Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CO)cn1
Yield: 63.9 %

Procedure:
A solution of methyl 6-methylnicotinate (16.3 g, 108 mmol) in MeOH (150 mL) was treated with sodium borohydride (12.2 g, 323 mmol) at ambient temperature in portions. The mixture was quenched with water (100 mL) and concentrated. This mixture was diluted with water (300 mL) and extracted with EtOAc. The combined organic extracts were dried (phase separator silicone treated filter paper) and concentrated to give (6-methylpyridin-3-yl)methanol (8.5 g, 64% yield) as a light yellow oil.
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[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.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][C:41]=1[C:47]1[CH:48]=[N:49][CH:50]=[N:51][CH:52]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:14]([C:1]2[C:13]3[NH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:16])=[CH:42][C:41]=1[C:47]1[CH:52]=[N:51][CH:50]=[N:49][CH:48]=1
Reactant: Cc1ccc(N)cc1-c1cncnc1
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc3c2[nH]c2ccccc23)cc1-c1cncnc1
Reaction time: 0.08 h
Yield: 52.8 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (148 mg) and 1-hydroxybenzotriazole (130 mg) in dichloromethane (3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg) and the mixture was stirred for 5 minutes. After adding 4-methyl-3-(pyrimidin-5-yl)aniline (130 mg) and 4-dimethylaminopyridine (128 mg), the mixture was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(4-methyl-3-(pyrimidin-5-yl)-phenyl)-9H-carbazole-1-carboxamide (140 mg, 52.8%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH4+].[Cl-].[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C)C=O.C(OC(=O)C)C>[NH:22]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][CH2:11]3)=[CH:7][CH:8]=2)=[N:2][N:24]=[N:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C#N)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nnn[nH]3)cc2)CC1
Temperature: 100 °C
Yield: 47.4 %

Procedure:
To a solution of tert-butyl (1-(4-cyanophenyl)cyclopropyl)carbamate (D15) (1.5 g, 5.81 mmol) in dimethylformamide (15 ml), NH4Cl (530 mg, 9.90 mmol) was added under nitrogen atmosphere, followed by addition of sodium azide (650 mg, 9.9 mmol). The reaction mixture was heated to 100° C. overnight, then cooled to room temperature with ice-water bath. Water and ethylacetate (100 ml) was added. The organic layer was separated and the solvent was removed. The residue was purified by column chromatography eluting with a mixture petroleum ether/ethyl acetate (1:1). Collected fractions after solvent evaporation afforded the title compound (D16) (830 mg) as a yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH3:11])[N:5]=1.[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1>>[CH3:11][C:6]1[CH:7]=[C:8]([CH2:14][CH2:13][CH:12]2[CH2:16][CH2:7][CH2:6][N:5]2[CH3:4])[N:9]=[C:4]([NH2:3])[N:5]=1
Reactant: C1CCOC1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(CCC2CCCN2C)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-(−)-1-methyl-2-pyrrolidine (320 mg, 2.78 mmol) in dry THF (10 mL) at 0° C. was added NaH (167 mg, 4.16 mmol). After stirred at RT for 1 h, 2-amino-4-chloro-6-methylpyrimidine (600 mg, 4.16 mmol) in dry THF (10 mL) was added dropwise via the addition funnel. The resulting mixture was heated to reflux under Ar gas for 20 h. The reaction was cooled to RT and quenched with sat. NH4Cl. Solvent was removed. The residue was partitioned between H2O and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4, and evaporated to dryness. This crude compound was purified in column eluted with CH2Cl2:MeOH=95%:5% to yield the title compound. MS m/z: 223.2 (M+H). Calc'd. for C12H20N4—222.2.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].N1C(C)=CC=CC=1C.[CH3:14][NH:15][C@H:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:14][N:15]([C@@H:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:23])[P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: CN[C@H](C)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H](c1ccccc1)N(C)P(=O)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
To a cooled (ice/water bath) solution of phosphorus oxychloride (2.83 mL, 30.3 mmol) in DCM (30 mL) was added sequentially, dropwise, and with stirring 2,6-lutidine (7.06 mL, 60.6 mmol) and a DCM solution of (R)-(+)-N,a-dimethylbenzylamine (3.73 g, 27.6 mmol). After 5 minutes, the bath was removed and reaction mixture allowed to warm to ambient temperature. After 1 hour, the reaction solution was washed with a citric acid solution (50 mL×3, 10% w/v aq), dried (MgSO4), filtered through SiO2 and concentrated to provide the title compound (3.80 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C19H25N4O4P 404.2. found m/z=403.1 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:12](=[O:23])[C:13]1[CH:18]=[C:17]([F:19])[C:16](F)=[C:15]([F:21])[C:14]=1F)=[CH:6][NH:7][N:8]([CH:10]=[O:11])[CH3:9])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:12](=[O:23])[C:13]2[C:14](=[C:15]([F:21])[C:16]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[C:17]([F:19])[CH:18]=2)[N:7]([N:8]([CH3:9])[CH:10]=[O:11])[CH:6]=1)=[O:24])[CH3:2]
Reactant: CCOC(=O)C(=CNN(C)C=O)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(N(C)C=O)c2c(F)c(N3CCN(C)CC3)c(F)cc2c1=O
Reaction time: 0.83 h
Yield: 88.3 %

