Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>O.CC(O)C>[CH:25]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: N
Reactant: Clc1nccn2c(C3CCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: O
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h

Procedure:
20 M NH3 in H2O (2 mL) was added to a suspension of 8-chloro-3-cyclopentyl-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazine (21 mg, 0.054 mmol) in i-PrOH (2 mL). The mixture was heated in an oil bath set at 105° C. overnight. Reaction mixture was concentrated in vacuo and purification by prep TLC using 10% MeOH in DCM afforded 9 mg of the title compound as an off white solid. The compound was registered as OSIP 700099. 1H NMR (400 MHz, CDCl3): δ=1.61-1.95 (m, 4H), 2.02-2.23 (m, 4H), 3.30-3.43 (m, 1H), 5.07 (br. s., 2H), 7.03-7.08 (m, 3H), 7.08-7.16 (m, 3H), 7.23 (d, J=5.05 Hz, 1H), 7.30-7.41 (m, 2H), 7.61 (d, 2H). MS (ES+): m/z 370.83 (100)[MH+]. HPLC: tR=2.61 min (Open Lynx polar—5 min).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:19]1(=[O:30])[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[CH2:20]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Yield: 55 %

Procedure:
A solution of 1.28 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.81 g of homophthalic anhydride, 50 ml of toluene and 25 ml of tetrahydrofuran was heated to reflux for 0.5 hr. The solvents were removed by rotary evaporation and the residual materials were triturated with ethyl ether to yield 1.15 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid. Recrystallization from acetonitrile yielded 0.81 g of material; m.p. 204°-206° C. Anal. Calcd for C24H22N2O3S: C, 68.88; H, 5.30; N, 6.69. Found: C, 68.15; H, 5.21; N, 6.54.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:17](=[O:28])([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[NH2:18]>C(OCC)C>[CH3:3][C:2]([CH3:4])=[CH:1][NH:18][C:17](=[O:28])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCOC(N)=O
Reactant: CC(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCCCCOC(=O)NC=C(C)C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
126 parts of isobutyraldehyde and 7 parts of p-toluenesulfonic acid are added in succession to a solution of 605.5 parts of n-octyl carbamate in 1,750 parts by volume of diethyl ether at 25° C., after which the temperature rises to 40° C. for one hour. After one day, the solid product which as crystallized out is filtered off with suction and fractionally distilled in the presence of 10 parts of p-toluenesulfonic acid and one part of hydroquinone. 298.3 parts of n-octyl N-(2-methyl-1-propenyl)-carbamate (75.1% yield, based on isobutyraldehyde employed) of boiling point 126° C./1 mbar are obtained, and 279.5 parts of n-octyl carbamate are recovered and can be re-used.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][C:13]1[C:33]([Cl:34])=[CH:32][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][C@H:21]2[O:30][CH3:31])=[O:18])=[C:15]([O:35][CH3:36])[CH:14]=1.CC1C=CC=CC=1>O>[NH2:12][C:13]1[C:33]([Cl:34])=[CH:32][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:29]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])[CH2:22][C@H:21]2[O:30][CH3:31])=[O:18])=[C:15]([O:35][CH3:36])[CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN2C(=O)c3ccccc3C2=O)C[C@H]1OC
Reaction time: 3 h
Yield: 42 %

