Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N:20][NH:19][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccccc1C=O
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCCC
Product: COc1ccccc1C=NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1.5 g (7.3 mmol) 2-methoxybenzaldehyde and 1 g (7.3 mmol) benzhydrazide in 35 mL n-hexane was stirred overnight at room temperature. The precipitate was suctioned off, dried, and used without further purification (1.75 g).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Cl.[H][H]>[Ru].C(O)C>[OH:4][C@H:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: [H][H]
Agent: [Ru]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C[C@@H](C)O
Temperature: 80 °C
Reaction time: 19 h

Procedure:
30 g of ethyl acetoacetate, 5 ml of degassed ethanol and 0.9 ml of 1 N HCl are introduced in succession into a Schlenk vessel filled with argon. This solution and the catalyst solution from Example C1 are then transferred in succession by means of a steel capillary into a 50 ml steel autoclave filled with argon. The s/c (substrate/catalyst) ratio is 75 000. The autoclave is closed and a pressure of 50 bar is set using 4 flushing cycles (pressurization with 20 bar of hydrogen). The autoclave is then heated to 80° C., and after 30 minutes the reaction pressure is set to 80 bar. The autoclave is stirred for 19 hours. The heating is subsequently switched off and the autoclave is cooled to room temperature. After depressurization, a reddish reaction solution is isolated. The conversion is >98% (determined by means of GC and 1H-NMR). Removal of the solvent on a rotary evaporator gives a quantitative yield of ethyl (R)-3-hydroxybutyrate having an enantiomeric purity of 97.1% ee. (determined by means of GC after reaction with trifluoroacetic anhydride; column: Lipodex E, 50 m).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:21][C:22]([F:28])([F:27])[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:21][C:22]([F:28])([F:27])[S:23]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2([CH3:13])[CH:11]3[CH:9]2[CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12]3)[CH:15]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 0.10 g, 0.37 mmol) in pyridine (10 ml) cooled at 0° C. was treated with trifluoromethanesulphonyl chloride (0.14 g, 0.88 mmol) and 4-dimethylaminopyridine (5 mg). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was poured into saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (Na2SO4) and then concentrated in vacuo. The crude residue was purified by preparative HPLC (condition 7) to give a brown solid, (17 mg, 12%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([N:32]=[C:33]=[O:34])=[CH:26][C:25]=2[O:24]1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([NH:32][C:33]([NH:2][CH2:3][C:4]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:5]=3[C:6](=[O:22])[N:7]([CH:14]3[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]3=[O:21])[C:8]4=[O:13])=[O:34])=[CH:26][C:25]=2[O:24]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc2c(c1)OCO2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 77.7 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-methylenedioxyphenyl isocyanate (0.25 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.56 g of the product in 81% yield: mp 216-218° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.50-2.58 (m, 2H), 2.84-2.91 (m, 1H), 4.69 (d, J=5.8 Hz, 2H), 5.16 (dd, J=12.4 Hz, d=5.1 Hz, 1H), 5.93 (s, 2H), 6.67-6.70 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 7.75-7.88 (m, 3H), 8.67 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.7, 48.9, 100.5, 100.6, 108.0, 110.4, 121.8, 127.2, 131.6, 133.6, 134.7, 134.8, 140.3, 141.5, 147.1, 155.3, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C22H18N4O5: C, 58.67; H, 4.03; N, 12.44. Found: C, 58.35; H, 3.95; N, 12.25.