic matter was extracted five times with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of ethyl 1H-imidazol-4-ylacetate (4.10 g).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:9][C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([O:17][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[Cl:19])=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccccc1Cl
Reactant: O=C(Oc1cc(Cl)c(O)c(Cl)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Oc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
A mixture of 2.27 g of 4-benzoyloxy-2,6-dichlorophenol, 1.29 g of 2-chlorobenzyl chloride, 1.21 g of potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at 80° C. for 6 hours. The reaction mixture was cooled to room temperature, poured in ice water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, and dried with anhydrous magnesium sulfate, followed by removal of the solvent by distillation under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 2.87 g of 1-benzoyloxy-4-(2-chlorobenzyloxy)-3,5-dichlorobenzene (88% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[H-].[Na+].Br[CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1>O1CCCC1>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a solution of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (3.50 g, 11.9 mmol) in anhydrous tetrahydrofuran (75 mL) at 0° C., was added sodium hydride (60% w/w dispersion in mineral oil, 0.72 g, 17.9 mmol). The solution was stirred at 0° C. for 0.5 h and methyl 4-(bromomethyl)benzoate (3.00 g, 13.1 mmol) was added. The solution was stirred at ambient temperature for 16 h, further sodium hydride (60% w/w dispersion in mineral oil, 0.30 g, 7.5 mmol) and methyl 4-(bromomethyl)benzoate (0.50 g, 2.2 mmol) were added and the mixture was stirred for 1 h, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 25% to 50% gradient of ethyl acetate in hexanes to afford methyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate (4.51 g, 86%) as a colorless solid: mp 167-169° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.15 (d, J=7.4 Hz, 2H), 7.03-6.96 (m, 1H), 6.73-6.68 (m, 1H), 6.48 (s, 1H), 6.22 (s, 1H), 5.10 (d, J=15.9 Hz, 1H), 4.92 (d, J=8.9 Hz, 1H), 4.84 (d, J=16.0 Hz, 1H), 4.65 (d, J=8.9 Hz, 1H), 4.19-4.04 (m, 4H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 166.6, 155.3, 144.7, 141.8, 140.9, 138.4, 132.2, 130.3, 129.8, 128.9, 127.3, 124.0, 123.6, 120.9, 111.5, 109.2, 99.5, 80.1, 64.5, 63.9, 58.1, 52.2, 43.9; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1.BrC(C)C.C1C=CC2C(=CC=CC=2O)C=1>CS(C)=O>[CH3:1][CH:2]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1)[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCc2ccc(O)cc21
Agent: Oc1cccc2ccccc12
Agent: [K+]
Solvent: CC(C)Br
Solvent: CS(C)=O
Product: CC(C)Oc1ccc2c(c1)C(=O)CCC2
Temperature: 0 °C
Yield: 65 %

Procedure:
A suspension of 24.3 g (0.22 mole) of potassium tert-butoxide in 240 ml of dimethyl sulfoxide under a nitrogen atmosphere was stirred and cooled in a cold water bath while a solution of 29.2 g (0.18 mole) of 3,4-dihydro-7-hydroxy-1(2H)-naphthalenone in 400 ml of dimethyl sulfoxide was added dropwise over 45 minutes. The mixture was stirred at room temperature for an additional 45 minutes, and then 23.7 ml (31.0 g; 0.25 mole) of 2-bromopropane was added in one portion. After stirring for an additional 30 hours, the mixture was added to 2.0 kg of ice/water and extracted with dichloromethane (4×300 ml). The combined organic layers were back-washed with water (2×150 ml), dried (anhydrous magnesium sulfate), and evaporated (vacuum) to an oil residue. Flash chromatographic purification (silica gel, dichloromethane elution) of the residue yielded 24.0 g (65% yield) of the analytically pure ether product as an oil, suitable for conversion to the naphthol described in Example 4.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: COCCCc1ccc(Br)cc1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCc1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1
Temperature: 80 °C

Procedure:
1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (276 mg, obtained in example 121, step 3) was dissolved in DMF (18 mL) at r.t. Then, 1-bromo-4-(3-methoxy-propyl)-benzene (599 mg, obtained in example 130, step 2), N,N′-dimethylethylenediamine (sym) (230 mg), Cuprous iodide (373 mg) and K3PO4 (832 mg) were added to the reaction mixture and the mixture was heated to 80° C. for 3 hours. The reaction mixture was cooled, poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The title compound was obtained as a yellow liquid (460 mg, 93%) and was used without further purification. MS (m/e): 360.2. [MH+].
Reaction SMILES: [BH3-]C#N.[Na+].[Cl:5][C:6]1[CH:33]=[CH:32][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:16]=3[CH:31]=2)=[O:11])=[CH:8][CH:7]=1.[NH4+].[OH-]>C(O)(=O)C.CO>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][NH:18][CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:16]=3[CH:31]=2)=[O:11])=[CH:32][CH:33]=1
Reactant: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1C(=O)CNC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
NaBH3CN (0.0472 mol) was added at 5° C. to a mixture of intermediate (7) (0.0236 mol) in acetic acid (50 ml) and methanol (300 ml). The mixture was stirred at 5° C. for 30 min and then stirred at room temperature for 2 hours. Ice water and then NH4OH 35% (60 ml) were added. The mixture was stirred for 2 hours. The precipitate was filtered off, washed with water and taken up in DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 8.25 g (85%) of 7-(4-chlorobenzoyl)-5-(3-chlorophenyl)-1,3,4,5-tetrahydro-1-methyl-2H-1,4-benzodiazepin-2-one (intermediate 8), mp. 177° C.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18]C)=[O:17])=[CH:14]N=1)[CH3:10])=O)(C)(C)C.[ClH:20].[CH3:21]O>O1CCOCC1>[ClH:20].[NH2:8][CH:9]([C:11]1[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH:21]=1)[CH3:10]
Reactant: CO
Reactant: COC(=O)c1cnc(C(C)NC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylate (0.9 g, 3 mmol) in MeOH (5 mL) was added 4M HCl in dioxane (4 mL). The reaction was stirred overnight at room temperature. The reaction was evaporated to dryness to afford 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride (0.7 g, 100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH:12](OC)([O:15][CH3:16])[O:13][CH3:14].Cl>CO>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:7]1[CH:10]=[CH:11][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: CCCc1ccc(C=O)cc1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Product: CCCc1ccc(C(OC)OC)cc1
Temperature: -5 °C