Procedure:
A mixture of 1.85 parts of 1,3-isobenzofurandione, 4.4 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 45 parts of methylbenzene was stirred for 3 hours at reflux temperature, using a water separator. The reaction mixture was evaporated. The residue was taken up in trichloromethane. The organic phase was washed with a saturate solution of sodium carbonate and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.5 parts (42,4%) of cis-4-amino-5-chloro-N-[1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 208.2° C. (compound 88).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[C:3]=1[OH:10]
Reactant: Cc1cc(C)c(O)c(Br)c1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(O)c(-c2cccs2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
2-Bromo-4,6-dimethylphenol (500 mg, 2.49 mmol), 2-thiophenyl boronic acid (88 mg, 2.99 mmol), sodium carbonate (791 mg, 7.47 mmol) and Pd2(dppf)2Cl2 (406 mg, 0.49 mmol) were dissolved in dimethoxyethane/water 6 mL/3 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2,4-dimethyl-6-(thiophene-2-yl)phenol (231 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:18][OH:19])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:18]=[O:19])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A solution of (1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)methanol (1.14 g, 4.45 mmol) was dissolved in DCM (46 mL) and treated with Dess-Martin periodinane (1.87 g, 4.45 mmol). The reaction was stirred at ambient temperature for about 1 h and filtered over a plug of SiO2 rinsing with DCM (50 mL). The filtrate was partially concentrated under reduced pressure and then filtered over a second plug of SiO2 rinsing with DCM (40 mL). The filtrate was concentrated under reduced pressure and the crude material was purified by column chromatography (EtOAc/heptane 100:0 to 0:60) to afford 1-(4-fluorophenyl)-6-methyl-1H-indazole-5-carbaldehyde (1.09 g, 4.29 mmol, 96%). LC-MS (Table 1, Method g) Rt=2.01 min, m/z 257 (M+H)+. 1H NMR (CDCl3) δ 10.27 (s, 1H), 8.29 (bs, 2H), 7.72-7.63 (m, 2H), 7.45 (s, 1H), 7.32-7.23 (m, 2H), 2.80 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[N:3]=1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[CH:22]([C:21]([NH:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[N:3]=1)=[O:25])([CH3:24])[CH3:23]
Reactant: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reactant: CC(C)C(=O)Cl
Product: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(NC(=O)C(C)C)n1

Procedure:
This compound was prepared in an analogous manner to Example 9 from 2-amino-6-acetamido-3-(2,3,5-trichlorophenyl)pyrazine (Example 1) and one equivalent isobutyrylchloride (Aldrich). Yield 0.120 g M.p. 230-232° C.
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[OH:41][CH:42]1[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]1>>[OH:41][CH:42]1[CH2:47][CH2:46][CH2:45][N:44]([C:4](=[O:6])[CH2:3][S:7](=[O:8])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:9][C:10](=[O:11])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)[CH2:43]1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Reactant: OC1CCCNC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CC(=O)N3CCCC(O)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and 3-hydroxypiperidine were reacted to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4].[H][H]>[Pd].C(O)C.CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)c1cccc(/C=C/C(=O)OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(CCC(=O)OC)c1
Yield: 80.1 %

Procedure:
A solution of (E)-methyl 3-[3-(methylcarbamoyl)phenyl]prop-2-enoate (3.77 g, 17.20 mmol) and 10% palladium on carbon (0.458 g, 0.43 mmol) in a mixture of ethanol (100 mL) and DMF (10.00 mL) was stirred at room temperature for 18 h under a balloon of hydrogen. The reaction mixture was filtered through celite and evaporated to dryness to afford methyl 3-(3-(methylcarbamoyl)phenyl)propanoate (3.05 g, 80%) as a white solid. MS: m/z 222 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](O)=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:31]4[S:30][CH:34]=[CH:33][CH:32]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccs1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cccs2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and thiophene-2-carboxylic acid (9 mg, 0.07 mmol). Yield 26 mg (72%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22][NH2:23]>CO>[NH:22]([C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:23]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (Aldrich, 300 mg, 1.07 mmol) in MeOH (5.4 mL) was added hydrazine hydrate (170 μL, 3.44 mmol). The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was triturated with hexanes (2×) and then from a minimal amount of 2:3 hexanes/MeOH (2×) to give the title compound (195 mg, 65%) as a white solid. 1H NMR (CDCl3) δ 7.41-7.25 (m, 3H), 7.20 (d, J=6.8 Hz, 2H), 4.39-4.21 (m, 1H), 3.07 (d, J=7.0 Hz, 2H), 1.42 (s, 9H); MS (ESI+) m/z 280.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].CN(C=O)C.Br[CH:17]([CH3:23])[C:18](OCC)=[O:19].C([O-])(O)=O.[Na+]>[Cl-].[Na+].O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:10][C:18](=[O:19])[CH:17]([CH3:23])[NH:9]2
Reactant: Nc1ccc(F)c(Br)c1N
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Nc2ccc(F)c(Br)c2NC1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 95.5 %

