Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Br)nc2N1C1CCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3nccs3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 54, with (R)-2-(2-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 65) used instead of (R)-2-(4-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 43) and with 2-(tributylstannyl)thiazole instead of 4-(tributylstannyl)thiazole. LCMS: 410.1 m/z (M+H)+; ret. Time: 3.11 min (Analytical Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([N:31]([S:41]([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=3)(=[O:43])=[O:42])[CH3:32])[CH2:29][CH2:30]2)[C:10]([CH:12]2[CH2:13][CH2:14][N:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CCN(CCCN(C(=O)C2CCN(S(C)(=O)=O)CC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N(C)C2CCN(CCCN(C(=O)C3CCN(S(C)(=O)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Yield: 87 %

Procedure:
The title compound was prepared using a similar procedure to that described for example 195 from the title compound of example 323 and 4-methoxybenzenesulfonyl chloride, yield 87%.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:13][O:14][CH3:15])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[CH3:1][O:2][C:3]1([CH2:13][O:14][CH3:15])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]1
Reactant: COCC1(OC)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COCC1(OC)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
13.3 g (61.5 mmol) of the compound from Example 10A were dissolved in 200 ml of acetone and 100 ml of water, 1.87 g (9.84 mmol) of 4-toluenesulphonic acid monohydrate were added and the mixture was stirred at room temperature for two days. The acetone was then distilled off, the aqueous residue was neutralized by addition of sodium bicarbonate and 23.2 g of sodium chloride were added. The mixture was extracted repeatedly with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. This gave 10.3 g (97% of theory) of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:16][C:17]([OH:19])=O)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:20][N:21]([CH3:24])[CH:22]=O>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16](=[CH:20][N:21]([CH3:24])[CH3:22])[CH:17]=[O:19])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C=O)=CN(C)C)cc1OC
Temperature: 70 °C

Procedure:
The intermediate 2-(3,4-dimethoxyphenyl)-3-dimethylamino-2-propenal was prepared as follows: To a chilled 1260 ml. portion of dimethylformamide was added dropwise 230 ml. of phosphorus oxychloride followed by addition of 196 g. of α-(3,4-dimethoxyphenyl)acetic acid. The reaction mixture was heated at about 70° C. on a steam bath for 3 hours, allowed to cool and then concentrated in vacuo to remove the solvent and excess volatile reactants. The resulting product was used directly in the above procedure.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=3[CH:11]=[CH:10][N:9]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][N:9]=[C:8]2[O:7][C:6]1[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=1)=[O:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3ccc(C(F)(F)F)cc3)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(C(F)(F)F)cc4)nccc23)c1
Yield: 18.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(4-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-41, 100 mg, 0.32 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 177 mg, 0.65 mmol), oxalyl chloride (123 mg, 0.98 mmol), DMF (1 drop) and DIPEA (124 mg, 0.96 mmol) in CH2Cl2 (5 mL) to afford 33 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.30 (d, J=7.8 Hz, 1H), 8.21 (t, 1H), 8.08 (d, J=6.9 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.73 (d, J=6.3 Hz, 1H), 7.54 (m, 4H), 7.37 (d, J=8.4 Hz, 2H), 4.32 (d, J=5.7 Hz, 2H), 1.14 (s, 9H); MS (m/z): 556.29 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32]I)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32][S:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Sc1nc(-c2ccccc2)cs1
Reactant: CC(C)(C)OC(=O)N1CCCC(CI)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(CSc2nc(-c3ccccc3)cs2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
2-Mercapto-4-phenylthiazole (304 mg, 1.54 mmol) and potassium carbonate (261 mg, 1.85 mmol) were added to 1-(tert-butoxycarbonyl)-3-iodomethylpiperidine (500 mg, 1.54 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 30 min. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was then washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=40:1->10:1) gave 598 mg (99%) of the desired compound as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[C:8](=O)[C:9](=[O:13])[NH:10][C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[O:13]=[C:9]1[C:8](=[N:22][NH:21][C:20]2[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=2)[C:7]2[CH:6]=[C:5]3[O:1][CH2:2][O:3][C:4]3=[CH:12][C:11]=2[NH:10]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2cc3c(cc2C1=O)OCO3
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc4c(cc32)OCO4)cc1
Yield: 55 %

