Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[CH:48][N:47]=[C:46]2[C:50]([O:52]C)=O)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[CH:48][N:47]=[C:46]2[C:50]([NH:2][CH3:1])=[O:52])=[CH:31][CH:30]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12
Agent: CN
Product: CNC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-imidazole-2-carboxylate and methylamine 1H-NMR (CDCl3, 400 MHz, δ) 8.54 (d, J=4.4 Hz, 1H), 8.09 (d, J=9.3 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (s, 1H), 7.47 (d, J=7.9 Hz, 2H), 7.37 (dd, J=4.5, 9.2 Hz, 1H), 6.93 (s, 1H), 6.90 (s, 1H), 6.31 (s, 2H), 2.91 (s, 3H) ppm; m/e 367 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O.O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cis-4-hydroxy-D-proline (9.0 g, 68.6 mmol) is dissolved in 100 mL mixture of water and p-dioxane (1:1) and then triethyl amine (19.1 mL, 137.3 mmol), 4-methoxyphenylsulfonyl chloride (15.6 g, 75.5 mmol), and 4-dimethylaminopyridine (0.86 g, 6.86 mmol) are added. The solution is stirred at room temperature overnight. The reaction mixture is washed with sodium bicarbonate and extracted once with ether. The water layer is acidified with 1N HCl until pH~2 is achieved and then the solution is extracted three times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, and dried (MsSO4), filtered and evaporated to give the crude acid. Cl+ MS: m/z (rel intensity) 302.0(M+ +H, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]4[C:29]([CH3:30])=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:17][C@@H:16]2[CH3:31])=[N:10][S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=[CH:6][CH:7]=1.CO[CH:34](OC)[N:35]([CH3:37])[CH3:36]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]4[C:29]([CH3:30])=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:17][C@@H:16]2[CH3:31])=[N:10][S:11](=[O:14])(=[O:13])[N:12]=[CH:34][N:35]([CH3:37])[CH3:36])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2ncnc(N3CCN(C(=NS(N)(=O)=O)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Reactant: COC(OC)N(C)C
Solvent: CO
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NS(=O)(=O)N=CN(C)C)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
Crude (S)—N-(3-bromophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N′-sulfamoylpiperazine-1-carboximidamide from Example 20, step C, (˜25 mg, 0.068 mmol) was dissolved in MeOH (0.5 ml) and N,N-dimethylformamide dimethyl acetal (7 μl) added. The mixture was stirred at room temperature for 20 minutes and then concentrated. The mixture was purified by preparative HPLC to afford the desired compound (5 mg, 0.0088 mmol, 13%) as a white solid.
Reaction SMILES: [Cl:1][CH:2]([C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.C(#N)C>[Cl-:1].[N:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:12][C:4]=1[CH:2]([P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:3]
Reactant: CC(Cl)c1nc2cccnc2[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(c1nc2cccnc2[nH]1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 150 °C
Yield: 19.7 %

Procedure:
8.66 g of 2-(1-chloroethyl)-3H-imidazo[4,5-b]pyridine (compound B2) are suspended in 40 ml of N,N-dimethylformamide and 120 ml of acetonitrile. 12.6 g of triphenylphosphine are added and the mixture is heated to 150° C. for 17 h. The mixture is concentrated to dryness and the crude product purified by chromatography on silica gel (eluent: dichloromethane/methanol 20:1) to afford 4.16 g of the title compound as an oil. MS: 408.0 (M+). TLC: Rf=0.22-0.47 (dichloromethane/methanol 10:1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[O:9][CH:8]=1)(=O)=O>C(#N)C.C(O)C#C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:9][CH2:8][C:7]#[C:12][C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[O:9][CH:8]=1
Reactant: O=c1cc(COC2CCCCO2)occ1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1cc(COC2CCCCO2)occ1C#CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To a solution of 16 g of 4-oxo-6-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-3-yl trifluoromethanesulfonate in 100 mL of acetonitrile, 5.1 mL of propargyl alcohol, 18 mL of triethylamine, 0.62 g of dichlorobis(triphenylphosphine)palladium(II) and 0.42 g of copper (I) iodide were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=100:0 to 97:3 to obtain 6.2 g of 5-(3-hydroxy-1-propyn-1-yl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one as a brown oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([O:5][CH:6]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][OH:8])=[O:4].[P:30](Cl)([O-:44])([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br)=[O:31].[CH3:46][N:47]([CH3:49])[CH3:48]>>[P:30]([O-:44])([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N+:47]([CH3:49])([CH3:48])[CH3:46])([O:8][CH2:7][CH:6]([O:5][C:3](=[O:4])[N:2]([CH3:29])[CH3:1])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31]
Reactant: O=P([O-])(Cl)OCCCCCCCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OC(=O)N(C)C
Reactant: CN(C)C
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCCCC[N+](C)(C)C)OC(=O)N(C)C
Yield: 61.3 %