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[N:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=2)=[O:19])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1cc(Cl)ccc1N1CCN(C(=O)c2ccc(O)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)N2CCN(c3ccc(Cl)cc3C(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 6-{[4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl]carbonyl}pyridin-3-ol (Example 208, 0.26 g, 0.69 mmol), methyl bromoacetate (0.13 g, 0.82 mmol) and potassium carbonate (0.19 g, 1.38 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was filtered through NH-silica gel pad to give the title compound (0.27 g, 89%) as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=2)[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (42 mg, 0.156 mmole) and p-trifluoromethylbenzoyl chloride (32.5 mg, 0.156 mmole) were combined in 3 ml of methylene chloride (CH2Cl2), treated with triethylamine (0.0157 g, 0.156 mmole) and stirred at room temperature 15 minutes. The mixture was diluted with CH2Cl2 (20 ml), washed with 10% citric acid (2×5 ml), dilute sodium bicarbonate (2×5 ml), and water (2×5 ml), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate (0.4 ml)/ether (1 ml) to give the title compound which was dried in vacuo at 90°: (m.p. 209°-211°).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.O.[CH2:21](O)[CH3:22]>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
To a slight suspension of 4-methyl-3-(trifluoromethyl)benzoic acid (2.18 g, 10.7 mmol, ABCR) in ethanol (30 ml) was added concentrated sulphuric acid specific gravity 1.84 (0.5 ml, 9.38 mmol). The resulting solution was heated to reflux overnight under nitrogen. The solution was diluted with DCM (100 ml) and then water (100 ml). The phases were separated and the organic extract washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a mobile pale yellow oil (2.27 g); LCMS: (System 4) MH+=233, tRET=3.29 min.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C@@H:14]([CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][C:32](=[O:50])[C:33]3[CH:38]=[CH:37][C:36]([NH:39]C(OCC4C=CC=CC=4)=O)=[CH:35][CH:34]=3)=[O:27])[C:15]([O:17]CC3C=CC=CC=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C)C>[Pd].C1COCC1>[NH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([O:31][CH2:30][CH2:29][O:28][C:26](=[O:27])[CH2:25][C@H:14]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:15]([OH:17])=[O:16])=[O:50])=[CH:38][CH:37]=1
Reactant: O=C(C[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCOC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Nc1ccc(C(=O)OCCOC(=O)C[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Reaction time: 6 h
Yield: 90.4 %

Procedure:
10% Palladium on charcoal (0.040 g) was added in one portion to a stirred solution of 18 (0.360 g, 0.57 mmol) in a 1:1 mixture of isopropanol (4 mL) and THF (4 mL) under nitrogen atmosphere. The suspension was then stirred under hydrogen atmosphere for 6 h. The solution was filtered through celite and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography CH3OH:CH2Cl2 (5:95) to afford to obtain (S)-4-(2-(4-aminobenzoyloxy)ethoxy)-2-(9H-carbazol-9-yl)-4-oxobutanoic acid 19 (0.230 g, 96%) as a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9]C)=[O:8])(=[O:4])=[O:3].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>C1COCC1>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([OH:9])=[O:8])(=[O:4])=[O:3]
Reactant: CN(C)CCN
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Reaction time: 18 h
Yield: 15.8 %

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (500 mg, 1.79 mmol) and 2-dimethylaminoethylamine (316 mg, 3.58 mmol) in THF (35 ml) was stirred in an ice bath for 1 hour then at 20°-25° for 18 hours. After removing THF under reduced pressure, the residue was partitioned between saturated Na2CO3 solution and EtOAc. The organic extract was washed (saturated NaCl solution), dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography over silica gel (elution with 5% MeOH-95% CHCl3) gave an oil which when triturated with EtOAc afforded 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzoic acid (90 mg, 16%), m.p. 193° decomposed with effervescence.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C@@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[OH-].[Na+]>O>[C:1]([CH2:5][C@@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)C[C@H](O)CCl
