Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH:7]=O.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+]>C(O)C.O>[CH3:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7][NH:16][S:13]([NH2:17])(=[O:15])=[O:14]
Reactant: NS(N)(=O)=O
Reactant: Cc1oc2ccccc2c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1oc2ccccc2c1CNS(N)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylbenzofuran-3-carbaldehyde (0.51 g, 3.18 mmol) was dissolved in anhydrous ethanol (25 mL). Sulfamide (1.5 g, 16 mmol) was added and the mixture was heated to reflux for 4 days. The mixture was cooled to room temperature. Sodium borohydride (0.132 g, 3.50 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction was diluted with water (100 mL) and extracted with DCM (3×75 mL). The extracts were concentrated and suspended in a minimal amount of DCM and filtered to yield the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)=[O:17]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
3.1 g (23 mmol) of 4-hydroxybenzamide and 2.8 g (23 mmol) of 4-fluorobenzaldehyde were dissolved in DMSO, combined with 4.4 g (32 mmol) of K2CO3 and stirred overnight at 140° C., filtered through basic Alox, washed with DMF, concentrated by rotary evaporation and purified by chromatography (silica gel column, dichloromethane with a gradient of 10-20% methanol). As there was still some DMF present, the mixture was triturated with water, suction filtered and dried
Reaction SMILES: [NH2:1][C:2]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:2]1([CH3:5])[CH2:3][O:4][C:26](=[O:28])[NH:1]1)[CH2:15][CH2:14]2
Reactant: COc1ccc2c(c1)CCC(C(C)(N)CO)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(C1(C)COC(=O)N1)C2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
To 25 grams of 2-amino-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol in 575 mL of dichloromethane was added 45 g of triethylamine. The mixture was cooled to 0° C., and kept below 5° C. while 21 g of triphosgene in dichloromethane was added dropwise. The mixture was stirred at 20-25° C. for 1.5 hrs. The reaction was followed by HPLC until the starting material disappeared. The mixture was concentrated under reduced pressure, 375 mL ethyl acetate was added to the residue. It was washed with water (50 mL×2), dried, decolorized with carbon, and concentrated and dried to afford 10 g of 4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one, M=261, purity 97%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>C(OCC)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:30][CH:31]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethane sulfonic anhydride (32.2 mmol) was added dropwise over 5 minutes to a −40° C. pyridine (70 mL) solution of (4-hydroxy-phenyl)-acetic acid methyl ester (5.35 g, 32.2 mmol). The reaction was stirred at −40° C. for 10 minutes and then at 0° C. for 2 hours. The reaction was diluted with diethyl ether and washed with water and 2N hydrochloric acid. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on a Biotage Flash 40M column eluting with ethyl acetate/hexanes (1:4) to provide the title compound as a clear, colorless oil, which crystallized upon standing 9.27 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.34 (m, 2H), 7.24-7.21 (m, 2H), 3.70 (3H), 3.64 (2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:15][CH:16]=2)=[C:9]([C:19]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in methanol and powdered 3A sieves were added. Morpholine (2 eq) was added, followed by acetic acid (5 eq). After stirring for 30 minutes, sodium cyanoborohydride (2 eq) was added portionwise and the suspension was stirred under nitrogen at ambient temperature for 16 hours. The reaction mixture was filtered through celite and concentrated to dryness. Column chromatography, eluting with 5% MeOH in DCM gave 5-(2,4-bis-benzyloxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:37][C:38]1[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:41]2[CH:51]=[CH:52][CH:53]=[CH:54][C:40]=2[N:39]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:37][C:38]2[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[C:41]3[CH:51]=[CH:52][CH:53]=[CH:54][C:40]=3[N:39]=2)[C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2(C)CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: C[Si](C)(C)CCOCn1c(CCl)nc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(Cc1ccc(CN(Cc2nc3ccccc3n2COCC[Si](C)(C)C)C2(C)CCCc3cccnc32)cc1)Cc1ccccn1
Yield: 47.2 %

