Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([OH:15])=O)[C@H:11]([C:16]([OH:18])=O)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:19]([N:10]1[C@H:11]2[CH2:16][O:18][C:13](=[O:15])[C@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A mixture of the anhydride of cis-1,3-dibenzyl-2-oxo-imidazolidine-4,5-dicarboxylic acid (50.0 g), (R)-1-phenethylamine (18.9 g) and toluene (200 ml) is stirred and refluxed at 105° to 110° C for 2 hours. The toluene is distilled off, and the resulting residue is heated at 210° to 220° C for 1 hour. cis-1,3-Dibenzyl-5-[(R)-1-phenethyl]-hexahydropyrro[3,4-d]imidazole-2,4,6-trione left as the residue is dissolved in ethanol (750 ml), to which 97 % sodium borohydride (23.3 g) is added below 10° C. The mixture is stirred at room temperature for 16 hours. After the reduction is completed, the mixture is neutralized by the addition of acetic acid (35 ml) and concentrated in vacuo. The residue which contains cis-1,3-dibenzyl-4-[N-(R)-1-phenethylcarbamoyl]-5-hydroxymethyl-tetrahydroimidazol-2-one is heated under reflux with n butanol (500 ml) and 35 % hydrochloric acid (100 ml) for 2 hours. After the reaction is over, the mixture is cooled to room temperature. The n-butanol layer is separated, washed with water and concentrated in vacuo. The precipitate is collected by filtration to yield cis-1,3-dibenzyl-hexahydrofuro[3,4-d]imidazole-2,4-dione (44.6 g, 93.1 %). M.P. 96° to 101° C. [α]D25 + 13.8° (C = 2 in CHCl3). IR (Nujol) 1775, 1690 to 1700 cm-1 (C = 0).
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:16][C:17](=[O:27])[NH:18]CCC2C=CC=CC=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:28]([OH:31])(=O)[CH3:29]>[Pd]>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][C:1]2[CH:10]=[CH:5][C:4]([O:31][CH2:28][CH3:29])=[CH:3][CH:2]=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(=Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Reactant: CC(=O)O
Agent: [Pd]
Product: CCOc1ccc(NC(=O)CC(Cc2cccc3ccccc23)C(=O)O)cc1

Procedure:
A solution of 500 mg of 2-(1-naphthylmethylene)-3-(phenethylcarbamoyl)propionic acid in 50 ml of acetic acid was hydrogenated over 250 mg of a 10% palladium/charcoal under a hydrogen atmosphere at room temperature. After filtration of the catalyst, the filtrate was concentrated under reduced pressure, and hexane was added to the residue. The precipitates were collected to obtain 500 mg of (±)-2-(1-naphthylmethyl)-3-(phenetylcarbamoyl)propionic acid as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:22]=4)[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:36])[CH3:35])=[CH:3][CH:4]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: Nc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Yield: 10 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(4-amino-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and acetyl chloride as starting materials, 17 mg (10%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 2.1 (s, 3 H); ES-MS m/z 474.23 [M+H]+, HPLC RT (min) 3.01.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=C[C:30]=1OCC1C=CC(CNC(C2C(N)=NC(N)=CN=2)=O)=CC=1.C=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O1CCCC1>[CH2:1]([N:8]([CH3:30])[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[O:16])=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc(C(=O)NCc2ccc(COc3ccccn3)cc2)c(N)n1
Reactant: O=C(NCc1ccc(NCc2ccccc2)cc1)c1ccc2ncccc2c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)c1ccc(CNC(=O)c2ccc3ncccc3c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
Quinoline-6-carboxylic acid 4-benzylamino-benzylamide described in Preparation Example E+-3 (30 mg, 82 μmol), formalin (9 μl, 115 μmol), triacetoxy sodium borohydride (25 mg, 115 μmol) and acetic acid (several drops) were suspended in tetrahydrofuran (1 mL), and the solution was stirred at room temperature for 4 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction suspension at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, purification was carried out using thin layer NH silica gel chromatography (hexane:ethyl acetate=1:1), and the title compound (11 mg, 28 μmol, 35%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][C:14]1[C:15]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[N:16][CH:17]=[CH:18][CH:19]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH2:13][C:14]3[C:15]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Product: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
N-{3-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.4302 mmol) and N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide (102.0 mg, 0.4738 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.056 g, 35%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=4.6 Hz, 1H), 8.11 (d, J=6.5 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.40-7.32 (m, 2H), 6.93 (t, J=7.5 Hz, 1H), 6.26 (d, J=7.9 Hz, 1H), 4.62 (d, J=6.3, 2H), 3.24 (s, 3H), 3.16 (s, 3H). MS=367, 369 (MH)+.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])O.[Na+].[C:20](Cl)(=[O:24])[O:21][CH2:22][CH3:23].O>ClCCl>[CH2:22]([O:21][C:20]([NH:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4])=[O:24])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1ccc(C(C)(C)N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NC(C)(C)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(1-amino-1-methylethyl)benzoate (410 mg) in dichloromethane (15 mL) was added saturated aqueous sodium hydrogen carbonate solution (3 mL), a solution of ethyl chlorocarbonate (0.24 mL) in dichloromethane (5 mL) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 1 hr and at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (551 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[C:9]1(O)[CH2:10][CH2:11][CH2:12]2.[CH3:19][O:20]C(CC)CCCCC1CCC2C1CC(O)C2.[I-].[Na+].CI>O1CCCC1>[CH3:19][O:20][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Reactant: CCC(CCCCC1CCC2CCCC12O)OC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCC(CCCCC1CCC2CC(OC)CC12)OC
Temperature: 50 °C

