Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[CH3:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:11]=1>C(O)C>[CH3:9][C:10]1[N:15]=[C:14]([C:16]([NH2:17])=[O:2])[CH:13]=[C:12]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[CH:11]=1
Reactant: Cc1cc(OCC(F)(F)F)cc(C#N)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(OCC(F)(F)F)cc(C(N)=O)n1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To 6 ml of ethanol were added 0.54 g of sodium bicarbonate and 0.44 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.69 g of 6-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 2 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.76 g of 6-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>ClCCl>[N:1]1([S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCOCC1
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of morpholine (1.91 g, 22 mmol and triethylamine (2.2 g, 22 mmol) in dichloromethane (100 mL) at 0° C. was added 2-nitrobenzenesulfonyl chloride (4.42 g, 20 mmol). The mixture was stirred for 4 h and then additional dichloromethane (100 mL) was added. The dichloromethane solution was washed with saturated NaHCO3 (2×50 mL), 10% HCl (2×50 mL) and brine (50 mL) and dried over Na2SO4. Evaporating the solvent in vacuo gave the title compound as a yellow solid (5.3 g, 97%). 1H-NMR (300 MHz, CDCl3) δ7.97 (d, J=7.3 Hz, 1H), 7.62-7.77 (m, 3H), 3.75 (t, J=4.7 Hz, 4H), 3.30 (t, J=4.8 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[N:21]=[C:20]4[CH3:28])=[CH:15][CH:14]=3)[CH2:9][C:8](=[O:29])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>N1C=CC=CC=1>[CH2:30]([S:32]([NH:1][C:2]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[N:21]=[C:20]4[CH3:28])=[CH:15][CH:14]=3)[CH2:9][C:8](=[O:29])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:34])=[O:33])[CH3:31]
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3c(N)cccc3NC(=O)C2)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc2c1N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(=O)N2
Reaction time: 1 h

Procedure:
A suspension of the aniline from example 14 (0.5 g, 1.3 mmol) in dry pyridine (3 ml) was treated with ethanesulphonyl chloride (0.133 ml, 1.4 mmol). After 1 h, the mixture was evaporated to dryness then partitioned between dichloromethane and dilute aqueous sodium bicarbonate. The organic phase was dried over magnesium sulphate and evaporated to a yellow solid which was recrystallised from ethyl acetate (0.37 g, 59%). M.p. 258°-260° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[S:5][CH:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])(=[O:22])=[O:21])[S:5][CH:6]=1
Reactant: CC(C)CNCc1cc(Br)cs1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Br)cs1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 13, step 2, (4-bromo-thiophen-2-ylmethyl)-isobutyl-amine was reacted with 2-chlorobenzenesulfonylchloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give N-(4-bromo-thiophen-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[O:15])=[CH:8][C:7]=1[CH3:33].COC1C(SCC2C=CC(C3C=CC(C(F)(F)F)=CC=3)=CC=2)=CC(C)=C(C=1)OCC(O)=O.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=O)C=CC=CC=1.O>ClCCl>[CH3:13][O:12][C:10]1[C:9]([S:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[O:15])=[CH:8][C:7]([CH3:33])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:34])=[O:2]
Reactant: COC(=O)COc1cc(OC)c(S(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(OCC(=O)O)c(C)cc1S(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1 h

