Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:15]([Cl:20])[C:16]([C:17](=O)[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P(=S)=[S:36])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:15]([Cl:20])[C:16]([C:17](=[S:36])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCn2c(c(C(N)=O)c(Cl)c2-c2cccnc2)C1
Reactant: COc1ccc(P(=S)=S)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2c(c(C(N)=S)c(Cl)c2-c2cccnc2)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 8-carbamoyl-7-chloro-6-pyridin-3-yl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (486 mg, Reference Example 2b) in toluene (25 mL) was treated with 4-methoxyphenylthionophosphine sulfide dimer (513 mg). After stirring at 80° C. for 2 hours the reaction mixture was allowed to cool to room temperature and then evaporated. The residue was subjected to column chromatography on silica eluting with dichloromethane, then with a mixture of methanol and dichloromethane (1:99, v/v) and then with a mixture of methanol and dichloromethane (1:49, v/v) to give the title compound (129 mg) as a off white solid, m.p. 220–221° C. [Elemental Analysis: C, 54.79; H, 5.10; N, 13.86%. Calculated for C18H21ClN4O2S: C, 55.03; H, 5.39; N, 14.26%].
Reaction SMILES: [CH2:1]([C:21]([CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:22])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:43](O)[CH:44]([OH:48])[CH2:45][CH2:46][OH:47].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:21]1([CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:48][CH:44]([CH2:45][CH2:46][OH:47])[CH2:43][O:22]1)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCCC(O)CO
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(=O)CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC1(CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC)OCC(CCO)O1
Temperature: 25 °C

Procedure:
A mixture of diarachidonyl ketone (V, 0.30 g, 0.52 mmol), 1,2,4-butanetriol (0.25 g, 2.4 mmol) and pyridinium p-toluenesulfonate (20 mg) in 60 mL of toluene was refluxed under argon overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×30 mL), brine (30 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in a yellowish oily residual. The crude product was purified by column chromatography on silica gel (230-400 mesh, 40 mL) with 0-2% methanol in dichloromethane as eluent. This afforded 0.29 g (84%) of pure VI as pale oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C([N-]C(C)C)(C)C.[Li+].[Br:24]N1C(=O)CCC1=O>O1CCCC1>[Br:24][C:10]1[S:11][C:6]2[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH3:15])[C:3]([S:2][CH3:1])=[N:8][C:7]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCn1c(SC)nc2ccsc2c1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCn1c(SC)nc2cc(Br)sc2c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
In a sulfonation flask, 9.6 g (0.04 mol) of 2-methylsulfanyl-3-propyl-3H-thieno[3.2-d]-pyrimidin-4-one are added to 200 ml of absolute tetrahydrofuran. Subsequently, 4.07 g (0.042 mol) of lithium diisopropylamide, dissolved in 50 ml of absolute tetrahydrofuran, are added dropwise under N2 such that the internal temperature remains constant at about −78° C. The mixture is stirred for 1 hour at −78° C. and then a solution of 8.5 g (0.048 mol) of N-bromosuccinimide in 40 ml of absolute tetrahydrofuran is added dropwise such that the internal temperature remains constant at about −78° C. The condenser is then removed and the mixture is slowly warmed to room temperature. The tetrahydrofuran is removed in a water-jet vacuum and the residue is dissolved in ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and the ethyl acetate is then removed in the water-jet vacuum. The crude product is purified by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:5), giving 3.8 g of 6-bromo-2-methylsulfanyl-3-propyl-3H-thieno[3.2-d]pyrimidin-4-one in the form of a yellow powder having a melting point of 138-141° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH2:18][NH2:19])[OH:17].[SH:20][CH2:21][C:22](O)=[O:23]>C1C=CC=CC=1>[OH:17][CH2:16][CH2:18][N:19]1[C:22](=[O:23])[CH2:21][S:20][CH:11]1[C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: NCCO
Reactant: O=C(O)CS
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: O=C1CSC(c2cccc(Oc3ccccc3)c2)N1CCO
Yield: 97.2 %