Procedure:
A suspension of 4.92 g (15 mmol) of 3-(2-formyl-2-methylhydrazino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylic acid ethyl ester and 3.41 ml (30.1 mmol) of N-methyl-piperazine in 15 ml of toluene were heated at reflux for 7.5 hours after which a clear, yellow solution was formed. After the addition of further 2.08 ml of N-methyl-piperazine the mixture was heated for 2 hours, cooled and evaporated at 49° C./130 torr. The yellowish oil (13.7 g) was taken up in 30 ml of dichloromethane, washed with 50 ml of water and subsequently twice with each 7.5 ml of half-saturated brine. The aqueous extracts were washed twice with each 15 ml of dichlormethane, the organic phases united, dried over magnesium sulphate, filtered and evaporated at 47° C./20 torr. The crystalline, beige residue (6.1 g) was suspended in 40 ml of tert.-butylmethyl ether, vigorously digested for 50 min., the crystals filtered, washed twice with each 10 ml of tert.-butylmethyl ether and dried at 45° C./13 torr. 5.41 g (88%) of 6,8-difluoro-1,4-dihydro-1-(N-methylformamido)7-(4-methyl- 1-piperazinyl)-4-oxo-3-quinoline-carboxylic acid ethyl ester were obtained as beige crystals of mp 180° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH2:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:21])[CH2:22][NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Reactant: COc1ccc(CC(C)(C)N)cc1
Solvent: CCCCO
Product: COc1ccc(CC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1

Procedure:
587 mg (2 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 358 mg (2 mmol) 2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamine are stirred in 5 mL n-butanol for 6 hours at 140° C. Then the solvent is distilled off and the residue is purified by chromatography (reverse phase; water/acetonitrile gradient).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH3:13])=[N:7]2.[NH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[S:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:14][C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=3[S:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: CCc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 3f (92 mg, 0.47 mmol) was reacted with the product from Example 18b (130 mg, 0.47 mmol) for 22 h following the procedure from Example 1g giving the title compound as a solid after purification of the crude product by HPLC with TFA as a trifluoroacetic acid salt (68 mg, 26%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J=7.72 Hz, 1H) 2.04 (s, 3H) 2.35 (s, 3H) 3.05 (q, J=7.72 Hz, 2H) 6.31 (d, J=6.98 Hz, 1H) 7.15 (d, J=8.83 Hz, 1H) 7.20-7.35 (m, 3H) 7.49 (d, J=8.83 Hz, 2H) 7.82 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.82 Hz, 1H) 10.04 (s, 1H) 11.01 (br s, 1H) 14.39 (br s, 1H). MS (ESI+) m/z 429 (M+H−Cl)+; (ESI−) m/z 427 (M−H−Cl)−.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]2[NH:10][C:11]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)NCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCC1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 2 h
Yield: 109.9 %

Procedure:
N-[(5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (0.040 g. 0.122 mmol) was dissolved in ethanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (10 mg, 0.09 mmol) catalyst. The reaction vessel was charged to 50 PSI with hydrogen, and shaken for 2 h. The mixture was then filtered and concentrated to give crude N-[(5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (0.040 g, 80%). LCMS calculated for C16H19N4O2 (M+H)+: m/z=299.1. found: 299.0.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[H][H]>[Pd].CO>[F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(NCC(F)F)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Yield: 88.6 %

