Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C2C=CC=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:22](N=O)[CH2:21][CH2:20][O:19][CH2:18][C:17]=2[CH:25]=1.Cl.N1CCC(=O)CC1>>[ClH:12].[Cl:12][C:13]1[CH:14]=[C:15]2[C:4]3[CH2:3][NH:2][CH2:11][CH2:6][C:5]=3[N:22]3[C:16]2=[C:17]([CH:25]=1)[CH2:18][O:19][CH2:20][CH2:21]3
Reactant: C1=Cc2ccccc2ON=C1
Reactant: O=NN1CCOCc2cc(Cl)ccc21
Agent: Cl
Agent: O=C1CCNCC1
Product: Clc1cc2c3c(c1)c1c(n3CCOC2)CCNC1

Procedure:
By the procedure described in Example 1, the appropriate benzoxazepine is converted to 7-chloro-1,2,3,5-tetrahydro-1-nitroso-4,1-benzoxazepine, m.p. 54°-56°. The latter is reduced to the corresponding 1-amino derivative hydrochloride, which is reacted with 4-piperidone hydrochloride to yield the title compound, m.p. 304°-305°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:21][C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:21][C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(Cc2ccccc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(Cc2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-I), the title compound was prepared as a solid having a melting point of 106-107° C.
Reaction SMILES: [C:1](=[O:49])([O:18][C:19]1[C:20]([CH3:48])=[C:21]2[C:26](=[C:27]([CH3:30])[C:28]=1[CH3:29])[O:25][C:24]([CH3:47])([CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:23][CH2:22]2)[O:2][CH2:3][C:4]1([CH2:16][OH:17])[CH2:9][O:8]C(C2C=CC=CC=2)[O:6][CH2:5]1>C(O)(=O)C.[C].[Pd]>[C:1](=[O:49])([O:18][C:19]1[C:20]([CH3:48])=[C:21]2[C:26](=[C:27]([CH3:30])[C:28]=1[CH3:29])[O:25][C:24]([CH3:47])([CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:43])[CH3:44])[CH2:23][CH2:22]2)[O:2][CH2:3][C:4]([CH2:9][OH:8])([CH2:16][OH:17])[CH2:5][OH:6]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCC1(CO)COC(c3ccccc3)OC1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC(CO)(CO)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 80.2 %

Procedure:
5.3 g of 5-hydroxymethyl-2-phenyl-1,3-dioxan-5-ylmethyl 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanyl carbonate was dissolved in 50 ml of acetic acid. To the obtained solution was added 0.3 g of 10% palladium carbon. Then the mixture was catalytically reduced under a hydrogen pressure of 3 kg/cm2. After filtering off the catalyst, the filtrate was poured into water. The oily matter thus precipitated was extracted with ether. The extract was successively washed with water, an aqueous solution of sodium hydrogencarbonate and water, and dried. After distilling off the solvent, 4.5 g of a colorless and resinous product was obtained. It was purified by column chromatography (silica gel, benzene:ethyl acetate=1:1). Thus 3.7 g of the title compound was obtained as a colorless waxy solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>>[Cl:1][C:2]1[C:3]([CH:8]([NH:22][C:26]([CH:23]2[CH2:25][CH2:24]2)=[O:27])[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CC1
Reactant: NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 120.4 %

Procedure:
In a 10 mL flask were added C-(3-chloropyrazin-2-yl)-C-(4-phenoxyphenyl)-methylamine (110 mg, 0.00035 mol), cyclopropanecarboxylic acid (0.056 mL, 0.00070 mol), DIEA (0.55 mL, 0.0032 mol), TBTU (0.17 g, 0.00053 mol) and DMF (5 mL, 0.07 mol). The reaction mixture was stirred at rt for 10 min. Reaction was left to stir over weekend. The reaction mixture was concentrated in vacuo, dissolved in DCM and washed with sat aq NaHCO3 followed by brine. The organics were collected and concentrated in vacuo to give 160 mg of the compound as a yellow solid. Purification by prep TLC in 60% EtOAc: hexanes afforded 55 mg of the title compound as a yellow solid. The compound was carried on to the next step. MS (ES+): m/z 380.08 (20)[MH+]. HPLC: tR=3.56 min (Open lynx polar—5 min).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH:15]C=O)[CH2:6][C@@H:5]1[CH3:18])(=[O:3])[CH3:2].Cl.[OH-].[Na+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC=O)C[C@@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Yield: 91 %

Procedure:
To a suspension of [(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see Intermediate 43) (4 g, 12.9 mol) in MeOH (50 mL) was added 6N HCl (6.5 mL, 38.6 mmol). The resulting mixture was stirred at reflux for 3 hours and the medium was made basic by the addition of 2N NaOH. The MeOH was evaporated under reduced pressure and the organic material extracted with EtOAc (250 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness to afford the title compound as an oil (3.3 g, 91%); LC/MS (Method E) m/z 284 [M+H]+, Rt=2.18 min
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH3:21])=N)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[SH2:28]>C1COCC1>[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH3:21])=[S:28])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S
Reactant: CCOC(=N)C1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=S)C1CCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Yield: 47 %