Procedure:
In accordance with Example 7, 2.49 g of 2-dimethylcarbamoyloxy-3-octadecyloxypropanol, 3.17 g of 10-bromodecyl chlorophosphate and trimethylamine were used for reaction and purification to give 2.55 g (yield: 61.3%) of the desired product.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[Br:12]Br>O1CCOCC1>[Br:12][CH2:11][C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][CH3:1])[CH:8]=1)=[O:10]
Reactant: BrBr
Reactant: CCc1cccc(C(C)=O)c1
Solvent: C1COCCO1
Product: CCc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a stirred solution of 3-ethylacetophenone (Maybridge Chemical Company Ltd.; 1.103 g, 7.44 mmol) in dry 1,4-dioxane (15 mL) was added bromine (383 μL, 7.44 mmol). The solution was stirred at room temperature for 30 min. and then the solvent was removed on a rotary evaporator. The residue was chromatographed on a Foxy 200 machine (Isco, Inc., P.O. Box 82531, Lincoln, Nebr. 68501, USA.; eluent, 5% CH2Cl2/Hexane, 0–2 min. then 20–30% CH2Cl2/Hexane, 2–20 min.) to give 2-bromo-1-(3-ethylphenyl)ethanone (1.15 g, 68%) as a clear oil.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:10]([CH3:29])=[N:9][CH:8]=1)=[O:6]>CO.C1COCC1.O>[NH2:4][C:5]([C:7]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[C:10]([CH3:29])=[N:9][CH:8]=1)=[O:6]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(-c3nc(C(N)=O)cnc3C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(C(N)=O)nc1-c1ccc([C@H]2CC[C@H](C(=O)O)CC2)cc1

Procedure:
Lithium hydroxide monohydrate (42 mg, 1.00 mmol) was added to a stirred solution of methyl trans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohexanecarboxylate (Example 65, 71 mg, 0.20 mmol) in MeOH (2 mL), THF (1 mL) and water (0.5 mL). After 16 h the reaction mixture was concentrated in vacuo and purified by reverse phase HPLC (150 mm×21 mm Phenomenex Column packed with Luna 10u C18 silica, eluting with 5-95% acetonitrile/water) to give the title compound as a yellow solid (6 mg, 9%); 1H NMR δ 9.01 (1H, s), 8.08 (1H, s), 7.73 (1H, s), 7.70 (2H, d), 7.40 (2H, d), 2.70-2.50 (1H, m), 2.65 (3H, s), 2.37-2.25 (1H, m), 2.10-2.00 (2H, m), 1.95-1.85 (2H, m), 1.65-1.40 (4H, m); MS 340.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([CH:19]([CH2:22]O)[CH2:20][OH:21])[CH2:17][CH3:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:16]([C@@H:19]1[CH2:20][O:21][C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:13][CH:12]=2)[O:15][CH2:22]1)[CH2:17][CH3:18]
Reactant: CCCC(CO)CO
Reactant: O=Cc1ccc(-c2ccc(F)cc2)nc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CO[C@H](c2ccc(-c3ccc(F)cc3)nc2)OC1
Reaction time: 1.5 h