Procedure:
The starting material, 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 3.9 mmoles) is added to a reaction vessel containing sodium iodide (0.12 g, 4.9 mmoles) and tetrahydrofuran (12 ml). The solution is stirred while methyl iodide (0.84 g, 5.9 mmoles) is rapidly added. The reaction is heated in a 50° C. water bath for 4 hours. The water bath is removed and the reaction neutralized with the addition of water (5 ml). The organic phase is separated and the aqueous phase extracted with ether (2×50 ml). The ether extracts are combined and washed with brine (50 ml). The solution is dried over anhydrous magnesium sulfate and the solvent removed under vacuum leaving a clear yellow oil. The product is then kugelrohred under reduced pressure leaving a pale yellow oil (0.8 g, 3.1 mmoles).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCOCC>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1OCc1ccccc1

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (2.00 g), benzyl bromide (1.54 mL), and cesium carbonate (4.60 g) in N,N-dimethylformamide (50 mL) were stirred for 24 hours. The reaction was taken up in ether and washed with 3× 1M NaOH solution, and brine, then concentrated to give the pure product.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]=O)=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:22]([CH2:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:24])[F:25])=[CH:15][CH:16]=3)[C:5]2=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Reactant: CCc1nc(C)cn1CCN
Product: CCc1nc(C)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2-ethyl-4-methyl-imidazol-1-yl)-ethylamine with 3-(4-trifluoromethyl-phenyl)-propionaldehyde. LC-MS: tR=0.65 min.; [M+H]+=338 g/mol.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.CCCCCC.[C:39]([O:43][C:44]([N:46]1[CH2:50][CH2:49][CH:48]([C:51](=[O:56])N(OC)C)[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44]([N:46]1[CH2:50][CH2:49][CH:48]([C:51]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)=[O:56])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4CCN(C(=O)OC(C)(C)C)C4)c3n2)cc(OC)c1OC
Reaction time: 0.01 h

