Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:26]([N:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:32](Cl)=[O:33])[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:32](=[O:33])[N:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1C(=O)O
Reactant: CCCCCN(CCCCC)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1

Procedure:
A partial solution of 1.32 g (5.74 mmole) of (S)-1-(tert-butyloxycarbonyl)piperazine-2-carboxylic acid in 25 ml of dried DMF was treated dropwise over 5 min with 1.48 g (11.47 mmole of diisopropylethyl amine at 25° under nitrogen with stirring. The clear solution which resulted was treated dropwise over 15 min with a solution of 1.26 g (5.74 mmole) of dipentylcarbamoyl chloride in 5 ml of DMF and the mixture was stirred under nitrogen at 25° for 16 hr. The solution was concentrated in vacuo and the residue was dissolved in 100 ml of dichloromethane which was extracted with 2×100 ml of 0.5M citric acid and 2×25 ml of water. Without drying, the solution was concentrated in vacuo to 1.85g (78%) of medium yellow oil which was homogeneous by the (silica gel, 1:1:1:1 ethylacetate: n-butanol: acetic acid: water, Rf =0.50).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([CH2:32][CH2:33][CH2:34][OH:35])[CH2:23][CH2:22][CH2:21][N:20]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@@:18]([CH2:32][CH2:33][CH2:34][O:35][S:37]([CH3:36])(=[O:39])=[O:38])([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[CH2:19]1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccccc1)N1CCCC(CCCO)(c2ccc(Cl)c(Cl)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Diisopropylethylamine(1.6 mL, 9.18 mmol) was added to a solution of alcohol (10) (1.2 g, 3.06 mmol 3.0 eq) in CH2Cl2 (30 mL) followed by MsCl (0.28 mL, 3.67 mmol, 1.2 eq). The solution was stirred at room temperature for 2 hours, then quenched with water and diluted with CH2Cl2 (200 mL). The organic layer was washed with brine, 1N HCl, saturated NaHCO3, and dried over MgSO4. The crude oil was purified by flash chromatography (CH2Cl2-MeOH/95:5) to give light yellow solid (1.43 g, 99.3%).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15]N=CC=1)[NH2:6].FC(F)(F)C1C=C([N+]([O-])=O)C=CC=1SC1C=C[N:31]=[CH:30][CH:29]=1.C(O)(=O)C.[OH-].[Na+]>CCOCC.O.[Fe]>[N:31]1[CH:30]=[CH:29][CH:15]=[CH:16][C:11]=1[S:10][C:9]1[CH:3]=[CH:4][C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccncc2)c(C(F)(F)F)c1
Reactant: Nc1ccc(Sc2ccncc2)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(Sc2ccccn2)cc1

Procedure:
3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline: A slurry of 3-trifluoromethyl-4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 g, 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp. for 4 h. The mixture was diluted with Et2O (100 mL) and water (100 mL). The aqueous phase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired product (3.3 g): TLC (50% EtOAc/50% hexane) Rf 0.10; 1H-NMR (DMSO-d6) δ 6.21 (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=6.3 Hz, 2H). A3c. General Method for Substituted Aniline Formation Via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19](Cl)(Cl)Cl)=[C:11]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:10]=1)=[O:7].[CH3:35][N:36]([CH3:40])[CH2:37]CO.[O-2].[Mg+2]>C(OCC)(=O)C>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:19][O:18][C:17](=[O:23])[NH:16][CH2:15][CH2:14][O:13][C:12]1[CH:24]=[CH:25][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:32]=[CH:33][CH:34]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:10][C:11]=1[C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(Cl)(Cl)Cl)c(-c3ccnn3C)c2)c1
Reactant: CN(C)CCO
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OCCN(C)C)c(-c3ccnn3C)c2)c1
Temperature: 22 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
Trichloromethyl 2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (50.0 g, 94.74 mmol), 2-(dimethylamino)ethanol (14.50 g, 1.1 eq) and magnesium oxide (1.067 mL, 1.0 eq) were taken up in 2 mL of ethyl acetate in a round bottomed flask and stirred at 22° C. for 3 hr. The magnesium oxide was filtered off. The solvent was then evaporated and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 31.3% yield. LCMS m/z (%)=482 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.82 (s, 3 H), 2.84 (s, 3 H), 3.34 (q, J=5.05 Hz, 4 H), 3.69 (s, 3 H), 3.84 (s, 3 H), 4.06 (t, J=5.56 Hz, 2 H), 4.25-4.29 (m, 2 H), 6.28 (d, J=1.52 Hz, 1 H), 7.14-7.22 (m, 2 H), 7.40 (t, J=5.56 Hz, 1 H), 7.47 (d, J=2.02 Hz, 3 H), 7.51-7.55 (m, 1 H), 7.70 (d, J=2.53 Hz, 1 H), 7.84 (dd, J=8.84, 2.78 Hz, 1 H), 9.48-9.62 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 108 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)-propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23]/[C:24](/[C:29]#[N:30])=[C:25](\[NH2:28])/[C:26]#[N:27]>C(O)C>[OH:15][C:13]1[N:28]=[C:25]([C:26]#[N:27])[C:24]([C:29]#[N:30])=[N:23][C:12]=1[C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: N#C/C(N)=C(/N)C#N
Solvent: CCO
Product: N#Cc1nc(O)c(-c2cc(O)c(O)c([N+](=O)[O-])c2)nc1C#N