Procedure:
A mixture of 15.3 g (0.077 mole) of 3-phenoxybenzaldehyde (Fluka), 4.8 g (0.078 mole) of ethanolamine (99%, Aldrich) and 7.5 g (0.077 mole) of mercaptoacetic acid (95%, Aldrich) in 150 ml of benzene was stirred and heated at reflux temperature overnight utilizing a Dean-Stark trap to remove water. The reaction mixture was poured into a solution of 300 ml of water and 20 ml of concentrated ammonium hydroxide solution. The layers were separated and the organic layer was washed twice with 100 ml portions of 2N hydrochloric acid, twice with 100 ml portions of water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to give 23.6 g (97%) of the alcohol which was used without further purification.
Reaction SMILES: [C:1]1([S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>>[C:1]1([S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)(=[O:25])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCS(=O)c3ccccc3)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 3 from 6-(4-phenylsulfinyl-butoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]
Reactant: O=C(O)Cc1cc(Br)c(O)c(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(Br)c(O)c(Br)c1

Procedure:
3,5-Dibromo-4-hydroxyphenylacetic acid (60 g, 0.19 mol), from Preparation A, was suspended in 1 L of ethanol and 10 mL of concentrated sulfuric acid and heated at reflux overnight. The reaction mixture was cooled, concentrated and the product collected by filtration, washed with water, and dried in a vacuum oven to obtain ethyl 3,5-dibromo-4-hydroxyphenylacetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([I:24])[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([I:24])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(I)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C#N
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(I)c1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
3-(3-cyano-5-iodo-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (106 mg) was dissolved in N,N-dimethylformamide (1 mL), and lithium chloride (40 mg) was added to the solution, and then the mixture was stirred at 100° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (100 mg) as a yellow oily substance.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]=3[CH:20]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:21]=O.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:21][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]=2[CH:20]=1)[CH3:25]
Reactant: CNC
Reactant: C=O
Reactant: Cn1c(=O)sc2ccc(-c3cn4ccccc4n3)cc21
Product: CN(C)Cc1c(-c2ccc3sc(=O)n(C)c3c2)nc2ccccn12
Yield: 59.6 %

Procedure:
5-(3-Dimethylaminomethylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzothiazolinone (6.35 g) was prepared in substantially the same manner as that of Example 50 from 5-(imidazo[1,2-a]pyridin-2-yl)-3-methyl-2benzothiazolinone (8.86 g), 30% aqueous formaldehyde (2.57 g) and 50% aqueous dimethylamine (2.97 g).
Reaction SMILES: [CH3:1][C:2]1([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]#[N:20])[CH:16]=3)[C:11]2=[O:21])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9].[ClH:22]>CC(O)C.O.O=[Pt]=O>[ClH:22].[NH2:20][CH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:21])[N:10]([C:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[CH2:18]2
Reactant: CC1(N2Cc3cc(C#N)ccc3C2=O)CCC(=O)NC1=O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC1(N2Cc3cc(CN)ccc3C2=O)CCC(=O)NC1=O
Yield: 92 %

Procedure:
A mixture of 2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (1.20 g, 4.00 mmol) and PtO2 (0.4 g) in 5-6 N HCl in iPrOH was hydrogenated (55 psi, rt) for 24 h. The resulting mixture was diluted with water (30 mL) and filtered through celite. The celite was washed with water (30 mL) and the combined filtrates were concentrated in vacuo. The residue was triturated in acetonitrile (50 mL) and the product was isolated by filtration and dried in vacuo providing 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-3-methyl-piperidine-2,6-dione hydrochloride (1.2 g, 92% yield); 1H NMR (DMSO-d6) δ 1.70 (s, 3H), 1.87-1.93 (m, 1H), 2.55-2.82 (m, 3H), 4.14 (s, 2H), 4.66 (d, J=17.7 Hz, 1H), 4.75 (d, J=17.7 Hz, 1H), 7.61-7.74 (m, 3H), 8.60 (br, 3H), 10.88 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]1([S:19]([NH:22][C:23](=[NH:26])SC)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:13]1([S:19]([NH:22][C:23]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:26])(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSC(=N)NS(=O)(=O)c1ccccc1
Reactant: Cc1cccnc1CSCCN
Solvent: CC#N
Product: Cc1cccnc1CSCCNC(=N)NS(=O)(=O)c1ccccc1