Procedure:
2-Ethoxycarbonimidoyl-pyrrolidine-1-carboxylic acid benzyl ester hydrochloride (42.8 g, 146.0 mmol) was dissolved in THF (150 mL) and cooled to −20° C. Pyridine (80 ml) was added to the reaction and H2S was bubbled through the reaction for 60 min. The reaction's temperature was maintained at −20° C. for 2 hours while stirring. The pH was adjust to pH=4 by addition of 5M HCl. The resulting solution was transferred to a separatory funnel and extracted with diethyl ether (3×100 mL). The organic layers were combined and washed with brine (100 ml). The organic layer was dried over MgSO4 and concentrated under vacuo to afford 20.0 g (47%) of 2-ethoxythiocarbonyl-pyrrolidine-1-carboxylic acid benzyl ester as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1.O>C1COCC1>[CH3:37][N:34]1[CH2:35][CH2:36][CH:31]([O:30][C:2]2[N:7]=[C:6]([NH:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=2)[CH2:32][CH2:33]1
Reactant: CN1CCC(O)CC1
Reactant: CC(Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Nc1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-])c1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-chloro-3-nitro-N-[1-(pyridin-2-yl)ethyl]pyridin-2-amine E-3.8″(2 g; 7.17 mmol) is suspended in 20 ml THF and a potassium bis(trimethylsilyl)amide solution in THF (29 ml; 29 mmol) is slowly added at 25° C. After 15 min 4-hydroxy-N-methylpiperidine (3.37 g; 28.71 mmol) is added and the reaction mixture is stirred for 16 h at 25° C. The reaction mixture is diluted with ethyl acetated and water. The organic phase is separated and dried using MgSO4. The crude intermediate is purified using reversed phase chromatography (prep. HPLC1). The product containing fractions are combined and freeze-dried
Reaction SMILES: O1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:15]=[C:14]([C:24]#[N:25])[N:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].FC(F)(F)C([O-])=O.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[NH:42][C:43]([CH:46]2[CH2:51][CH2:50][NH2+:49][CH2:48][CH2:47]2)=[N:44][N:45]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.Cl.C(OCC)(=O)C.ClCCl.CCN(C(C)C)C(C)C>[C:18]1([C:17]2[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:2][N:49]4[CH2:50][CH2:51][CH:46]([C:43]5[NH:42][C:41]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=6)=[N:45][N:44]=5)[CH2:47][CH2:48]4)=[CH:11][CH:10]=3)=[N:13][C:14]([C:24]#[N:25])=[N:15][CH:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(-c2nnc(C3CC[NH2+]CC3)[nH]2)nc1
Reactant: N#Cc1ncc(-c2ccccc2)c(-c2ccc(C3OCCO3)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ncc(-c2ccccc2)c(-c2ccc(CN3CCC(c4nnc(-c5ccccn5)[nH]4)CC3)cc2)n1

Procedure:
A solution of 4-[4-(1,3-dioxolan-2-yl)phenyl]-5-phenylpyrimidine-2-carbonitrile (165 mg, 0.501 mmol) in THF (7 mL) and 6N HCl (4 mL) was stirred at rt for 1 h. The reaction mixture was neutralized with sodium hydroxide and diluted with ethyl acetate (50 mL). The solution was washed with water (2×25 mL) and dried over magnesium sulfate. Hunig's base (1 mL) was added to the solution and it was then added to a solution of 4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidinium trifluoroacetate (206 mg, 0.600 mmol) in dichloromethane (5 mL) and Hunig's base (1 mL). The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (10 mL). Sodium triacetoxyborohydride (320 mg, 1.509 mmol) was added and stirred over night. The reaction mixture was basified with sodium hydroxide, extracted with ethyl acetate (50 mL)j and purified on reverse phase HPLC to yield 5-phenyl-4-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidine-2-carbonitrile as a solid. MS (EI) m/z 499 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH:12]=[CH:13][N:14]([CH3:16])[CH3:15].[ClH:17]>C(OCC)C>[ClH:17].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[CH3:16]
Reactant: CN(C)C=CCN=c1sc2ccccc2s1
Agent: Cl
Solvent: CCOCC
Product: CN(C)CCCN=c1sc2ccccc2s1