Procedure:
A solution of 4.0 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 1.5 g of diaminomaleonitrile in 35 ml of ethanol is heated to boiling under reflux for 24 hours. The alcohol is then distilled, the residue is dissolved in ether, washed with water, dried over sodium sulfate, filtered and evaporated. There is obtained 6-hydroxy-5-(3,4-dihydroxy-5-nitrophenyl)-2,3-pyrazinedicarbonitrile of m.p.>300° (from ether/methylene chloride).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O1CCCC1>[C:14]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
15.8 g Indole-5-carboxaldehyde were dissolved in 300 ml tetrahydrofuran and cooled to 0° C. Then, 5.12 g sodium hydride (55% in mineral oil) were added in small portions followed by slow, trop by trop addition of 15.2 ml of benzenesulfonyl chloride. The reaction mixture was then warmed up to ambient temperature and stirring continued for 16 hours. It was then poured onto ice, neutralized to pH 4 with HCl (1N) and extracted 3 times with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a crude product which was purified by chromatography (silicagel, eluent: gradient of n-heptane/ethyl acetate) to yield 4.09 g 1-benzenesulfonyl-1H-indole-5-carbaldehyde as rose solid.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CC)oc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Yield: 92.5 %

Procedure:
A mixture of ethyl 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (0.80 g, 2.1 mmol) and KOH (0.35 g, 6.3 mmol) in MeOH (40 mL) and water (4 mL) was heated to reflux overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 4:1). The reaction mixture was concentrated to dryness and poured into water (50 mL). The aqueous layer was acidified to pH˜2 with concentrated HCl (4 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with brine (50 mL×2), dried over Na2SO4 and concentrated to afford the desired compound (0.70 g, 94%) as an off-white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:13][CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:24]=1)[N:14]([C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:13][CH2:12]2
Reactant: CC(C)(C)C(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)C(=O)N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1

Procedure:
A mixture of 1-{6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2yl}-2,2-dimethylpropan-1one, ammonium formate (0.033 g, 0.52 mmol), and 20% Pd(OH)2/C (0.002 g) in MeOH (10 ml) was refluxed under N2 for 1.5 hr, then filtered to remove the catalyst. The filtrate was evaporated in vacuo to a residue that was suspended in H2O (0.4 ml) and saturated NaHCO3 (0.4 ml). The aqueous mixture was extracted with CH2Cl2 (3×0.8 ml) and all of the combined organic solutions were evaporated to give the crude product. Purification by reverse-phase HPLC on a Primesphere C-18HC (50.0 mm×10.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:1% TFA/H2O (85:10:5), increasing to H2O:CH3CN:1% TFA/H2O (5:90:5) at 8 min., detected on a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave material which, after evaporation to dryness, was purified by reverse-phase HPLC on a Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1), increasing to H2O:CH3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV detector (300 nM +/−90 nM and 254 nM +/−25 nM), gave an eluent that was evaporated to dryness to give the pure product.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:8][C:9]1[O:10][C:11]([CH3:14])=[CH:12][CH:13]=1)C.[OH-].[K+]>C(O)C>[CH2:18]([O:17][C:15]([N:6]([CH2:5][C:4]([OH:20])=[O:3])[CH2:7][CH2:8][C:9]1[O:10][C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)CN(CCc1ccc(C)o1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N(CCc1ccc(C)o1)CC(=O)O
Yield: 30.7 %

Procedure:
Ethyl{ethoxycarbonyl[2-(5-methylfuran-2-yl)ethyl]-amino}acetate (0.65 g) prepared in the step 4 was dissolved in 5 mL of ethanol, 0.30 g of potassium hydroxide was added thereto and the mixture was heated to reflux for 3 hours. The solvent of the reaction solution was evaporated in vacuo and the residue was dissolved in ethyl acetate. The resulting solution was slowly neutralized with 1N aqueous solution of hydrochloric acid (ca. 80 mL) with stirring to adjust to pH 3. The organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.18 g of the objective compound as yellow liquid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:14][C:13]1=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[CH:14][C:13]2=[O:28])[C:3]([OH:29])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (620 mg, 0.002 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (190 mg, 0.008 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (295 mg, 49%) as a light brown solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19]>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: CN1CCc2[nH]c3ccc(I)cc3c2C1
Solvent: C1CCOC1
Product: CN1CCc2c(c3cc(I)ccc3n2CC(=O)N2CCCCC2)C1
Reaction time: 0.5 h