Procedure:
7-Iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine 0.057 gm, 0.1 mM was placed in an oven dried flask and 1 ml anhydrous THF was added. The flask was chilled in an Acetone-dry ice slurry and evacuated and refilled 3 times with nitrogen. Via syringe 0.061 ml of 2.13M Buli in hexane solution (0.13 mM, 1.3 eq) was added and the now yellow mixture was stirred for 30 seconds then 3-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, 0.052 gm, 0.2 mM, 2 eq.) in a minimal amount of THF was added by syringe. The mixture was stirred for 30 minutes, removed from the dry ice-acetone bath and immediately quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted two times with ethyl acetate and the organic extracts dried over magnesium sulfate. After filtering and concentrating, the oil was redissolved in THF and 0.2 ml of 1M Tetrabutylammonium Fluoride in THF added. After 5 minutes the mixture was concentrated and purified on a preparative thin-layer chromatography plate (Ethylacetate/hexane) to give 3-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. The 3-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 3 ml of dichloromethane and 0.4 ml trifluoroacetic acid was added and stirred overnight. The solution was concentrated and the solid dried overnight at 2 torr in a 60° C. vacuum oven to give 0.012 gm of Pyrrolidin-3-yl-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone trifluoroacetate salt. (M+H)+=383.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=O)=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([Cl:15])=[O:11])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(Cl)ncc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)ncc1C(=O)Cl
Yield: 61.3 %

Procedure:
A solution of 2-chloro-4-methylpyrimidine-5-carboxylic acid (0.81 g, 4.70 mmol), oxalyl chloride (0.89 g, 7.05 mmol), DMF (2 drops) in CH2Cl2 (23 mL) was stirred at room temperature under N2 for 4 h. The solution was concentrated and distilled to give the title compound (0.55 g, 61%); b.p. 90-100° C., 1.3 mm/Hg; 1H NMR (CDCl3) δ d9.02 (s, 1H), 2.74 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>C(Cl)Cl.C(OCC)C>[ClH:30].[ClH:30].[C:24]1([CH:20]2[C:18]3[N:19]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[S:16][C:17]=3[CH2:23][CH2:22][CH2:21]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(s2)CCCC3c2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(C2CCCc3sc(NC4CCNCC4)nc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.575 g, 3.8 mmol) in methylene chloride (13.8 mL) was added 2 M HCl solution in diethyl ether (6.9 mL). The reaction was stirred at room temperature over the weekend. The solvent was removed under reduced pressure and the residue was treated with diethyl ether and evaporated. The title compound was obtained as a light yellow solid (1.32 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23]>CC(=O)CC.O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)Br
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)C(C)Oc1cccc2cccnc12
Temperature: 25 °C

Procedure:
23.2 g of 8-hydroxyquinoline are dissolved in 400 ml of butan-2-one, under the influence of heat, and 30 g of potassium carbonate are added in portions. The mixture is refluxed for one hour. 2 g of potassium iodide are then added dropwise, followed by 40 g of methyl 2-bromopropionate in 100 ml of butan-2-one in the course of one hour, with stirring and boiling. The mixture is then refluxed for another 10 hours. After cooling to room temperature, the mixture is poured onto 1 liter of water and extracted with three 200 ml portions of ethyl acetate. The combined extracts are washed once with 50 ml of water, dried over sodium sulfate and filtered. The solvent is evaporated off and the oily residue is crystallised by trituration with petroleum ether. After recrystallisation from hexane, methyl 2-(8-quinolinoxy)-propionate (compound No.3) is obtained in the form of beige-coloured crystals of melting point 70° to 72° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]([CH2:18][NH:19][CH2:20][CH3:21])[CH2:13][C:14](OC)=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]#[N:10].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]2[CH2:13][C:14](=[O:15])[N:19]([CH2:20][CH3:21])[CH2:18]2)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CCNC[C@H](CC(=O)OC)Nc1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Yield: 84.3 %

Procedure:
Methyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-(ethylamino)butanoate, hydrochloride (4.0 g., 13.5 mmole) was redissolved in ethyl acetate (50 mL). Water was added (50 mL) and 10% sodium bicarbonate was added with stirring to bring the pH to 8.5. The organic layer was concentrated and redissolved in benzene (120 mL). The solution was heated with stirring at 75° C. for 6 h. The solvent was evaporated. The crude product was triturated with Et2O, chilled and the solid filtered to give the titled compound (3.0 g, 84%). LC-MS (ES) m/e 263 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13].[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:14][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[CH:11][N:10]=[C:9]3[CH3:13])=[C:2]([F:1])[CH:3]=2)[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Cc1nccn1-c1ccc(N)cc1F
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-n3ccnc3C)c(F)c2)n1