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C[C@H](O)CC#N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a 3-necked jacketed 3 L flask equipped with a mechanical stirrer and connected to an automatic titrater by a pH electrode and a feeding tube for addition of base, was charged H2O (1200 mL), NaCN (37.25 g) and NaH2PO4 (125 g) to bring the solution to pH 7. The water circulator was set to 40° C. After 10 minutes, halohydrin dehalogenase SEQ ID NO: 32 as cell lysate (250 mL) was added. The reaction mixture was allowed to stir for 5 minutes. Using an addition funnel, ethyl (S)-4-chloro-3-hydroxybutyrate (45 g of the material from Example 7) was slowly added over 1 hour. The pH was maintained at 7 by the automatic titrater by the addition of 10 M NaOH (27 mL) over 17 hrs. Subsequently, gas chromatography of a reaction sample showed complete conversion to product. Celite (16 g) was added to the flask, which was then connected to a diaphragm, whose exhaust is bubbled into 5M NaOH (200 mL), to remove HCN. The mixture was heated to 60° C. under 100 mm Hg pressure. After 1 hour a submerged air bubbler was added to the solution to aid the removal of the HCN. After 3 hours, an HCN detector indicated less than 5 ppm HCN in the off-gas. The mixture was allowed to cool to room temperature, then filtered through a celite pad. The filtrate was extracted with butyl acetate (3×800 mL) and the combined organic layers filtered through a pad of activated charcoal. The solvent was removed under vacuum by rotary evaporation to provide 28.5 g of ethyl (R)-4-cyano-3-hydroxybutyrate. The purity was 98% (w/w) by HPLC and the enantiomeric excess was >99% (by chiral GC, the S enantiomer was undetectable).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH2:5].C([O-])([O-])=O.[K+].[K+].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22][CH2:3][CH2:4][NH2:5])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: NCCCl
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(SCCN)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirring mixture of 4.36 g (38.0 mmol) of 2-chloroethylamine hydrochloride and 12.00 g (87.0 mmol) of K2CO3 in 30 mL of CHCl3 was added 4.82 g (29.0 mmol) of 4-t-butylbenzenethiol. The mixture was stirred at 50° C. in a sealed vial overnight. The mixture was washed three times with distilled water, dried with MgSO4 and filtered. Volatiles were removed in vacuo leaving 4.50 g (74%) of clear oil. 1H NMR (300 MHz, CDCl3): δ=7.32, m, 4H, 2.93, m, 4H, 1.42, broad singlet, 2H, 1.30, s, 9H.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:19]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:20]=1[CH2:21][C:22](Cl)=[O:23]>>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:2]([NH:1][C:22]([CH2:21][C:20]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)=[O:23])[CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C(N)CCN2CCCCC2)cc1
Reactant: O=C(Cl)Cc1ccc2ccccc2n1
Product: COc1ccc(C(CCN2CCCCC2)NC(=O)Cc2ccc3ccccc3n2)cc1
Yield: 82.2 %

Procedure:
The procedure of Example 1 was repeated using 745 mg (3.0 mmol.) of 1-[3-amino-3-(4-methoxyphenyl)propyl]piperidine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.03 g (yield: 85%) of the subject compound as a pale yellow oily product.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])=[CH:12][C:11]=1[N+:22]([O-])=O.C([O-])(O)=O.[Na+]>O.CCO>[NH2:22][C:11]1[CH:12]=[C:13]([CH:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])[CH:14]=[CH:15][C:10]=1[Cl:9]
Reactant: CC(=O)NC(C)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)NC(C)c1ccc(Cl)c(N)c1
Reaction time: 1.5 h

Procedure:
A solution of sodium dithionite (1.08 g, 6.1 mmol) in H2O (4 mL) was added to a vigorously stirred mixture of N-[1-(4-chloro-3-nitrophenyl)ethyl]acetamide (0.30 g, 1.2 mmol) in EtOH (20 mL) at 55° C. After 4 h at 55° C. additional sodium dithionite (0.20 g, 1.1 mmol) was added and stirring was continued at 55° C. for 1.5 h. The mixture was allowed to cool and NaHCO3 (aq, sat) was added. The mixture was extracted with EtOAc and the combined extracts were dried over Na2SO4 and concentrated to give the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CO)cc1
Reactant: Clc1ncnc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ncnc3cc(Br)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