Procedure:
The title compound was prepared from 5H-[1,3]dioxolo[4,5-f]indole-6,7-dione (Lackey and Stembach, Synthesis 1993, 993-7) and 4-sulfonamidophenylhydrazine hydrochloride in 55% yield as an orange crystalline solid following Procedure G: mp>220° C.; 1H NMR (DMSO-d6): δ 12.63 (s, 1H), 10.89 (s, 1H), 7.73 (d, J=7 Hz, 2H), 7.50 (d, J=7 Hz, 2H), 7.22 (s, 2H), 7.13 (s, 1H), 6.56 (s, 1H), 6.00 (s, 2H). Anal. Calcd for C15H12N4O5S: C, 50.00; H, 3.36; N, 15.55. Found: C, 50.08; H, 3.35; N, 15.49.
Reaction SMILES: [I:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH:8]([C:17]2[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[C:4]([N+:25]([O-])=O)[CH:3]=1.Cl>CO>[NH2:25][C:4]1[CH:3]=[C:2]([I:1])[CH:24]=[CH:23][C:5]=1[CH2:6][O:7][CH:8]([C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1)[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1
Reactant: Cn1cncc1C(OCc1ccc(I)cc1[N+](=O)[O-])c1ccc(C#N)cc1
Agent: Cl
Solvent: CO
Product: Cn1cncc1C(OCc1ccc(I)cc1N)c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
A solution of Example 46B (0.8 g, 2.1 mmol) in methanol (50 mL) at room temperature was treated with SnCl22H2O (1.41 g, 6.3 mmol) and concentrated HCl (20 mL), stirred for 12 hours, and concentrated. The concentrate was treated with aqueous NaOH and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with CH2Cl2:CH3OH:NH4OH (100:3:3, v/v) to provide the desired product. MS (DCI/NH3) m/z 445 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[S:11]1[CH:15]=[C:14]([CH:16]=O)[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2>>[S:11]1[CH:15]=[C:14]([CH2:16][NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N
Product: CCOC(OCC)[C@H](C)NCc1csc2ccccc12
Yield: 96.9 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 883 mg (6.0 mmol) was reacted with benzo[b]thiophene-3-carbaldehyde 827 mg (5.1 mmol) to obtain the title compound 1.45 g (97%).
Reaction SMILES: [N:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[C:2]=[O:3].[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)C1C=CC=CC=1>>[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:2]([NH:1][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[O:3]
Reactant: O=C(NCCCCO)c1ccccc1
Reactant: O=C=NC1Cc2ccccc2C1
Product: O=C(NCCCCO)NC1Cc2ccccc2C1
Yield: 61 %

Procedure:
1-(4-Hydroxybutyl)-3-indan-2-ylurea (60B) is prepared from 60A as described for 1D.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:21])=[O:16].[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:32](=[O:34])[CH3:33])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:21])=[O:16]
Reactant: CCCCCCCCCCN(C)CCNC(=O)Cc1cc(=O)oc2cc(O)c(Cl)cc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCN(C)CCNC(=O)Cc1cc(=O)oc2cc(OC(C)=O)c(Cl)cc12
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A sample of this 2-(6-Chloro-7-hydroxycoumarin-4-yl)-N-[2-(N-decyl-N-methyl-amino)ethyl]acetamide (26 mg, 0.06 mmole) was dissolved in anhydrous dichloromethane (5 mL) and acetic anhydride (0.5 mL, 5.3 mmole) and dry pyridine (0.5 mL, 6.2 mmole) added. This mixture was allowed to stir overnight, and the resulting solution, diluted with dichloromethane (30 mL) and extracted with water (1×25 mL), saturated sodium bicarbonate solution (1×25 mL), 1N HCl (1×25 mL) and water (1×25 mL). The resulting dichloromethane layer was dried over anhydrous sodium sulfate, filtered and evaporated. Drying in vacuo provided an off-white solid (22 mg, 79%). A biocompatible solution of this substrate was prepared by dissolving 22 mg in dry DMSO (0.446 mL) for staining live cells for esterase activity.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:2][C:3](=[O:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Chloroacetone (32.3 g, 0.347 mol) was added to a mixture of 4-chlorothiophenol (50 g, 0.347 mol) and sodium hydroxide (14 g, 0.347 mol) in water (400 ml) and the mixture was stirred at 25° C. for 1 hour. The mixture was extracted with ethyl ether and the organic phase was washed with water, dried with magnesium sulfate and concentrated to give 68 g (98%) of 1-[(4-chlorophenyl)thio]-2-propanone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15](B1OC(C)(C)C(C)(C)O1)=[CH2:16]>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:15]=[CH2:16])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Product: C=Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]

