Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:31]>>[CH3:1][C@@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: C[C@H](c1ccccc1)N1CCC(CCOS(C)(=O)=O)(Cc2ccc(F)cc2)C1=O
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(F)cc4)CCN([C@H](C)c4ccccc4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (Rf=0.55 silica gel, ethyl acetate) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give a diastereomer of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:16]=[C:15]3[C:10]([C:11](=[O:30])[C:12]([C:25]([O:27]CC)=[O:26])=[CH:13][N:14]3[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:9][C:8]=2[F:31])[CH2:3]1.O.[ClH:33]>>[ClH:33].[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:16]=[C:15]3[C:10]([C:11](=[O:30])[C:12]([C:25]([OH:27])=[O:26])=[CH:13][N:14]3[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:9][C:8]=2[F:31])[CH2:3]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)C1
Yield: 90.2 %

Procedure:
In 6 ml of 6N hydrochloric acid was suspended 1.00 g of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting suspension was subjected to reaction under reflux for 2 hours. Subsequently, 6 ml of water was added thereto and crystals were collected by filtration, and then washed with 2 ml of water to obtain 920 mg (yield 90.2%) of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride having a melting point of 247°-250° C. (decomp.). The physical properties of this compound were identical with those of the compound obtained in Example 54.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:9](=O)[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[CH:13][C:4]=12.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>C1C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH3:1][NH:2][CH:9]1[C:5]2[C:4](=[N:3][CH:8]=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=2
Reactant: O=c1c2ccccc2ccc2ncccc12
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CNC1c2ccccc2C=Cc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methylamine (3.72 g., 0.12 mole) is added to a mechanically stirred mixture of benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.0 g., 0.03 mole) in benzene (150 ml.). A solution of TiCl4 (2.1 ml.) in benzene (50 ml.) is added and the mixture is stirred at 25° C. for 18 hours. Anhydrous potassium carbonate is added to the mixture and it is filtered through diatomaceous earth. The filtrate is evaporated to an amber oil (5.47 g.) which is dissolved in acetonitrile (150 ml.). Sodium borohydride (5.47 g., 0.025 mole) is added and the mixture is heated on a steam bath for 11/2 hours. Dilute HCl (3N) is added to the cooled reaction mixture and it is evaporated to dryness under reduced pressure. The residue is dissolved in 3N HCl (150 ml.), extracted with ether and the aqueous filtrate is made alkaline by the addition of 40% NaOH solution. The basic material is extracted into CHCl3 and concentrated to an amber oil (3.96 g.). This oil is converted to a hydrochloride salt by treatment with ethanolic hydrogen chloride for use in Step B.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:4][CH2:5][CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1>>[CH2:13]([C:3]([CH2:11][CH3:12])([CH2:4][CH2:5][CH2:6][S:7](=[O:8])(=[O:9])[NH2:10])[CH2:2][O:1][C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1)[CH3:14]
Reactant: CCC(CC)(CO)CCCS(N)(=O)=O
Reactant: Cc1cc2ncnn2nc1Cl
Product: CCC(CC)(CCCS(N)(=O)=O)COc1nn2ncnc2cc1C

Procedure:
Using 5-hydroxy-4,4-diethyl-1-pentanesulfonamide and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction was conducted as in Example 5 to produce the title compound. m.p. 157°-158° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][NH:21][CH2:22]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH:19]2[CH2:25][CH2:24][CH:23]1[CH2:22][N:21]([C:8]([C:5]1[N:6]=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:10])[CH2:20]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Nc1ccc(C(=O)O)nn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nn1)C2
Yield: 51 %