Procedure:
A solution of N'-(1,3-benzodithiol-2-ylidene)-N,N-dimethyl-1,3-propenediamine (3.0g, prepared as described in Example 17) in 100 ml of anhydrous diethyl ether is treated dropwise with ethereal hydrogen chloride until precipitation is completed. The resultant solid is collected by filtration under a nitrogen atmosphere, wwashed several times with anhydrous diethyl ether and recrystallized twice from acetonitrile. The recrystallized product is washed with anhydrous diethyl ether and dried at atmospheric pressure under a slow stream of nitrogen to yield 3.1g of the title compound, melting point 188°-190° C. stirring at room temperature overnight. The reaction mixture is poured into water (2 liters) and extracted three times with 500 ml portions of benzene. The combined benzene layers are dried over anhydrous sodium sulfate and concentrated. The resultant oil is chromatographed on 500 ml of silica gel eluting with benzene (2 liters), chloroform (2 liters) and finally 10% methanol/chloroform (2 liters). The oil obtained from the elution with 10% methanol/chloroform is dissolved in ether, treated with ethereal hydrogen chloride, and filtered under nitrogen. This hygroscopic solid is dissolved in 5% sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane layer is dried over anhydrous sodium sulfate and concentrated. The resultant oil is dissolved in 15 ml of pentane, treated with charcoal, and filtered. The pentane solution was cooled to -78° C in a dry ice acetone bath. After 24 hours, the white precipitate is quickly filtered and transferred to a flask whereup the product is returned to an oil. The oil is dried in vacuo at room temperature overnight to yield 2g of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=3)[C:12]=2[O:23][C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([S-])C.[Na+]>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14][C:13]=3[C:12]=2[O:23][C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)=C2Oc1ccc(OCCN2CCCCC2)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C2=C(Oc3ccc(OCCN4CCCCC4)cc3)c3ccc(O)cc3CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.3 %

Procedure:
In a round bottom flask place the compound of Example 104 (50 mg, 0.094 mmol), sodium ethanethiolate (88 mg, 1.05 mmol) and dimethylformamide (4 mL) in a round bottom flask, at room temperature. Place the reaction in a 95° C. oil bath and stir it for 4 hours, then cool it to ambient temperature. Quench the room temperature mixture with brine and extract it into ethyl acetate. Wash the combined extracts with brine; then dry (sodium sulfate) and concentrate them in vacuo. Purify the crude material on a Chromatotron (silica gel; 5%-12% MeOH gradient in CH2Cl2) to give 7 mg of the title compound (14%). MS (IS+) nm/e 520 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[O:41]1[CH2:42][CH2:43][N:38]([C:2]2[CH:7]=[C:6]([N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:15])([CH3:14])[CH3:16])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[N:5]3[N:25]=[CH:26][C:27]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:4]3[N:3]=2)[CH2:39][CH2:40]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 130 °C
Yield: 82.4 %

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (77.9 mg, 0.14 mmoL), morpholine (36.7 mg, 0.42 mmoL), NaHCO3 (53 mg, 0.63 mmoL) in NMP (3 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded 5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (70 mg, 82%). LCMS tR=2.72 Min (5 min run, UV254nm). Mass calculated for, M+ 606.3, observed LC/MS m/z 607.2 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[O:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[O:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[CH:16]=[CH:15]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCc3occc3C2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1cc2c(o1)CCNC2

Procedure:
5-Benzyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine (410 mg, 1.9 mmol) was dissolved in ethanol (4 ml), and the solution was mixed with 10% palladium on activated carbon (80 mg) and stirred at room temperature for 15 hours in an atmosphere of hydrogen. The reaction solution was filtered to remove 10% palladium on activated carbon, and the solvent was removed by evaporation under a reduced pressure to obtain crude 4,5,6,7-tetrahydro-furo[3,2-c]pyridine. This compound and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (590 mg, 1.9 mmol) and potassium carbonate (400 mg, 2.9 mmol) were stirred at room temperature for 18 hours in anhydrous N,N-dimethylformamide (4 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 94 mg (0.27 mmol, 14% in yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].[C:25](#[N:28])[CH:26]=[CH2:27]>O1CCOCC1>[C:25]([CH2:26][CH2:27][C:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:28]
Reactant: C=CC#N
Reactant: CCOC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(CCC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2,2-bis(4-fluorophenyl)acetate (1.55 g, 5.64 mmol) in anhydrous dioxane (10 mL) was added sodium ethoxide (0.38 g, 5.61 mmol), and the reaction was stirred at a temperature between 40-50° C. for 30 minutes. Acrylonitrile (0.35 mL, 5.61 mmol) was added dropwise with stirring, and the reaction was heated at 60-70° C. for an additional 1 hour. The dioxane was removed in vacuo, and the residue was taken up in ether, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with a gradient of 3% to 10% ethyl acetate/hexane gave the title compound. MS (DCI) m/z 342 (M+NH4)+.
Reaction SMILES: Br[CH:2]([CH2:17][CH3:18])[C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4]>C(N)(CC)C>[CH:11]([NH:10][CH:2]([CH2:17][CH3:18])[C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4])([CH2:6][CH3:5])[CH3:12]
Reactant: CCC(Br)C(=O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CCC(C)N
Product: CCC(C)NC(CC)C(=O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 50 °C