Procedure:
A solution of 3-methyl-2-((2-aminoethyl)thiomethyl)pyridine (6.3 g) and N-benzenesulphonyl-S-methylisothiourea (8.0 g) in acetonitrile (100 ml) was heated under reflux for 24 hours. Concentration, followed by chromatographic purification on a column of silica gel and recrystallisation afforded N-benzenesulphonyl-N'-[2-((3-methyl-2-pyridyl)methylthio)ethyl] guanidine.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25]Br>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Clc1cc(Cl)cc(CBr)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 54.2 %

Procedure:
5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (235 mg, yield: 54.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C1COCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Yield: 42 %

Procedure:
To a solution of 7-amino-4-[(3-bromophenyl)amino]-quinazoline (163 mg, 0.52 mmol) in dry THF (3 mL) stirred under N2 at 25° C. was added dropwise propionyl chloride (0.05 mL, 0.58 mmol). A yellow solid formed at once. After 1 hour the solid was collected by Buchner filtration and washed with ether then dried. Recrystallized from wet methanol afforded the desired product as bright yellow solid (81 mg, 38%), mp 282-283° C.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([N:23]([CH2:31][C@H:32]([O:41]C(=O)C)[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(=O)C.[H-].[Na+].I[CH3:48]>O1CCCC1>[CH2:24]([N:23]([C@H:6]([CH2:5][OH:4])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:48])[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH2:31][C@H:32]([OH:41])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)OC[C@H](Cc1ccc(NC(=O)c2ccccc2)cc1)N(Cc1ccccc1)C[C@@H](COc1ccccc1)OC(C)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccccc1)c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of N-[4-[(2S)-3-acetoxy-2-[N-[(2S)-2-acetoxy-3-phenoxypropyl]-N-benzylamino]propyl]-phenyl]benzamide (107 mg) in tetrahydrofuran (1.1 ml) was added sodium hydride (60% in oil, 17 mg), and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added iodomethane (25 μl), and the mixture was stirred at room temperature for 1.5 hours before being partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was dissolved in methanol (1.1 ml)-1,4-dioxane (1.1 ml), then treated with 1N sodium hydroxide (0.5 ml) at room temperature for 1.5 hours. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-3-hydroxypropyl]phenyl]-N-methylbenzamide (55 mg) as a white amorphous powder.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]3[C:8](=[O:27])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2cc(-c3ccc(F)cc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 43.4 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 16; 100 mg) was reacted with 1-acetylpiperazine (73.0 mg) to obtain 9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (50.9 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH:18]([CH3:21])[C:19]#[N:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:19]([CH:18]([N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:21])#[N:20].[C:19]([CH2:18][CH2:21][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])#[N:20]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CC(Br)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)C#N
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCC#N
Temperature: 90 °C
Yield: 35 %
Yield: 27 %

Procedure:
Synthesized as described in Example 23 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile, 2-bromopropionitrile (2 eq) and Cs2CO3 (2 eq) with heating at 90° C. for 30 min. After aqueous workup, purification by flash chromatography afforded 1-(1-cyanoethyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.033 g, 27% yield) (MS (ES) m/z 278 (M+1)) and 1-(2-cyanoethyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.043 g, 35% yield) (MS (ES) m/z 278 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:16]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:24].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:32]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:24])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN)c2CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1c(Cl)ccc2c1CCNCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 11.4 %