Procedure:
The title compound was prepared from 3-fluoro-4-(2-methyl-imidazol-1-yl)-phenylamine (87 mg, 0.46 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (100 mg, 0.46 mmol) in analogous manner to the procedure described in example 1e). Obtained as a light yellow oil (140 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1.Cl[C:35]([F:40])([F:39])C([O-])=O.[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[F:39][CH:35]([F:40])[N:10]1[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][C:3]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:2]([F:1])[CH:7]=2)[C:9]1=[O:13]
Reactant: COc1cn(-c2ccc(N3CCNC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=C([O-])C(F)(F)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: COc1cn(-c2ccc(N3CCN(C(F)F)C3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 20 h
Yield: 2.3 %

Procedure:
A mixture of 1-[2-fluoro-4-(2-oxoimidazolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (100 mg, 0.22 mmol), sodium chlorodifluoroacetate (40 mg, 0.26 mmol), and 18-crown-6 (12 mg, 0.044 mmol) in acetonitrile (10 mL) was stirred at 90° C. for 20 h. After cooling to room temperature, to the reaction mixture was added silica gel. This mixture was evaporated, and purified by silica gel column chromatography eluting with AcOEt/MeOH (1/0 to 10/1) to give the title compound (2.5 mg, 2.3% yield) as a pale yellow powder: 1H NMR (300 MHz, DMSO-d6): δ ppm 1.11-1.40 (4H, m), 3.61-3.86 (4H, m), 6.96 (1H, d, J=1.9 Hz), 7.01-7.15 (1H, m), 7.16-7.50 (6H, m), 7.71 (1H, dd, J=13.6, 2.3 Hz), 7.79 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 497 [M+H]+.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([O:20][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Clc1nonc1-c1cccnc1
Reactant: CCCCCCO
Agent: [Na]
Product: CCCCCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (100 mg, 4.3 mmol) in 1-hexanol(10 ml) was added 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (180 mg, 1 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.ICC.Cl>C1COCC1>[CH2:2]([C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH3:3]
Reactant: O=C(O)C1CCC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of LDA (100 ml; 2.0 M THF solution) in THF (100 ml) was added dropwise over a period of 20 minutes under cooling with ice, a solution of cyclobutane carboxylic acid (10 g, 0.1 mol) in THF (15 ml) and the mixture was stirred at RT for 2 h. To the mixture iodoethane (15.6 g, 0.1 mol) was added dropwise and the mixture was stirred at RT overnight. To the reaction mixture was added 2N HCl and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine to afford the title compound as a light yellow oil (22.4 g), which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])C>>[CH2:31]([O:30][C:27](=[O:29])[CH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:32]
Reactant: CCOC(C)=O
Reactant: COc1cc(CCCO)cc(OC)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 3-(3,5-dimethoxyphenyl)propan-1-ol (24.3 g) in ethyl acetate (500 ml) were sequentially added triethylamine (16.3 g) and methanesulfonyl chloride (16.3 g) on an ice bath, and the solution was stirred for 25 minutes at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. To a solution of the total amount of the resulting 3-(3,5-dimethoxyphenyl)propyl methanesulfonate (crude product) in N,N-dimethylformamide (150 ml) was added sodium cyanide (15.2 g), and the solution was stirred for 8.5 hours at 80° C. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. To a solution of the total amount of the resulting 4-(3,5-dimethoxyphenyl)butyronitrile (crude product) in ethylene glycol (100 ml) was added an aqueous solution of 5N sodium hydroxide (75 ml), and the solution was refluxed for 9.5 hours. The reaction solution was acidified with concentrated sulfuric acid, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. To a solution of the resulting residue in ethanol (400 ml) was added concentrated sulfuric acid (4 ml), and the solution was stirred for 1 hour and 20 minutes at 70° C. The reaction solution was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (25.3 g).