Procedure:
Reaction of N-tert-Butoxycarbonyl-N-(2-pyridinylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (120 mg, 0.26 mmol), 2-chloromethyl-1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole (234 mg, 0.79 mmol) and diisopropylethylamine (229 uL, 1.31 mmol) in DMF (2.6 mL) for 18 h at 90° C. followed by purification of the crude material by radial chromatography (2 mm plate, 20:2:1 CHCl3-MeOH—NH4OH) afforded 90 mg (48%) of N-tert-butoxycarbonyl-N-(2-pyridinylmethyl)-N′-(1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-ylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine as a colourless oil.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>O>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
Carbazole (0.80 g, 4.80 mmol) and sodium hydride (NaH) (60% in mineral oil, 0.25 g, 6.2 mmol) were added to a flask, which was charged with argon. DMF (dimethylformamide) (12 mL) was added and the mixture was stirred at 60° C. for 1 hour (h), after which 4-bromomethyl benzoic acid methyl ester (1.16 g, 4.8 mmol) was added, and the mixture was stirred at 80° C. overnight. Water was added and the product was extracted with CH2Cl2 (dichloromethane), dried (Na2SO4, sodium sulfate) and concentrated. The product was purified by column chromatography to give 310 mg of compound 28 as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)nc2)C2CCCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
To a mixture of ethyl 3-{[(5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}pyridin-2-yl)carbonyl]amino}propanoate (274 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (235 mg, 91%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH2:18](O)[CH3:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH2:18][CH3:19])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)C(O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(O)c1ccc(F)cc1
Yield: 90 %

Procedure:
To a cooled solution of 2-(4-fluorophenyl)-2-hydroxyacetic acid (5.0 g, 29.4 mmol) in ethanol was added con. H2SO4 (10 mL) over a period of 10 min. The reaction mixture was heated at reflux for 5 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (25 mL). The organic solution was washed with aqueous saturated NaHCO3 (25 mL×2), water (20 mL), brine solution (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give ethyl 2-(4-fluorophenyl)-2-hydroxyacetate (5.0 g, 90%) as crude compound (oily liquid). The crude compound was taken to the next step without further purification. LC-MS (M+H2O)+=216. 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.46 (2H, m), 7.17-7.20 (2H, m), 6.11-6.13 (1H, m), 5.14 (1H, d, J=5.20 Hz), 3.35-4.13 (2H, m), 1.12-1.15 (3H, m).
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:23]O>>[C:1]1([C@@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([O:17][CH3:23])=[O:16])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C(=O)O)CC1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1

Procedure:
(3S)-1-((S)-1-Phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid (666 g, optical purity not less than 99%) was dissolved in methanol (6 l), and conc. sulfuric acid (15 ml) was added at room temperature. The mixture was stirred at refluxing temperature for 7 hr. Methanol was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with sodium hydrogencarbonate, dried over magnesium sulfate and concentrated under reduced pressure to give 738 g of methyl (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidine-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[CH:12])=[CH:4][N:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[C:12][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:23])([F:22])[F:13])=[CH:16][CH:17]=2)=[CH:4][N:3]=1
Reactant: C#Cc1cnc(N)c(C#N)c1C
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)cnc(N)c1C#N