Procedure:
To a solution of 6-(3-aminopropylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46.7 mg, 0.126 mmol) in dry DCM (0.5 mL) at ambient temperature under nitrogen, add triethylamine (19.3 μL, 0.139 mmol) and benzoyl chloride (16.1 μL, 0.139 mmol). Stir at ambient temperature for 2.5 h. Add aqueous saturated ammonium chloride and water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Dissolve the residue in DCM (0.16 mL), add trifluoroacetic acid (44.6 μL, 0.58 mmol) and stir for 18 h at ambient temperature. Concentrate in vacuo and purify by preparative HPLC [Column: YMC ODS-AQ 120 Å 20×250 mm [S10-20 μm]; eluent: 95:5 to 5:95 A/B; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol; flow rate 20 mL/min] to give the title compound (7.0 mg, 12%). MS (APCI+) m/z 375 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O:19][C@@H:20]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:31][S:30][C@H:21]1[O:22][C:23]1[CH:24]=[N:25][C:26](Br)=[CH:27][CH:28]=1)(=[O:18])[CH3:17]>>[C:16]([O:19][C@@H:20]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:31][S:30][C@H:21]1[O:22][C:23]1[CH:24]=[N:25][C:26]([C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[CH:27][CH:28]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: OB(O)c1ccc(N2CCCCC2)cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(N3CCCCC3)cc2)nc1

Procedure:
By following a procedure analogous to Example 43 starting from [4-(1-piperidinyl)phenyl]boronic acid and 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, the expected compound is obtained in the form of a gray powder (yield=14%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].C(N(CC)C(C)C)(C)C.[CH:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35]>C(#N)C>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH:34]=[O:35])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C=O)CC1
Reaction time: 2 h

Procedure:
To as solution of (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride (0.12 mmole) from experiment K4 in acetonitrile (1.0 ml) was added at 22° C. N,N-diisopropylethyl amine (0.38 mmole) and p-nitrophenyl formate (0.14 mmole) and stirring was continued for 2 h. The mixture was evaporated, the residue partitioned between ethyl acetate and aqueous sodium carbonate, the organic layer was washed with water, dried and evaporated. The residue was purified by prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-formyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 482.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=C(O)Cc1ccccc1Cl
Product: Clc1ccccc1CCNC1CC1

Procedure:
Synthesized according to typical procedures C and D from (2-chlorophenyl)-acetic acid and cyclopropylamine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.C(N(CC)CC)C.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22].[C:25](Cl)(=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl.O>[C:25]([N:4]1[C:5]2[CH:10]([CH2:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][Si:21]([CH3:23])([CH3:22])[CH3:20])([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:31]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C[Si](C)(C)Cl
Reactant: OCC1CCc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1C2=CC=CCC2CCC1CO[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of 2-hydroxymethyltetrahydroquinoline (7.86 g, 48.16 mmol) in dichloromethane (80 mL) containing triethylamine (10 mL, 72.23 mmol) was added trimethylsilyl chloride (6.7 mL, 52.97 mmol) at 0° C. The mixture was stirred for 10 min at 0° C. followed by addition of triethylamine (10 mL) and ethyl chlorooxalate (5.9 mL, 52.97 mmol). The mixture was stirred for 30 min at 0° C. and water was added. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated to give 15.6 g of N-ethoxalyl-2-trimethylsilyloxymethyltetrahydroquinoline (106%): 1H NMR (270 MHz, CDCl3) δ6.97~7.16 (m, 4H), 4.68 (m, 1H), 4.09 (q, 2H, J=7 Hz), 3.72 (m, 1H), 3.54 (m, 1H), 2.65 (m, 2H), 2.37 (m, 1H), 1.69 (m, 1H), 1.06 (t, 3H, J=7 Hz), 0.03 (s, 9H).