Procedure:
A 500 mL round-bottomed flask charged with 3-bromo-4-fluorobenzene-1,2-diamine (600c) (18 g, 88 mmol), DMF (100 mL), ethyl 2-bromopropionate (Sigma Aldrich, 11.54 mL, 89 mmol) and NaHCO3 (7.60 g powder, 90 mmol) was heated to 90° C. with a reflux condenser for 30 min, then at 120° C. for 15 h. The reaction mixture was cooled to RT, treated with brine and extracted with EtOAc (2×200 mL), washed with brine (3×) and dried over Na2SO4, filtered and concentrated affording crude 8-bromo-7-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (21.75 g, 84 mmol, 96% yield) as an orange-brown viscous oil. The material was used in the subsequent step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H) 6.78-6.89 (m, 1H) 6.48-6.78 (m, 1H) 6.07-6.35 (m, 1H) 1.25 (d, J=6.46 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) δ ppm −120.49 (1F, s). m/z (ESI, +ve ion) 259.0/261.0 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([NH:13][CH2:14][CH2:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C=O)C>O>[CH2:6]([N:13]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:14][CH2:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(CCN(CCc3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 25 °C
Yield: 386.6 %

Procedure:
Add sodium bicarbonate (0.0823 g, 0.0980 mmol) to a stirred solution of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3061 g, 0.0881 mmol), (2-bromoethyl)benzene (0.135 mL, 0.988 mmol), and DMF (5 mL). Heat the reaction to reflux for 3 h under nitrogen and then cool to room temperature. Pour the reaction into water (50 mL) and extract with diethyl ether (3×50 mL). Dry the diethyl ether extracts over magnesium sulfate and then filter off the magnesium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 90% ethyl acetate/hexanes to yield 0.1538 g (39%) of 6-{4-[2-(benzyl-phenethyl-amino)-ethyl]-phenoxy}-nicotinamide: mass spectrum (ion spray): m/z=452.1 (M+1); 1H NMR (CDCl3): 8.55 (d, 1H), 8.13 (dd, 1H), 7.29-7.11 (m, 14H), 7.01 (d, 2H), 6.92 (d, 1H), 3.71 (s, 1H), 2.94-2.77 (m, 9H).
Reaction SMILES: C([O-])(O)=O.[Na+].[Br:6][C:7]1[CH:8]=[C:9]([N+:21]([O-])=O)[C:10]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:11][CH:12]=1.Cl>CCOC(C)=O.O>[Br:6][C:7]1[CH:8]=[C:9]([NH2:21])[C:10]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1NCCN1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cnc1NCCN1CCCC1

Procedure:
2.44 g (10.8 mmol) Zinn(II)chloride dihydrate and 2.20 g (26.2 mmol) NaHCO3 are added to a solution of 680 mg (2.16 mmol) (5-bromo-3-nitro-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine in 40 mL EtOAc at RT. The reaction is refluxed for 1.5 h and then diluted with 20 mL water. The aqueous phase is acidified with 1 M HCl and separated off from the organic phase. The aqueous phase is made alkaline with saturated K2CO3 solution and extracted twice with 40 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[CH:8]([C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1)=[CH2:9]>>[O:14]1[C:13]2[CH:17]=[CH:18][C:10]([CH2:8][CH2:9][S:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: C=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CS
Product: CCOC(=O)CSCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.1 %