Procedure:
A solution of 1.51 g of 6-(4-fluorophenyl)-3-pyridinecarboxaldehyde and 1.10 g of 2-propyl-1,3-propanediol in 50 ml of toluene was treated with 10 drops of 10 percent (v/v) sulphuric acid. The mixture was heated to boiling for 1.5 hours, whereby moist toluene was distilled off and replaced by fresh toluene. Then, the reaction mixture was neutralized with triethylamine and, after cooling, washed three times with water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on 60 g of silica gel with toluene/acetone (vol. 99:1) and two-fold recrystallization of the trans/cis mixture from hexane/ethyl acetate (vol. 1:1) gave 0.51 g of pure 5-(trans-5-propyl-1,3-dioxan-2-yl)-2-(4-fluorophenyl)pyridine; m.p. (C-SA) 106.5° C., SA -N 117.5° C., cl.p. (N-I) 163° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([OH:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Intermediate 4, ethyl 3-(benzyloxy)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxylate (342 mg, 1 mmol) was suspended in 5 mL of methanol, treated with a solution of LiOH (48 mg, 2 mmol) in 5 ml H2O then stirred at room temperature for 1 h. The reaction was quenched with 2 mL of 1N HCl. The resulting precipitate was collected by filtration and dried to give 260 mg of the title compound as a crystalline solid (Yield=83%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.46–7.59 (2 H, m) 7.25–7.40 (3 H, m) 5.44 (2 H, s) 3.98–4.15 (2 H, m) 2.04–2.19 (2 H, m) 1.34 (6 H, s); LC/MS m/z 315 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.NC[CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:41][CH3:42]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH2:41][CH3:42])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCN1CCCC1CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid 5.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs with a stream of nitrogen bubbling throught it. The 2-(aminoethyl)-1-ethylpyrrolidine (4.46 g, 0.0348 mole) was added dropwise and the reaction mixture was allowed to stir at room temperature overnight.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:25])[C@@H:10]([CH2:22][O:23][CH3:24])[NH:11]C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:26][C:2]1([CH3:1])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:25])[C@@H:10]([CH2:22][O:23][CH3:24])[NH2:11]
Reactant: COC[C@@H](NC(=O)OCc1ccccc1)C(=O)OC1C(C)CCC1(C)C
Agent: [Pd]
Solvent: CO
Product: COC[C@@H](N)C(=O)OC1C(C)CCC1(C)C

Procedure:
To a solution of 5 g N-Cbz-D-serine 2,2,5-trimethylcyclopentyl ester in 50 ml dry CH2Cl2 is added 2 equivalents of Ag2O and 2 equivalents of methyl iodide. After stirring for 2 hours, the mixture is filtered and concentrated to yield the methyl ether of N-Cbz-D-serine 2,2,5,-trimethylcyclopentyl ester. 3 g of N-Cbz-D-serine methyl ether 2,2,5-trimethylcyclopentyl ester is hydrogenated over 0.5 g 10% Pd/C in 100 ml CH3OH. Upon completion, the mixture is filtered and concentrated to yield 3-methoxy-D-alanine 2,2,5-trimethylcyclopentyl ester. To a magnetically stirred solution of 2 g of 3-methoxy-D-alanine 2,2,5-trimethylcyclopentyl ester in 100 ml DMF at 0° C. is added 1 equivalent of N-Cbz-L-aspartic acid-β-benzyl ester followed by addition of 1 equivalent each of Cu(II) chloride and dicyclohexylcarbodiimide. After 18 hours the mixture is poured into 200 ml 0.1N HCl and extracted with 300 ml ethyl acetate. The organic phase is washed with saturated NaHCO3, and H2O, dried over MgSO4, filtered and concentrated to an oil that is reconstituted in 50 ml CH3OH and hydrogenated over 0.5 g 5% Pd/C. Filtration followed by concentration yields L-aspartyl-D-serine 2,2,5-trimethylcyclopentyl ester methyl ether.
Reaction SMILES: [F:1][C:2]1(CN)[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[CH:3]1[CH2:11]N.N([O-])=[O:16].[Na+].[C:19](=[O:22])([O-])O.[Na+]>C(O)(=O)C.O>[F:1][C:2]1([CH2:19][OH:22])[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[CH:3]1[CH2:11][OH:16]
Reactant: NCC1C(F)=C(F)C=C(F)C1(F)CN
Reactant: O=N[O-]
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: OCC1C(F)=C(F)C=C(F)C1(F)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 450.4 %