Procedure:
Preparation of [5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfinyl)-phenoxy]-acetic acid methyl ester (compound 51A) Example 4 (0.5 g, 1.0 mmol) was dissolved in 25 ml dichloromethane followed by the addition of 2-benzenesulfonyl-3-phenyl-oxaziridine (0.274, 1.04 mmol). The reaction was stirred 1 h. 10 ml water was added, the layers were separated, and dichloromethane solution was dried over anhydrous sodium sulfate, decanted, and concentrated. The product was recrystallized from ethyl acetate to give the title product. MS m/z 493 (M+1). Step 2. Preparation of [5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfinyl)-phenoxy]-acetic acid (compound 51) The title compound was prepared in the manner analogous to Example 1 using 51A. 400 MHz 1H NMR (DMSO-d6) δ 7.83 (d, 2H, J=8.78 Hz), 7.76 (d, 2H, J=8.30 Hz), 7.59 (d, 2H, J=8.30 Hz), 7.11 (d, 2H, J=8.30 Hz), 7.02 (s, 1H), 6.64 (s, 1H), 4.79 (s, 2H), 4.20 (d, 1H, J=12.7 Hz), 3.91 (d, 1H, J=12.4 Hz), 3.76 (s, 3H), 2.03 (s, 3H). MS m/z 479 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:12]=1)=[O:10]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccc(C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
1.65 g (11.9 mmol) of potassium carbonate are added at 25° C. under an argon atmosphere to 0.9 g (4.75 mmol) of 3-methoxycarbonyl-5-methyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 25° C. for 0.5 hour, 0.623 cm3 (4.75 mmol) of 4-chloroquinoline is added. After stirring at 100° C. for 48 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and then washed with 3 times 50 cm3 of water and 25 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.4 g of a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume)]. After concentrating the fractions under reduced pressure, 1.2 g of 3-methoxycarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a white solid melting at 168° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:16]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1ccccc1
Reactant: C1CCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: c1ccc(N2CCCCC2)cc1
Yield: 80 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), piperidine (119 μL, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rƒ=0.4) afforded N-(phenyl)piperidine (129 mg, 80% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403-1412; and Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513-1516.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH:60]([F:62])[F:61])[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:34]([CH2:38]Cl)[CH2:35][S:36](=[O:37])[C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:63].[Na+]>CC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH:60]([F:62])[F:61])[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:34]([CH2:38][I:63])[CH2:35][S:36](=[O:37])[C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (29 g), sodium iodide (14.6 g) and acetone (300 ml) was stirred for 2.0 hours at 0°-5° C. and evaporated. To the residue were added ethyl acetate (400 ml) and water (300 ml), and the organic layer was separated, dried and evaporated. The residue was subjected to column chromatography on silica gel (600 g) and the elution was carried out with a mixture of chloroform and ethyl acetate (15:1). The fractions containing the object compound were combined and evaporated. The residue was triturated with diisopropyl ether to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (13.57 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[N:13]=[C:14]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:15]=[C:16]([NH2:17])[C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:38]([N:41]=[C:42]=[O:43])([CH3:40])[CH3:39].C(OCC)(=O)C>O1CCCC1>[NH2:17][C:16]1[C:11]2[S:10][CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42]([NH:41][CH:38]([CH3:40])[CH3:39])=[O:43])[CH:7]=[CH:6][CH:5]=3)[C:12]=2[N:13]=[C:14]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[N:15]=1
Reactant: CC(C)N=C=O
Reactant: COc1cc(Nc2nc(N)c3scc(-c4cccc(N)c4)c3n2)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(N)c3scc(-c4cccc(NC(=O)NC(C)C)c4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
The 7-(3-aminophenyl)-N2-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2,4-diamine (20 mg, 0.047 mmol) synthesized in Example 11 was dissolved in anhydrous tetrahydrofuran (1 mL) and then triethylamine (20 μL, 0.14 mmol) and isopropyl isocyanate (5 mg, 0.057 mmol) were added. After stirring at room temperature for 4 hours, ethyl acetate (2 mL) was added and the mixture was washed with brine. After drying with MgSO4, the product was filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexane, 1/1) yielded the target compound of Example 12 (18 mg, 75% yield).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:32])[NH:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:54]2[C@H:55]([CH3:78])[C@H:56]3[C@@H:73]([C@H:74]([OH:76])[CH3:75])[C:72](=[O:77])[N:57]3[C:58]=2[C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=2)=[O:60])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:19]([NH:18][CH2:17][CH2:16][NH:15][C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:54]4[C@H:55]([CH3:78])[C@@H:56]5[C@@H:73]([C@H:74]([OH:76])[CH3:75])[C:72](=[O:77])[N:57]5[C:58]=4[C:59]([O:61][CH2:62][C:63]4[CH:64]=[CH:65][C:66]([N+:69]([O-:71])=[O:70])=[CH:67][CH:68]=4)=[O:60])[CH2:6]3)[S:10][CH:11]=2)=[O:32])=[O:20])=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)NCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCCNC(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of 3-acetylthio-1-{4-[(2-(p-nitrobenzyloxycarbonylamino)ethyl)carbamoyl]-1,3-thiazol-2-yl}azetidine (330.6 mg, 0.68 mmol) (obtained as described in Reference Example 56) in dimethylformamide (17 ml) was added hydrazine acetate (82 mg, 0.89 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (426 mg, 0.72 mmol) in acetonitrile (21 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.5 ml, 2.9 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: toluene:acetonitrile (1:2)) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(2-(p-nitrobenzyloxycarbonylamino)ethyl)carbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (348.1 mg, yield 66%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9](Br)[CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][N:19](C)C=O.C(N)CN>O>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9]([C:18]#[N:19])[CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1CCc2[nH]c3c(Br)cccc3c2C1
Reactant: CN(C)C=O
Solvent: O
Solvent: NCCN
Product: CN(C)C1CCc2[nH]c3c(C#N)cccc3c2C1