Procedure:
3.24 g of ethyl thioglycolate was added to 6 g of 5-ethenyl-1,3-benzodioxole and the mixture was stirred at room temperature for 14 h. The reaction product was purified according to silica gel column chromatography (benzene:ethyl acetate=40:1) to obtain 5 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[C:16](=[O:21])[CH2:17]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CBr)cc3)CC2=O)CC1
Yield: 49 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (500 mg) in ethyl acetate (15 ml) and sodium bicarbonate solution (10 ml) was added at 0° C. 4-(bromomethyl)benzenesulfonyl chloride (453 mg), and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:3) to give colorless crystals of 4-[4-(bromomethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (437 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1ccccc1
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-phenyl-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and phenylboronic acid under conditions analogous to Example 7(a). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.26 (s, 1H), 8.40 (d, J=9.1 Hz, 1H), 7.65-7.45 (m, 7H), 4.02 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Cl:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Cl:15])=[C:10]([Cl:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)c(Cl)s2)c1Br
Yield: 42 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2-sulfonamide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 4,5-dichlorothiophene-2-sulphonyl chloride in 42% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 135-138° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:4]([C:3]1([CH3:7])[CH2:8][O:9][CH:17]([C:16]2[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[O:1][CH2:2]1)(=[O:6])[CH3:5]
Reactant: CC(=O)C(C)(CO)CO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C1(C)COC(c2ccc([N+](=O)[O-])cc2)OC1

Procedure:
3,3-bis(Hydroxymethyl)-2-butanone (39.7 parts) and 4-nitrobenzaldehyde (30.2 parts) are combined in toluene (300 parts) containing p-toluenesulfonic acid, (p-TSA), (1.0 part) and the mixture held under reflux until a theoretical amount of water is removed by a Dean-Stark moisture trap. The solution is concentrated in vacuo and the residue washed once with dilute sodium bicarbonate solution. The product is recrystallized from ethyl acetate-heptane mixed solvent to give colorless needles, m.p. 101-102.5° C. Proton NMR and combustion analysis are consistent with those values predicted for the desired product. Combustion Analysis for C13H15NO5 --Calculated: C, 58.9%; H, 5.7%; N, 5.3%. Found: C, 59.0%; H, 5.8%; N, 5.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[Cl:16]N1C(=O)CCC1=O.O>COCCOC>[Cl:16][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: COc1cccc(OC)c1Cl
Reaction time: 0.67 h

Procedure:
To a solution of 1,3-dimethoxybenzene (13.8 g) in 1,2-dimethoxyethane (100 ml) is added 2.6M n-butyllithium (40 ml). After 40 minutes, N-chlorosuccinimide (13.5 g) is added and the reaction temperature is maintained below 55° C. by means of an ice-bath. After an additional 45 minutes, the reaction mixture is poured into water and extracted with ether. Evaporation of the organic extract affords an oil which is choromatographed on silica gel (125 g), eluting with 20% ether-hexane. Evaporation of the eluents affords an oil which crystallized on standing. Recrystallization from hexane gives 2-chloro-1,3-dimethoxybenzene, mp 62°-64° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.O.[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)NCc1ccccc1)c1ccc(O)cc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CNCc1ccccc1)c1ccc(O)cc1
Yield: 52.3 %

Procedure:
Dissolve N-benzyl-2-(4-hydroxy-phenyl)-propionamide (13.25 g, 51.9 mmol) in anhydrous tetrahydrofuran (100 mL) and add via a cannula to borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 300 mL, 300 mmol) under nitrogen. Heat the reaction to reflux for 18 h under nitrogen. Cool the reaction to 0° C. and quench with 6 M hydrochloric acid. Concentrate the tetrahydrofuran on a rotary evaporator to give the crude product. Add water (50 mL) and tetrahydrofuran (30 mL) to the crude product and heat the reaction to reflux for 1 h. Cool the reaction to room temperature and adjust the pH to pH=8 with 5 N sodium hydroxide. Add brine (200 mL) and extract with ethyl acetate (3×200 mL). Dry the ethyl acetate extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform to yield 6.55 g (52%) of 4-(2-benzylamino-1-methyl-ethyl)-phenol: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.08 minutes, Purity: 99.6%; mass spectrum (ion spray): m/z=242.1 (M+1).