Procedure:
A reaction flask was charged with 4-propyl benzaldehyde (1.064 Kg, commercially available from Mitsubishi Gas Chemical Company, Inc.), methanol (500 mL), and trimethyl orthoformate (TMOF) (1.144 Kg, commercially available from Sigma-Aldrich, Inc.). The reaction mass was cooled to −10 to 0° C. and hydrochloric acid (37%, 1 g) was added in one portion. The reaction was instantaneous and the temperature was allowed to rise to 25° C. for over 30 minutes. The reaction mass was then quenched with sodium acetate (20 g) and the solvent was removed by evaporation. The crude intermediate product 1-dimethoxymethyl-4-propyl-benzene (1.388 Kg) was obtained and charged to a second reaction flask at 25° C. Boron trifluride etherate (1 g, commercially available from Sigma-Aldrich, Inc.) was added. Ethyl vinyl ether (684 g, commercially available from Sigma-Aldrich, Inc.) was then fed for over 4 hours with the temperature maintained at 25-30° C. The reaction mass was quenched with saturated sodium carbonate (500 mL). The crude intermediate products methoxy ethoxy acetals were obtained, which were contained in the organic layer and confirmed by NMR analysis. Crude methoxy ethoxy acetals were hydrolyzed in the presence of water (500 mL) containing hydrochloric acid (37%, 50 g) at 90° C. for 5 hours and further catalytically hydrogenated in 2-propanol (200 mL) using palladium on carbon (5%, 1 g) and hydrogen in a 1 L zipper autoclave to provide the product 3-(4-propyl-phenyl)-propionaldehyde (1.008 Kg), which had a boiling point of 115° C. at a pressure of 6 mmHg.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[N:8][O:9][C:5]=2[CH:4]=1.C(Cl)Cl.B(Br)(Br)Br.C(Cl)Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C(C)NC(C)=O)noc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)NC(C)c1noc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a suspension of N-[1-(6-methoxy-1,2-benzisoxazol-3-yl)ethyl]acetamide (500 mg, 2.13 mmol) obtained in Reference Example 9 in toluene (10 mL) was added 1 M boron tribromide methylene chloride solution (6.40 mL, 6.40 mmol) under ice-cooling and, under a nitrogen atmosphere, the mixture was stirred at room temperature for 1 hr. Methylene chloride (5 mL) and 1 M boron tribromide methylene chloride solution (5.00 mL, 5.00 mmol) were added thereto at room temperature, and the mixture was stirred under heating at 50° C. for 16 hr. To the reaction mixture was added ethyl acetate, and the mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (470 mg, quantitative) as an oil. This was used for the next step without purification.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[Cl:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1Cl
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1Cl
Yield: 45.2 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol) and 2-chloroaniline (1.6 ml, 15 mmol) in dioxan (10 ml) were heated at reflux for 30 minutes, then allowed to cool. The product was filtered off, converted to free base, and recrystallised from methanol to give 3-butyryl-4-(2-chlorophenylamino)-8-methylquinoline (1.53 g), m.p. 130°-131°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:21][C:22]([C@@H:24]1[CH2:28][O:27]C(C)(C)[O:25]1)=O.O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([C@@H:24]([OH:25])[CH2:28][OH:27])[N:11]=2)=[N:6][CH:7]=1
Reactant: CC1(C)OC[C@@H](C(=O)CCl)O1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: OC[C@H](O)c1csc(Nc2ncc(Br)cc2Oc2ccc(F)cc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
To 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (0.5 g, 1.5 mmol) in ethanol (50 mL) was added (S)-2-chloro-1-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanone (0.34 g, 1.9 mmol) and the reaction stirred at 80° C. for 1 hr. The reaction was poured into water (250 mL) and then filtered. The solid was triturated with ethyl acetate and methanol. The solid was suspended in ethyl acetate (500 mL) and washed with 1 N NaOH (500 mL). The organics were concentrated and the crude material was purified by chromatography using 3 to 10% MeOH/CH2Cl2 as eluent to give (R)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol (0.043 g, 0.10 mmol, 7%) (ABCI POS 426, 428 M+H).