Procedure:
Following general amide formation method 1, 6-amino-pyridazine-3-carboxylic acid (212 mg, 1.0 mmol) was combined with 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (139 mg, 1.0 mmol), which gave 3-(6-Amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a white solid (169 mg, 0.51 mmol) in 51% yield. MS m/z 334.4 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:30]=[CH:29][C:15]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([O:26]CC)=[O:25])[CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[OH-].[Na+].Cl>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]3)=[O:17])=[CH:29][CH:30]=2)=[N:2]1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
Compound 49 (1.0 g, 2.80 mmol) was dissolved in ethanol (40 mL), then the solution was added with 2 mol/L aqueous sodium hydroxide solution (15.0 mL) at 0° C., and was warmed to room temperature. After stirring for 6 hours, the reaction mixture was neutralized with 2 mol/L hydrochloric acid and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and was concentrated. The residue was recrystallized from ethyl acetate and methanol to obtain Compound 50 (654 mg, 70%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][S-:11].[Na+]>C(O)C>[F:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([S:11][CH3:10])=[N:3][CH:4]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ncc(F)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 2-chloro-5-fluoropyrimidin-4-amine (15.50 grams (g), 105 millimoles (mmol)) in ethyl alcohol (EtOH; 420 milliliters (mL)) was added sodium thiomethoxide (NaSCH3; 9.20 g, 131 mmol), and the resulting turbid mixture was warmed to reflux and stirred for 3 hours (h). The reaction mixture was cooled to room temperature, the solvent evaporated, and the residue partitioned between ethyl acetate (EtOAc; 250 mL) and water (H2O; 250 mL). The phases were separated, and the aqueous phase was extracted with additional EtOAc (100 mL). The organic phases were combined, dried over sodium sulfate (Na2SO4), filtered, and concentrated to an off-white solid. The solid was purified by flash chromatography (330 g silica gel (SiO2); 0→30% EtOAc/hexanes) to give 5-fluoro-2-methylsulfanylpyrimidin-4-ylamine (16.38 g, 98%) as a white solid: mp 114-115° C.; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=3.0 Hz, 1H), 5.29 (s, 2H), 2.50 (s, 3H); CIMS m/z 159 ([M]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Crude (R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (66.7 g) is dissolved in THF (340 ml) and cooled to 10° C. Sulphuric acid (96%; 6.9 ml) is added followed by water (152 ml). The mixture is stirred at room temperature for 0.5 h. Phases are separated. The organic phase is added to formaldehyde solution (37% in water; 138 ml). 1% Tetra-n-butylammoniumhydroxide solution (14.2 ml) is added. Potassium carbonate (27.8 g) is added portionwise over 0.5 h. Sodium hydroxide solution (15.1 g) is added over 3 h, maintaining pH 10.5. The phases are separated. The organic phase is washed with water (100 ml) followed by sodium bisulfite solution (21.4 g). Toluene (100 ml) and sodium chloride solution (50 ml) added. The phases are separated. The organic phase is extracted with sodium chloride solution (20%; 50 ml), dried (Na2SO4) and concentrated in vacuo to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (63 g). Material can be recrystallised as follows: crude (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (58.4 g) is dissolved in methanol (525 ml) at 50° C. Water (175 ml) is added and the mixture is cooled to 0° C. The solid is collected by filtration and the cake washed with a mixture of methanol (53 ml) and water (18 ml). The solid is then dried in vacuo, giving (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as in Example 23.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1)=[O:5])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=2)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)c1ccc(Br)c(C(=O)OCC)c1
Agent: [Cu]
Product: CCOC(=O)c1ccc(Oc2cccc(OC)c2)c(C(=O)OCC)c1
Yield: 41.8 %