Procedure:
50 g of α-bromobutyric acid bromide (V), 50 g of anhydrous aluminum chloride and 400 ml of carbon disulfide were added to 20 g of 8-hydroxycarbostyril (VI). The resulting mixture was heated at a temperature of 50° C for 13 hours and the carbon disulfide layer was removed by decantation. Crushed ice was added to the residue, and the precipitated crystals were filtered, washed with water and recrystallized from methanol to obtain 27 g of 5-(α-bromobutyryl)-8-hydroxycarbostyril (IV) having a melting point of 218°-219° C (with coloring and decomposition). To 5 g of the thus obtained 5-(α-bromobutyryl)-8-hydroxycarbostyril (IV) was added 100 ml of iso-propylamine (III), and the mixture was heated at a temperature of 50° C for 4 hours followed by concentration to dryness. Crystals which formed upon addition of water were filtered, washed with water and then recrystallized from methanol to obtain 4.6 g ofa methanol solvate of 5-(α-iso-propylaminobutyryl)-8-hydroxycarbostyril (II) having a melting point of 136°-137° C (with foaming and decomposition).
Reaction SMILES: [Mg].Br[C:3]1[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH:5]=[CH:6][CH:7]=1.[CH2:16]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19].[NH4+].[Cl-]>O1CCCC1.CCOCC.BrC(Br)C>[CH2:16]([N:20]1[CH2:25][CH2:24][C:23]([C:3]2[N:4]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[CH:5]=[CH:6][CH:7]=2)([OH:26])[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]
Reactant: Fc1ccccc1Cn1cccc1Br
Reactant: CCCCN1CCC(=O)CC1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCN1CCC(O)(c2cccn2Cc2ccccc2F)CC1
Yield: 34.3 %

Procedure:
To a suspension of magnesium turnings (1.0 g, 0.04 mole) in 25 ml tetrahydrofuran (THF) and 10 ml ether, was added a few drops of a solution of 2-bromo-1-(2-fluorobenzyl)pyrrole (10 g, 0.04 mole) in 35 ml THF. The reaction was initiated with a few drops of dibromoethane and heat, and reflux was maintained by the addition of the bromo compound. After stirring at reflux for thirty minutes, the mixture was cooled with an ice-bath, then a solution of 1-butyl-4-piperidone (4.6 g, 0.03 mole) in 25 ml THF was added. After stirring at ambient temperature for one hour, the mixture was poured into an NH4Cl solution, then extracted with ether. The ether solution was washed with water, then dried over anhydrous MgSO4. After evaporation of the solvent, the resultant oil (11 g) was purified by HPLC using ethyl acetate as the eluent to give 3.4 g of 1-butyl-4-[1-(2-fluorobenzyl)pyrrol-2-yl]-4-piperidinol; m.p. 132°-5° C.
Reaction SMILES: C(N1C[CH2:6][CH2:5][C:4]1=[O:8])=C.[C:9](OC(C)(C)C)(=[O:13])[C:10]([CH3:12])=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N>O>[C:9]([O:6][CH2:5][CH:4]=[CH2:8])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=CN1CCCC1=O
Reactant: C=C(C)C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: *CC(*)C
Solvent: O
Product: C=CCOC(=O)C(=C)C

Procedure:
The dimer of allyl methacrylate, which was prepared according to Example 1, was added to the mixture containing 97 wt.-% N-vinylpyrrolidone and 3 wt.-% tert-butyl methacrylate in the amount of 1 wt-% on the whole mixture. The mixture was polymerized in a polypropylene mold at 60° C. for 16 h in the presence of 0.4 wt.-% azobisisobutyronitrile. The resulting gel contained, after swelling with water, 90 wt.-% water at G=0.038 MPa.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([O:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21])[C:16](O)=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.CCN(C(C)C)C(C)C.C(N=C=NC(C)C)(C)C>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[C@@H:20]([O:19][C@H:15]([C:16](=[O:17])[NH:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:21])[CH3:26]
Reactant: Nc1nnn[nH]1
Reactant: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethoxy)-propionic acid (62 mg, 0.165 mmol) in THF (5 ml) at room temperature was added 5-aminotetrazole (38.0 mg, 0.447 mmol), DIPEA (0.086 ml, 0.494 mmol) and followed by 1,3-diisopropylcarbodiimide (0.060 ml, 0.387 mmol). The reaction was stirred at room temperature for 3 hr. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. HPLC retention time=0.99 minutes (condition C); MS (m+1)=444.