Procedure:
(2,2-Difluoro-ethyl)-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amine (625 mg, 2.31 mmol) was charged to 30 ml methanol and 200-400 mg 10% palladium on carbon was added. The suspension was hydrogenated at 30 psi hydrogen for 2.5 hours and followed by NMR. The reaction was filtered through a ¼″ pad of celite and the pad washed with 4×10 ml portions of methanol. The resulting solution was clarified through a 45 micron frit to yield a yellow solution that was evaporated to yield N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (492 mg, 89% yield) as a white solid. 1H-NMR (CDCl3) δ 6.88 (m, 1H), 6.44 (m, 2H), 5.82 (m, 1H), 3.00 (m, 2H), 2.66 (m, 5H), 2.04 (m, 2H), 1.27 (m, 2H). LC/MS (ESI+)=241 (M+H).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]([CH3:80])[CH2:69][CH2:70][O:71][C:72]1[CH:79]=[CH:78][C:75]([CH:76]=O)=[CH:74][CH:73]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:75]3[CH:78]=[CH:79][C:72]([O:71][CH2:70][CH2:69][N:68]([CH3:67])[CH3:80])=[CH:73][CH:74]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)CCOc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 24.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(2-(dimethylamino)ethoxy)benzaldehyde (1.2 eq, 0.091 mmol, 18 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (10 mg, 23%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.23 (s, 6H, N(CH3)2), 2.62 (s, br, 4H, piperazine N(CH2)2), 2.65 (t, J=5.8 Hz, 2H, Me2NCH2), 3.61 (s, 2H, NCH2), 3.65 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 4.13 (t, J=5.8 Hz, 2H, OCH2), 7.09 (d, J=8.8 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.78 (dt, J=7.8, 1.7 Hz, 1H, pyridine H-4), 8.11 (d, J=8.8 Hz, 2H, phenyl H-2 & H-6), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.4 Hz, 1H, pyridine H-6), 8.56 (d, J=1.4 Hz, 1H, pyridine H-2), 13.34 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:26][CH:23]2[CH2:25][CH2:24]2)[CH:14]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C=O)c1)C1CC1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CNC2CC2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-cyclopropyl-carbamic acid tert-butyl ester (1.32 g, 4.08 mmol) and cyclopropylamine (0.438 mL, 6.1 mmol) in MeOH (41 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (232 mg) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. EtOAc (100 mL) was added, and the mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (883 mg, 59%). LC-MS: tR=0.82 min; ES+: 365.38.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:8]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:46][C@H:47]([CH2:64][OH:65])[CH2:48][N:49]1[CH2:54][CH2:53][CH:52]([C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)=[O:56])[CH2:51][CH2:50]1>ClCCl>[Cl:63][C:60]1[CH:61]=[CH:62][C:57]([C:55]([CH:52]2[CH2:53][CH2:54][N:49]([CH2:48][C@H:47]([NH:46][C:11](=[O:13])/[CH:10]=[CH:9]/[C:7]3[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:14][CH3:15])[CH2:64][OH:65])[CH2:50][CH2:51]2)=[O:56])=[CH:58][CH:59]=1
Reactant: N[C@H](CO)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CO)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid (0.31 g, 1.55 mmol), triethylamine (0.2 ml, 1.55 mmol) and 2-(1H benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (0.49 g 1.55 mmol) in dichloromethane (5 ml), is added to a solution of [1-((S)-2-amino-3-hydroxy-propyl)-piperidin-4-yl]-(4-chloro-phenyl)-methanone hydrochloride and triethylamine (0.4 ml, 3.1 mmol) in dichloromethane (5 ml), and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture is diluted with dichloromethane (20 ml), washed successively with saturated sodium bicarbonate solution (25 ml) and brine (25 ml), then dried over magnesium sulphate. The solvent is evaporated and the crude residue purified by flash silica chromatography (methanol:dichloromethane; 5:95) to afford (E)-N-{(S)-2-[4-(4-chloro-benzoyl)-piperidin-1-yl]-1-hydroxymethyl-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide. [MH]+482.2.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH3:12]I>CN(C=O)C.[Ag]=O>[OH:1][C@H:2]1[C@@H:6]([O:7][CH3:12])[CH2:5][C@@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1
Reactant: CI
Reactant: COC(=O)C1C[C@@H](O)[C@@H](O)C1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](O)[C@@H](OC)C1
Reaction time: 3 h