Procedure:
Sodium hydride was washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 8-iodo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.32 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone in THF was added drop wise in reaction mixture. Then reaction mixture stirred at rt for 2 h. Reaction monitored by TLC, after completion of reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was purified by column chromatography to gives 25 mg of desired compound. Out of that 5 mg was stirred with ethanolic HCl to give HCl salt of 2-(8-iodo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH2:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][C:8]2[C:9](=[O:10])[N:5]([CH:1]([CH3:3])[CH3:4])[S:6](=[O:18])(=[O:19])[C:7]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COc1ccc(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc1OC

Procedure:
The title compound was prepared from 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and [2-(3,4-dimethoxyphenyl)ethyl]amine in a similar manner as described for Example 24. 1H NMR (500 MHz CDCl3): δ 7.58-7.52 (m, 2H), 7.50-7.46 (m, 3H), 6.76 (d, 1H), 6.46 (dd, 1H), 6.36 (d, 1H), 5.40 (t, 1H), 4.41 (sept, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.13 (q, 2H), 2.57 (t, 2H), 1.59 (d, 6H); 13C NMR (125 MHz, CDCl3): δ 158.7, 149.3, 148.1, 135.4, 131.7, 130.0, 129.9, 128.8, 125.4, 120.8, 111.8, 111.7, 107.2, 56.1, 47.8, 45.3, 35.6, 20.3; Mass Spectrum M+H+ 431
Reaction SMILES: C(C1C=CC(C#N)=CC=1)(=O)C.NCC(OC(C)(C)C)=O.CC(O)=O.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33](=[N:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:34])=[CH:29][CH:28]=1)#[N:26].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([CH:33]([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH3:34])=[CH:31][CH:32]=1)#[N:26]
Reactant: CC(=NCC(=O)OC(C)(C)C)c1ccc(C#N)cc1
Agent: CC(=O)c1ccc(C#N)cc1
Agent: CC(C)(C)OC(=O)CN
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(NCC(=O)OC(C)(C)C)c1ccc(C#N)cc1

Procedure:
4-acetylbenzonitrile (500 mg; 3.4 mmol; 1 eq.) and tert-butyl glycinate (588 mg; 4.5 mmol) were dissolved in toluene (10 mL). AcOH (103 μl; 1.7 mmol) was added. The mixture was stirred at reflux with a dean stark trap overnight. Solvents were evaporated and the resulting tert-butyl N-[1-(4-cyanophenyl)ethylidene]glycinate (889 mg; 3.4 mmol) was dissolved in MeOH (18 mL). Sodium borohydride (390 mg; 10.3 mmol) was added in portions, resulting in an exothermic reaction (reflux). The reaction was stirred at RT overnight. Solvents were evaporated. The crude residue was suspended in EtOAc, washed with NH4Cl saturated solution, NaHCO3 saturated solution, brine and dried over MgSO4. After evaporation of the solvents the resulting yellow oil was purified by flash chromatography, affording the title compound as a colorless oil. LC/MS (Method B): 261.0 (M+H)+. HPLC (Method A): 2.77 min (purity: 98.2%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>>[CH:30]1([CH2:29][N:22]2[CH2:21][C@H:20]([CH3:25])[N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])[CH2:32][CH2:31]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@@H](C)CNC2=O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@@H](C)CN(CC3CC3)C2=O)CC1
Yield: 55 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 11), sodium hydride and 1-(bromomethyl)cyclopropane, to give the desired product as a light yellow solid (55%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1>CCO>[C:11]1([C:8]2[S:7][C:6]([CH2:5][C:1]#[N:2])=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C-]#N
Reactant: BrCc1ncc(-c2ccccc2)s1
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ncc(-c2ccccc2)s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
NaCN (0.46 g, 9.4 mmol) was added to a solution of 2-(bromomethyl)-5-phenylthiazole (2.0 g, 7.87 mmol) in dry EtOH (10 mL). The resulting reaction mixture was stirred at 70° C. for 2 h and then concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in petroleum ether) to afford 2-(5-phenylthiazol-2-yl)acetonitrile (350 mg, yield 22%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.56-7.54 (m, 2H), 7.46-7.40 (m, 3H), 4.15 (s, 2H). MS (ESI) m/z: Calculated for C11H8N2S: 200.04. found: 201.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:12])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c(C)c1

Procedure:
From 4-methoxy-2-methylbenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.7° (c=0.62, CHCl3), ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH:10]1[C:15]([C:16]([CH2:18]Br)=O)=[CH:14][CH:13]=[C:12]([Cl:20])[CH:11]=1.C(=O)(O)[O-].[Na+]>>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]([C:16]2[N:9]=[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]3[CH:18]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc2nc(-c3ccc(Cl)cc3)cn2c1

Procedure:
A mixture of 1.3 g (10.5 mmol) of 5-methoxy-2-pyridinamine, 2.44 g (1eq) of α-bromo-4-chloroacetophenone and 1.76 g (2eq) of sodium bicarbonate in 20 ml of 95% strength alcohol is heated under reflux for 4 h 30 min. under argon. The mixture is evaporated to dryness and the residue taken up between CH2Cl2 and H2O, followed by washing, drying and evaporation. The product is purified by chromatography and then crystallized in ether. M.p. 148°-9° C.