Procedure:
A solution of 1.6 grams (0.010 mole) of 2-amino-3-cyano-4-methyl-5-ethynylpyridine, 3.8 grams (0.014 mole) of 4-trifluoromethylphenyl iodide (commercially available), 3.5 grams (0.035 mole) of triethylamine, 0.3 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.3 gram (catalyst) of copper(I) iodide in 75 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The aqueous layer and the organic layer are separated, and the aqueous layer is washed with ethyl acetate. The ethyl acetate wash is combined with the organic layer, and the combination is washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-[(4-trifluoromethylphenyl)ethynyl]pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[H+].[B-](F)(F)(F)F.CCOCC.[Br:21]N1C(=O)CCC1=O>CC#N>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([Br:21])=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccccc1O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cooled (−20° C.) solution of 2-cyanophenol (30 g, 252 mmole) in dried MeCN (400 mL) was added HBF4.Et2O (45 g, 277.1 mmole), and N-bromosuccinimide (53.8 g, 302.3 mmole). After addition was completed, the mixture was warmed to RT, and stirred in 4 h. The mixture was cooled and quenched by 50% aqueous NaHSO3. The mixture was concentrated to removed excess of MeCN. The off-white solid thus obtained was filtered and dried by air (42.4 g, 85%). 1H-NMR (300 MHz, DMSO-d6): δ6.99 (d, J=8.9 Hz, 1H), 7.67 (dd, J=2.5, 8.9 Hz,1H), 7.88 (d, J=2.5 Hz,1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][CH:30]([C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: Cc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: Cc1ccc(C2CCN(C(=O)c3cnc4c(Br)cnn4c3NCc3ccccc3)CC2)cc1
Yield: 75.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in Example 22, step 3 instead of 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid and 4-(4-methylphenyl)piperidine hydrochloride (0.15 g, 0.69 mmol), the title compound (0.22 g, 77%) was obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:24]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]([C:32](O)=[O:33])=[N:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:32]([C:26]3[NH:25][N:24]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=3)=[O:33])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(C(=O)O)n[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of Intermediate 8-1 (130 mg, 0.367 mmol), 1H-pyrazole-3,5-dicarboxylic acid (74.5 mg, 0.477 mmol), EDCl (91 mg, 0.477 mmol) and HOBt (64.5 mg, 0.477 mmol) in DMF (3 mL) is added triethylamine (149 mg, 0.203 mmol) and the mixture is stirred at room temperature for 18 hours. Any insoluble material is removed by filtration and the filtrate is chromatographed by HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compound; HPLC Retention time 1.31 minutes (condition C); MS 456.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.07 Hz, 3H), 2.54-2.67 (m, 2H), 2.84-2.97 (m, 2H), 4.02 (q, J=7.07 Hz, 2H), 4.54 (m, 1H), 7.11 (s, broad, 1H), 7.32 (d, J=8.08 Hz, 2H), 7.39 (m, 1H), 7.46 (t, 1H), 7.62 (d, J=8.08 Hz, 3H), 7.69 (s, 1H), 8.41 (s, broad, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[O:8]=[C:6]1[NH:7][CH:3]([CH2:2][O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC[C@H](CO)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCC(=O)N1
Yield: 91.7 %

Procedure:
To 1.0 g (8.69 mmol) of (R)-(−)-5-(Hydroxymethyl)-2-pyrrolidinone and triethylamine (2.42 ml, 17.37 mmol) in 80 mL of methylene chloride at 0° C. was added 1.01 mL (13.03 mmol) of methanesulfonyl chloride. The resultant solution was stirred at 0° C. for 1 hour. The solvent was removed. Silica gel chromatography using (10:1 ethyl acetate/methanol) gave 1.54 g (92%) of methanesulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as an off-white solid that was used in the next step. Rf=0.21 (10:1 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 1.82–1.88 (m, 1H), 2.25–2.40 (m, 3H), 3.06 (s, 3H), 3.98–4.02 (m, 1H), 4.05–4.09 (dd, J=10.2, 7.1 Hz 1H), 4.22–4.25 (dd, J=9.1, 3.7 Hz 1H), 6.96 (bs, 1H). To 150 mg (0.40 mmol) of 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-H-quinolin-2-one, potassium carbonate (55 mg, 0.40 mmol), and and catalytic KI in 5 mL of DMF was added methanesulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester (92 mg, 0.47 mmol) The suspension was heated to 70° C. for 16 hours. The reaction was diluted with methylene chloride and washed three times with water, twice with brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (9:1 ethyl acetate/methanol) gave 30 mg (16%) of the title compound, a white foam. Rf=0.20 (9:1 ethyl acetate/methanol). MS (M+H)+=477.2; 1H NMR (400 MHz, CDCl3): δ 1.45–1.60 (m, 2H), 1.65–1.78 (m, 1H), 1.90–2.15 (m, 5H), 2.18–2.30 (m, 3H), 2.36–2.41 (dd, J=13.1, 6.7 Hz, 1H), 2.53–2.57 (t, J=7.4 Hz, 2H), 2.75–2.80 (m, 3H), 3.03–3.06 (m, 1H), 3.14 (s, 3H), 3.45–3.49 (m, 2H), 3.53 (s, 3H), 3.67–3.75 (m, 2H), 6.08 (bs, 1H), 6.50 (s, 1H), 6.66 (s, 1H), 7.24–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 21.2, 25.3, 25.5, 27.0, 29.7, 31.8, 45.3, 52.5, 55.5, 56.2, 61.5, 72.0, 109.9, 116.1, 127.3, 128.1, 129.4, 133.6, 140.4, 152.9, 170.0, 178.0. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:20])C)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][OH:26].[OH-].[Na+].O>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:21]([CH3:22])[CH3:23])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]([O:26][CH2:25][CH3:24])=[O:20])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 16 h