Procedure:
Following the general method as outlined in Intermediate 20, starting from 2-bromo-5-methylsulfonylnitrobenzene and vinylboronic acid pinacol ester, the title compound was obtained as a brown oil in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][C:9]([OH:13])=[C:10]([CH3:12])[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][C:9]1[N:8]=[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]2=[N:11][C:10]=1[CH3:12])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2ccnc(Cl)c2nc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccnc(Cl)c2nc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A solution of 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-ol (1.88 g, 9.61 mmol) in DCM (30 mL) at 0° C. was treated with DIEA (3.34 mL, 19.22 mmol) followed by methanesulfonyl chloride (1.11 mL, 14.42 mmol) (Sigma Aldich). The reaction mixture was warmed to RT and stiffed for 1 h. The mixture was diluted with DCM and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a silica gel column (10-35% EtOAc in Hexanes) to give 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-yl methanesulfonate (1.68 g, 6.14 mmol, 64% yield) as a brown solid. MS (ESI, pos. ion) m/z: 274.0 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (1H, d, J=5.7 Hz), 7.85 (1H, d, J=5.7 Hz), 3.83 (3H, s), 2.85 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:12][C:13]2[S:17][C:16]([CH3:18])=[N:15][C:14]=2[CH3:19])[CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[C:20]([OH:29])(=[O:28])[C@@H:21]([C@H:23]([C:25]([OH:27])=[O:26])[OH:24])[OH:22]>CO>[C:25]([CH:23]([CH:21]([C:20]([OH:29])=[O:28])[OH:22])[OH:24])([OH:27])=[O:26].[CH:1]1([CH2:4][N:5]([CH2:12][C:13]2[S:17][C:16]([CH3:18])=[N:15][C:14]=2[CH3:19])[CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: Cc1nc(C)c(CN(CC2CC2)C2CCNCC2)s1
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 1.5 h

Procedure:
N-(Cyclopropylmethyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]piperidin-4-amine (1.25 g, 4.46 mmol) and L-Tartaric acid (0.67 g, 4.46 mmol) are dissolved in methanol (25 ml). The solution is stirred for 1.5 h and concentrated. The solid is dried in a vacuum oven overnight to yield (1.86 g, 97%) N-(cyclopropylmethyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]piperidin-4-amine tartrate: mass spectrum (ion spray): m/z=280.2 (M+1); 1H NMR (CD3OD): δ=4.45 (2H, s), 3.87 (2H, s), 3.45 (2H, brs), 3.11-2.93 (3H, m), 2.62 (3H, s), 2.45 (2H, d), 2.32 (3H, s), 2.02 (2H, brd), 1.96-1.76 (2H, m), 0.95-0.85 (1H, m), 0.56-0.49 (2H, m), 0.17-0.10 (2H, m).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:28])[C:17]3=[C:18]([F:27])[CH:19]=[N:20][C:21]4[CH:22]=[C:23]([Cl:26])[C:24](=[O:25])[N:15]([C:16]=43)[CH2:14]2)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1.[Na].O>C(O)C>[Cl:26][C:23]1[C:24](=[O:25])[N:15]2[CH2:14][C:13]([CH2:12][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:33][CH2:34]3)([OH:28])[C:17]3=[C:18]([F:27])[CH:19]=[N:20][C:21]([CH:22]=1)=[C:16]23
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)CC1
Reaction time: 8 h

Procedure:
To a solution of crude ((4R/S)-8-chloro-3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl 4-methylbenzenesulfonate (˜2.5 g, assumed 6.10 mmol) in ethanol (50 mL), at room temperature, under argon was added 1,1-dimethylethyl 4-piperidinylcarbamate (1.22 g, 6.10 mmol) and sodium hydrogenocarbonate (1.94 g, 18.31 mmol). The reaction mixture was stirred for 8 hours. A further 0.5 equivalent of 1,1-dimethylethyl 4-piperidinylcarbamate (0.61 g, 3.05 mmol) and 1.5 equivalent of sodium hydrogenocarbonate (0.97 g, 9.15 mmol) were added. The reaction mixture was stirred for an additional 18 hours, treated with water (200 mL) and extracted with a 10% solution of methanol in dichloromethane (3×200 mL). The combined organic layers were dried over magnesium sulphate, evaporated and chromatograped affording an impure material which used crude in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[F:19])=[CH:4][CH:3]=1>C1COCC1.[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[F:19])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1cc([N+](=O)[O-])ccc1F
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(F)c(C(=O)Nc2ccc(Br)cc2)c1
Reaction time: 20 h