Procedure:
Into a 200 ml-volume flask equipped with a thermometer, a stirring unit, a nitrogen inlet and a reflux condenser, 10.4 g (50.0 mmol) of 2,3,5,6-tetrafluoroxylylenediamine synthesized in Example 1, 50 g of water and 10.35 g (150.0 mmol) of sodium nitrite were charged, and the mixture was stirred at room temperature for 30 minutes. Subsequently, under cooling of the reactor in a water bath, 7.51 g (125.0 mmol) of acetic acid was added dropwise over 60 minutes while keeping the inside of the reaction system at 40° C. or less. After the completion of dropwise addition of acetic acid, 0.8 g of sodium hydrogencarbonate was charged, and the mixture solution was further stirred at 40° C. for 60 minutes. The reaction solution obtained was extracted with 10.0 g of methyl ethyl ketone, the organic phase was washed with 5.0 g of an aqueous 5 mass % sulfuric acid solution, and then the methyl ethyl ketone was removed by distillation, as a result, 9.1 g of 2,3,5,6-tetrafluorobenzenedimethanol was obtained as white crystals. The purity determined from the GC area in percentage was 98.9% and the yield was 85.7%.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:39]=1)OC1C=CC=CC=1)#[N:23]>>[C:22]([NH:24][C:25]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:1])=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]2)[CH:39]=1)#[N:23]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCN)CCC(c1ccccc1)c1ccccn1
Product: CN(CCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.57 g (2 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; IR (KBr): 2164 cm-1 (C≡N).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:32][C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To 10 mL of a chloroform solution containing 252 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 136 mg of 2-naphtoaldehyde, 50 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 276 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=2:1], to give 279 mg of 7-fluoro-1-(2-(4-((naphthalen-2-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13][CH2:12][C:11](=[O:15])[N:10]2[CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1.C[OH:28]>OO.Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:28])[CH2:12][C:11](=[O:15])[N:10]2[CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(CN1C(=O)CSC[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Reactant: CO
Agent: Cl
Agent: OO
Product: O=C(CN1C(=O)CS(=O)C[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of benzyl [(3R)-3-(3,5-difluorophenyl)-5-oxothiomorpholin-4-yl]acetate (151 mg, 0.399 mmol, from Step A.) in MeOH (10 mL) was added aqueous hydrogen peroxide (30 drops, ˜0.8 mL, 30% by weight), and aqueous HCl (5 drops, 3 M HCl). This mixture was then heated to 40° C. for 2.5 hours. After cooling to ambient temperature, the bulk of the MeOH was removed in vacuo, and the residue was partitioned between 50 mL of water and 100 mL of diethyl ether. The organics were washed with saturated brine, then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography eluting with a gradient of Hexanes:EtOAc—1:1 to 100% EtOAc, to yield 24.5 mg of the minor sulfoxide isomer and 93.6 mg of the major sulfoxide isomer. MS: m/z=394 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].O[N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:5][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CBr)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
Bromoacetic acid (4.30 g) and N-hydroxysuccinimide (4.03 g) were dissolved in DCM (25 ml). The mixture was stirred on a magnetic stirrer at room temperature. DCC was added (7.42 g) in one portion and the mixture was reacted overnight. The reaction mixture was filtered to remove dicyclohexylurea. The filter cake was washed several times with DCM. The combined filtrates were washed three times with saturated aqueous sodium chloride solution (30 mL/each wash), dried over anhydrous magnesium sulfate, and filtered. The title compound was obtained as a white solid (5 g) after rotary evaporation in vacuo.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[CH3:6][NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)O.Cl[Si](C)(C)C.O>C(O)C.C(OCC)(=O)C>[ClH:3].[CH3:6][NH:7][CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CNCC1CCCCC1(O)c1cccnc1
Reactant: O=S(Cl)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CNCC1=C(c2cccnc2)CCCC1
Temperature: 65 °C

Procedure:
26 ml thionyl chloride were added dropwise to 5.20 g 2-methylaminomethyl-1-pyridin-3-yl-cyclohexanol hydrochloride and the mixture was heated (bath temperature 65 ° C) for 90 minutes, while stirring, and then concentrated under a water pump. After cooling, dilute sodium hydroxide solution (2 mol/l) was added, the mixture was extracted repeatedly with a mixture of equal volumes of tetrahydrofuran and ethyl acetate, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. The crude product obtained (3.25 g) was dissolved in 25 ml absolute ethanol and 8 ml ethyl acetate, and 4.1 ml chlorotrimethylsilane and 0.58 ml water were added in succession. The solid which had precipitated out (1.84 g) was filtered off with suction (cf. Example 79), the mother liquor was rendered basic with dilute sodium hydroxide solution (2 mol/l) and extracted repeatedly with a mixture of equal volumes of tetrahydrofuran and ethyl acetate, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. The residue obtained (1.45 g) was chromatographed on silica gel with methanol, to which 0.05 percent by volume of aqueous ammonia solution (25 percent strength by weight) had been added. The product fraction (0.52 g) was dissolved in 50 ml ethyl acetate, and 0.66 ml chlorotrimethylsilane, followed by 92 μl water, were added. 0.57 g methyl-(2-pyridin-3-yl-cyclohex-1-enylmethyl)amine hydrochloride was obtained as a precipitate.