Procedure:
Methyl (3S,4R)-3,4-dihydroxycyclopentanecarboxylate (0.481 g, 3 mmol), freshly prepared silver oxide (0.348 g, 1.500 mmol) and methyl iodide (0.375 ml, 6.00 mmol) were combined in DMF and allowed to stir for 3 hrs. The reaction mixture was filtered through celite and washed with 15 ml of ether. The organic filtrate was washed 2× with brine, dried over sodium sulfate and evaporated. Purification by silica gel chromatography eluting with 20-40% acetone hexane gave the title compound. 1H NMR (500 MHz, CDCl3) δ 2.01-2.18 (m, 4H), δ 2.48 (s, br, 1H), δ 2.77 (m, 1H), δ 3.40 (s, 3H) δ 3.6-3.65 (m, 1H), δ 3.71 (s, 3H), δ 4.10 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1N=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:37]OC1C=CC(N2CCC(=O)CC2)=CC=1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=4)[CH2:16]3)[CH2:13][CH2:14]2)=[CH:7][CH:37]=1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
N-[2-({(3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide whereby 1-(4-methoxyphenyl)piperidin-4-one was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.82-1.89 (m, 2H), 2.17-2.21 (m, 3H), 2.43-2.46 (m, 1H), 2.68 (q, J=11.7 Hz, 2H), 3.17-3.25 (ma 1H), 3.38-3.46 (m, 2H), 3.57-3.66 (m, 4H), 3.72 (s, 3H), 4.04 (s, 2H), 4.50-4.52 (m, 1H), 6.80-6.85 (m, 2H); 6.92-6.96 (m, 2H), 7.69 (t, J=7.9 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.22 (s, 1H), 8.29 (s, 2H). MS m/z: 505 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:25])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([CH:23]=[O:24])=[CH:12][CH:11]=3)[O:4][N:3]=1.[OH:26]P([O-])(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:25])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([C:23]([OH:26])=[O:24])=[CH:12][CH:11]=3)[O:4][N:3]=1
Reactant: O=P([O-])(O)O
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(C=O)ccc3[nH]c2=O)on1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(C(=O)O)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
3-(3-methyl-isoxazol-5-yl)-2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carboxaldehyde (a) (16 mg, 0.05 mmol) was dissolved in tert-butanol (2 mL) followed by the sequential addition of saturated aqueous sodium phosphate monobasic solution (0.25 mL), 2-methyl-2-butene (0.05 mL), and sodium chlorite (NaClO2) (7 mg, 0.08 mmol). The mixture was stirred at room temperature for 3.5 h and concentrated. The residue was dissolved in ethyl acetate (15 mL), dried (MgSO4), filtered, and concentrated to give 3-(3-methylisoxazol-5-yl)-2-oxo-4-phenyl-1,2-dihydroquinoline-6-carboxylic acid (b) as a white solid (17.3 mg, 100%). 1H NMR (300 MHz, CD3OD) δ 8.19 (dd, J=6.4, 8.0 Hz, 1H), 7.96 (d, J=6.4 Hz, 1H), 7.51-7.43 (m, 4H), 7.31-7.23 (m, 2H), 6.33 (s, 1H), 2.18 (s, 3H). MS: 347.2 (M+H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)(=O)/C=C/C(O)=O.[CH3:17][N:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]([NH2:28])[CH2:20][CH2:19]1.[OH-].[Na+].[C:31](Cl)(=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.C(O)(=O)/C=C/C(O)=O>C(#N)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:17][N:18]1[C:22]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:21]([NH:28][C:31](=[O:40])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:20][CH2:19]1.[CH3:17][N:18]1[C:22]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:21]([NH:28][C:31](=[O:40])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:20][CH2:19]1
Reactant: CN1CCC(N)C12CCCCC2
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1ccc(C(=O)NC2CCN(C)C23CCCCC3)cc1
Reaction time: 5 h
Yield: 15.9 %

Procedure:
To a stirring suspension of 3.5 g (0.021 mole) of 1-methyl-4-amino-1-azaspiro[4.5]decane of Example 2 and 150 ml of 10% NaOH was added dropwise 3.8 g (0.022 mole) of p-anisoyl chloride. The reaction was stirred vigorously for 5 hours, the aqueous solution was decanted and the remaining oil was dissolved in ethyl acetate and dried over Na2SO4. The solvent was then evaporated to give a solid which was recrystallized from hexane to give 4.4 g. The solid was dissolved in 20 ml of acetonitrile and 1.7 g of fumaric acid was added. The suspension was stirred until the amine salt precipitated from solution. The compound was filtered and recrystallized twice from ethanol-ether to give 1.2 g (15.8%) of 1-methyl-4-(4-methoxybenzamido)-1-azaspiro[4.5]decane hemifumarate, m.p. (softens at 110° C.) 152°-155° C.