Procedure:
Following the general procedure of Example 1A, 3.49 g of 4-bromo-1,3-benzenedicarboxylic acid diethyl ester and 1.43 g of 3-methoxyphenol were allowed to react in the presence of powdered copper metal to provide 1.66 g of the desired subtitle intermediate as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[CH:38]=[CH:37][C:21]3[N:22]([CH3:36])[C:23]([NH:25][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:11]1)(C)(C)C>Cl.O1CCOCC1>[ClH:35].[ClH:35].[ClH:35].[NH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[CH:38]=[CH:37][C:21]3[N:22]([CH3:36])[C:23]([NH:25][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:11]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(CCNC(=O)OC(C)(C)C)C3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(CCN)C3)ccc21
Yield: 323.3 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [1-(2-amino-ethyl)-pyrrolidin-3-yl]amide trihydrochloride (46 mg) was prepared by following General Procedure L starting from [2-(3-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (56 mg) in 4M HCl in dioxane (1 mL).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16](OC)=[O:17])[C:10]=2[CH:9]=[CH:8]1>C1COCC1>[OH:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][NH:7]2
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a mixture of lithium aluminum hydride (1.3 g, 34 mmol) in THF (200 mL), methyl 4-indole carboxylate (3.0 g, 17 mmol) in THF (100 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h and then quenched with ethyl acetate. The mixture was treated with water (1.3 mL), 15% NaOH (1.3 mL) and water (3.9 mL), and then filtered. The filtrate was concentrated in vacuo to afford the crude 4-(hydroxymethyl)-indole (2.5 g,99%): 1H NMR (500 MHz, CDCl3) δ 8.29 (br s, 1H),7.34 (d, J=9.0 Hz, 1H), 7.16-7.22 (m, 2H), 7.12 (d, J=7.0 Hz, 1H), 6.67 (t, J=1.0 Hz, 1H), 4.98 (d, J=4.2 Hz, 2H); CI MS m/z 147 [C9H9NO+H]+.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:56])[CH2:53][CH2:54][CH3:55].Cl>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:52](=[O:56])[CH2:53][CH2:54][CH3:55])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (100 mg) and pyridine (19 μl) are dissolved in methylene chloride (1 ml) and thereto is added butyryl chloride (19 μl) at room temperature. The reaction solution is stirred at room temperature for 30 minutes, and thereto are added methylene chloride and 1N-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (84 mg). MS (m/z): 723 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][CH2:20][N:21]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>O>[NH:21]1[CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCCN1
Solvent: Cc1ccccc1C
Solvent: O
Product: OC(CCNC1=NCCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α-(2-aminoethyl)benzylalcohol, 7.2 parts of 2-(nitramino)-1,4,5,6-tetrahydropyrimidine and 40 parts of xylene is stirred and refluxed for 48 hours with water-separator. Upon cooling the reaction mixture, the product is separated as an oil. The xylene is decanted and the oily product is triturated in diisopropylether. The solid product is filtered off and crystallized from acetone, yielding α-[2-(1,4,5,6-tetrahydro-2-pyrimidinylamino)ethyl]benzylalcohol; m.p. 130°-135°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:24](Cl)(=[O:26])[CH3:25].C(OCC)(=O)C.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:24](=[O:26])[CH3:25])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3NC(=O)[C@@H]2O)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3NC(=O)[C@@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
226 mg of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are suspended in 2 ml of pyridine, and 59 mg of acetyl chloride are added thereto under ice-cooling. The mixture is stirred at room temperature for 2 hours. After the reaction is completed, ethyl acetate-chloroform (1:1) is added to the reaction mixture. The mixture is washed with 10% hydrochlric acid and water, successively. Then, the mixture is dried and evaporated under reduced pressure to remove solvent. 219 mg of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1OC1C>C(COC)OC>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=[C:2]2[CH:11]=1
Reactant: Nc1cc(Br)c2ccccc2n1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC1CO1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(Br)c3ccccc32)n1
Reaction time: 1 h