Procedure:
A mixture of N-(4-Bromophenyl)-2-fluoro-5-nitro-benzoic acid amide (1.57 g, 4.6 mmol) and 500 mg Ra-Ni in 100 mL THF was stirred for 20 h under an atmosphere of hydrogen (3 bar). After filtration and concentration i. vac. the subtitle compound was obtained. Yield: 1.46 g (quantitative). MS [M+H]+=309 (Br-isotope pattern); TLC: Rf=0.68 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [C:1]([C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:5]([CH3:7])=[O:6])(=O)[CH3:2].Cl.[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(OCC)(=O)C>C(O)CCC>[C:5]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[NH:27][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:26][C:1]=1[CH3:2])(=[O:6])[CH3:7]
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(=O)C1=C(C)N=C(c2ccccc2)NC1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 31 %

Procedure:
A mixture of 1-acetyl-1-(3-nitrobenzyliden)acetone (10 g), benzamidine hydrochloride (8.06 g) and triethylamine (8.4 ml) in n-butanol (100 ml) was refluxed for 2 hours. The reaction mixture was added ethyl acetate (100 ml), washed with water (100 ml) and 5% hydrochloric acid (100 ml) successively. The solvent was evaporated and the residue was stirred with ethyl acetate (100 ml) for 1 hour. The crystals were collected by filtration, added a mixture of chloroform (100 ml) and water (100 ml) and adjusted to pH 8.5 by saturated potassium carbonate. The organic layer was evaporated in vacuo to give 5-acetyl-4-methyl-6-(3-nitrophenyl)-2-phenyl-1,6-dihydropyrimidine (4.46 g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:36][CH2:37][CH3:38])[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1)[CH2:21][CH3:22]>C(OCC)(=O)C>[CH2:36]([N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29][CH2:28]1)[CH2:37][CH3:38]
Reactant: CCCN(CCC)CCCC1CCN(CCN)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCOC(C)=O
Product: CCCN(CCC)CCCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 43 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(dipropylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 43% of theory. Colourless crystals, m.p. 169°-170° C. (ethyl acetate).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>C(O)(=O)C>[C:15]([O:18][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccccc1OC/C=C/CCl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC/C=C/COc1ccccc1C=O

Procedure:
The mixture of 50 g of 2-(4-chloro-trans-2-butenyloxy)-benzaldehyde, 50 g of sodium acetate and 200 ml of acetic acid is refluxed for 2 hours and concentrated. The concentrate is diluted with water, extracted with diethyl ether, the extract washed with water and 5% aqueous sodium bicarbonate, dried and evaporated, to yield the 2-(4-acetoxy-trans-2-butenyloxy)-benzaldehyde.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@H:6]2[C@H:4]([CH2:5]2)[C@H:3]1[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[C:19](=O)([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[O:20]N1C(=O)CCC1=O.C(N(CC)CC)C>O1CCOCC1.O.C(OCC)(=O)C>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[C@H:3]1[C@@H:2]([NH:1][C:19](=[O:20])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2
Reactant: N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O
Yield: 78.3 %

Procedure:
A solution of 2-((1S,2R,3S,5S)-3-aminobicyclo[3.1.0]hexan-2-yl)isoindoline-1,3-dione (2.0 g, 8.264 mmol), 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (3.2 g, 12.396 mmol) and triethylamine (3.4 mL, 24.792 mmol) in dioxane/water (100 mL, v/v=1/1) was stirred at room temperature for 1.5 hours. The reaction mixture was then diluted with ethyl acetate (100 mL), washed by 1 M hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (2×50 mL) and brine (50 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:4) to afford the title compound (2.5 g, 78%) as a yellow oil. MS (ES+) C20H26N2O4Si requires: 386, found: 410 [M+23]+.