Procedure:
A mixture of 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}-N,N-3-oxapentamethyleneacetamide (4.9 g prepared as described in Example 214), ethylene glycol (30 ml) and 18N aqueous sodium hydroxide solution (10 ml) was heated under reflux for 21/2 hours and then cooled. Water (30 ml) was added and the aqueous mixture washed with ether. The ether extracts were washed with 5N aqueous sodium hydroxide solution and the alkaline washings combined with the aqueous reaction mixture and the resulting mixture neutralised by addition of concentrated hydrochloric acid. The neutralised mixture was evaporated and the residue dried by azeotropic distillation with methanol and then propan-2-ol. The residue was mixed with propan-2-ol and the mixture filtered. The filtrate was evaporated and the residue was heated at 63°/0.7 mm to remove excess ethyleneglycol and then dissolved in ethanol (50 ml). Thionyl chloride (3.5 ml) was added dropwise with stirring and the mixture allowed to stand for 16 hours under anhydrous conditions. The reaction mixture was then poured into a mixture of ice and excess aqueous sodium bicarbonate solution. The mixture was extracted with ether and the extracts were dried and evaporated to give an oil which was mixed with ether. The mixture was filtered and a solution of maleic acid in ether was added to the filtrate to produce a gum. The supernatent was decanted and the residual gum washed with ether, which was decanted, several times and then basified with sodium bicarbonate. The product was extracted with ether and the extracts were dried and evaporated to give ethyl 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}acetate. A sample of this material (2.8 g) was dissolved in methanol (300 ml). Ammonia gas was bubbled into the solution which was cooled in ice, saturated with ammonia gas and then evaporated and heated at 90°/20 mm to leave 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}acetamide a residual oil the boiling point of which was not determined.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20](=[O:21])[CH2:19][C@@H:18]([NH:22]C(=O)OCC3C=CC=CC=3)[CH2:17]2)[CH:5]=[CH:6][C:7]=1[S:8]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].[H][H]>CO.[Pd]>[NH2:22][C@H:18]1[CH2:17][N:16]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)[C:20](=[O:21])[CH2:19]1
Reactant: Cc1cc(N2C[C@H](NC(=O)OCc3ccccc3)CC2=O)ccc1S(=O)(=O)N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N2C[C@H](N)CC2=O)ccc1S(=O)(=O)N1CCCC1

Procedure:
45 mg (98 μmol) benzyl(R)-{1-[3-methyl-4-(pyrrolidine-1-sulphonyl)-phenyl]-5-oxo-pyrrolidin-3-yl}-carbamate are dissolved in 10 ml of methanol, combined with 25 mg palladium on charcoal and hydrogenated for 8 hours in a Parr apparatus at 3 bar hydrogen pressure at ambient temperature.