Procedure:
1 g of 2-amino-4-bromoquinoline was dissolved in 20 ml of dimethoxyethane and a mixture of 1.5 g of ethyl bromopyruvate and 0.5 g of propylene oxide was added thereto. The solution was allowed to stand at room temperature for 1 hour and the quaternary salt thus precipitated was filtered off, was washed with ether and then was dissolved in 20 ml of ethanol. The solution was refluxed for 1 hour, cooled and then was evaporated to dryness under vacuum. The residue was partitioned between 50 ml of chloroform and 50 ml of 2 N sodium carbonate and the organic extract was washed with 50 ml of water, was dried over MgSO4, and was reduced in volume under vacuum. Then, ether was added thereto to give cream needles of ethyl 5-bromoimidazo-[1,2-a]-quinoline-2-carboxylate melting at 205°-207° C.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51]>CO>[O:13]=[C:12]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:1]
Reactant: O=C(O)CCCCCCCCCCI
Reactant: NCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CO
Product: O=C(O)CCCCCCCCCCCNC(=O)CCCCCCCCCCI
Yield: 82.1 %

Procedure:
Similar to example 2, reaction of 07.90 g (25.3 mmol) 11-iodoundecanoic acid with 2.90 g (25.3 mmol) N-hydroxysuccinimide and 5.22 g (25.3 mmol) DCC gave 10.0 g (96%) of the succiminidylester, which was reacted with 5.40 g (25.1 mmol) 12-aminododecanoic acid to yield 10.5 g (84%) of colourless crystals, m.p. 107°-110° C. (methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[Cl-].[NH4+].CCO.C1COCC1>[Fe].O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCC(c3ccccc3)CC2)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(F)c(N2CCC(c3ccccc3)CC2)c(F)c1
Yield: 95.8 %

Procedure:
In a 500 mL round-bottom flask was added 1-(2,6-difluoro-4-nitrophenyl)-4-phenylpiperidine (4.53 g, 14.23 mmol), iron (3.97 g, 71.2 mmol), and ammonium chloride (1.142 g, 21.35 mmol) in a solvent mixture of EtOH (60 mL)/THF (60 mL)/water (20 mL). The mixture was refluxed for 3 hours with vigorous stirring, cooled, filtered through diatomaceous earth and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to give the title compound as yellow solid (3.93 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.81 (m, 4 H) 2.54-2.64 (m, 1 H) 2.95-3.03 (m, 2 H) 3.09 (t, J=10.57 Hz, 2 H) 5.42 (s, 2 H) 6.10-6.21 (m, 2 H) 7.15-7.22 (m, 1 H) 7.25-7.34 (m, 4 H); MS (ESI+) m/z 289 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:30])[CH2:26][CH2:27][C:28]#[CH:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][OH:30])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(F)cc3)csc2c1)C(F)(F)F
Product: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-fluoro-phenyl)-benzo[b]thiophene-6-yl ester and 4-pentyn-1-ol were converted to yield 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol as light green solid, MS: 310 (M).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.Cl.[NH2:33][C:34](N)=[NH:35].O>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:1][C:34]([NH2:35])=[NH:33])=[N:11][C:10]2[C:5]([N:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Reactant: N=C(N)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(=N)N
Temperature: 70 °C
Reaction time: 24 h
Yield: 10.8 %

Procedure:
A mixture of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 10 mg, 0.33 mmol), DIEA (0.29 mL, 1.68 mmol), and guanidine hydrochloride (0.025 mL, 0.37 mmol) in DMSO (3 mL) was stirred at 70° C. for 24 h. The reaction mixture was cooled, H2O was added, and extracted with DCM (3×). The extracts were dried over Na2SO4, concentrated and purified by reverse phase HPLC. The pure fractions were concentrated, dissolved in MeOH, and neutralized by Stratosphere SPE (PL-HCO3 MP-resin) to give the title compound (12 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, br. s.), 9.95 (1H, br. s.), 8.53-8.39 (3H, br. s.), 7.84 (1H, br. s.), 7.73 (1H, br. s.), 7.02 (1H, br. s.), 6.77 (1H, s), 3.38-3.52 (2H, t, J=6.8 Hz), 2.87 (2H, t, J=6.8 Hz), 2.73 (3H, s). m/z (ESI, +ve) 336 (M+H)+.