226.0 g (01.64 mol) of 4-methoxybenzyl alcohol in 0.5 l of toluene were added dropwise to a suspension of 80.0 g (2.0 mol) of sodium hydride [60% in paraffin oil] in 3.0 l of toluene between 15° C. and 20° C. The mixture was subsequently stirred at room temperature for a further 1 h. 165.9 g (1.64 mol) of 7-bromo-4-chloroquinazoline were then added in portions, and the reaction mixture was stirred for 48 h. Conventional work-up gave 194.8 g of 7-bromo-4-(4-methoxybenzyloxy)quinazoline as solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[F:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:36][CH:35]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Fc1ccc(OCCCCCBr)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2ccc(F)cc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound and 5-(4-fluorophenoxy)-pentyl bromide (1.1 g) were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(4-fluorophenoxy)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.Cl.N[C@H](C([C:20]1([NH2:35])[C:26](=[O:27])[N:25]([CH3:28])[C:24]2[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=2[N:22]([CH3:33])[C:21]1=[O:34])=O)C>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:35][C@H:20]([C:26]([NH:35][CH:20]2[C:21](=[O:34])[N:22]([CH3:33])[C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[N:25]([CH3:28])[C:26]2=[O:27])=[O:27])[CH3:21])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(C)c2ccccc2N(C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and the product from Example 8-R, the title compound was prepared as an amorphous white solid. Purification was by L.C. 2000 eluting with straight EtOAc then flash chromatography eluting with CH2Cl2/Acetone (4:1 gradient to 3:1). Rf=0.39 and 0.34 (EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(I)c[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
4-Iodo-1H-pyrrole-2-carboxylic acid methyl ester (24.6 g, 98 mmol, 1.0 equivalent) was dissolved in dichloromethane (150 mL) and triethylamine (30 mL, 215.6 mmol, 2.2 equivalents). 4-(Dimethylamino)pyridine (1.2 g, 9.8 mmol, 0.1 equivalent) and p-toluenesulfonylchloride (20.6 g, 107.8 mmol, 1.1 equivalents) were added and the reaction mixture was stirred for 16 hours at room temperature. The reaction was quenched with 1 M HCl and the organic layer was washed with aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was removed under reduced pressure and the residue was crystallized from tert-butylmethyl ether, yielding the title compound as a pale yellow solid (30 g, 75%). Rt(min) 8.259 minutes.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1.O>[C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)NC(=O)c1ccc2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1ccc2cc(C(=O)NC(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 14.1 %

Procedure:
N-tert-Butyl indole-5-carboxamide was dissolved in dry THF and solution was cooled to −78° C. Butyllithium was added dropwise with continuous stirring. The reaction mixture was stirred at −78° C. for 40 minutes followed by dropwise addition of acetyl chloride. After addition was complete, the reaction mixture was stirred at −78° C. for 30 minutes and then stirred for 1 hour at room temperature. The reaction mixture was diluted with water and organic phase separated. The aqueous phase was saturate with sodium chloride and was extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatrography to afford the title compound as a white solid (14.1% yield), melting point=186.8° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C1N2CCN(CC2)C1.C1C=CC=CC=1>[F:9][C:10]([F:20])([F:21])[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:19])[O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:16]=1
Reactant: OCc1cccnc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)OCc1cccnc1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 2.5 g. (0.023 mole) of 3-pyridylcarbinol in 50 ml. of benzene containing 0.1 g. of Dabco catalyst (1,4-diazabicyclo [2,2,2] octane) was added, dropwise, a solution of 43 g. (0.023 mole) of p-trifluoromethyl-phenyl isocyanate in 50 ml. of benzene. A temperature rise from 23° to 35° was noted during the addition, and a white precipitate formed. After stirring for 1 hr., the mixture was filtered, and the solid product was air-dried. There was obtained 6.3 g. (93% of theory) of product; melting point 173° - 175° C. (decomposed). This is a 93% yield of 3-pyridylmethyl N-(4'-trifluoromethylphenyl)-carbamate.