Procedure:
3-(Dimethylamino)-8-bromo-1,2,3,4-tetrahydrocarbazole (18.8 g.) (Example 211) and 17.5 g. of cuprous cyanide in 150 ml. of dimethylformamide was heated under reflux for four hours. The warm reaction mixture was poured into a solution of 200 ml. of ethylenediamine in 400 ml. of water. This was mixed thoroughly and extracted several times with chloroform. The chloroform layer was separated and washed with a dilute solution of ethylenediamine, water, saturated salt solution, and evaporated to dryness to give, after recrystallization from benzene, 6.9 g. of 3-(dimethylamino)-8-cyano-1,2,3,4-tetrahydrocarbazole, m.p. 177°-179° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl.C(O[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])C>C(O)C>[CH2:1]([NH:4][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[CH:2]=[CH2:3]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: C=CCN
Agent: Cl
Solvent: CCO
Product: C=CCNc1ccncc1[N+](=O)[O-]

Procedure:
Allyl amine (40 mL) was added to a solution of 4-ethoxy-3-nitropyridine hydrochloride [CAS No. 94602-04-7] (18.0 g) in ethanol (400 mL), and this was heated under reflux for eight hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction eluted by ethyl acetate-hexane (1:1) gave the title compound (13.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[C:7]1/[C:8]([CH3:21])([CH3:20])[CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]/1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]1([CH3:20])[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)/C=C1\CCN(C(=O)OC(C)(C)C)CC1(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1(C)C
Reaction time: 10 h
Yield: 68.3 %

Procedure:
A solution of (E)-tert-butyl 4-{(ethoxycarbonyl)methylene}-3,3-dimethylpiperidine-1-carboxylate (784 mg, 2.64 mmol) in MeOH (10 mL) containing Pd/C (131 mg) was hydrogenated at 1 atm. After 10 h, the mixture was filtered, and the filter cake was washed with MeOH. The combined filtrates were concentrated to afford the titled compound (540 mg, 68%): 1H NMR (CDCl3) δ 4.13 (q, J=6.8 Hz, 2H), 4.05 (m, 1H), 3.57 (m, 1H), 2.57 (m, 1H), 2.46 (dd, J=15.2, 3.2 Hz, 1H), 1.93 (dd, J=15.2, 10.4 Hz, 1H), 1.76 (m, 1H), 1.59-1.50 (m, 2H), 1.45 (s, 9H) 1.34 (m, 1H), 1.26 (t, J=6.8 Hz, 3H), 0.91 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)=[C:6]([C:16](=[O:18])[CH3:17])[CH:5]=[C:4]([Cl:19])[C:3]=1[CH3:20].N1C=CC=CC=1.Cl[CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32].CC(C)([O-])C.[K+]>C(Cl)Cl.O1CCCC1>[C:16]([C:6]1[C:7]([C:8]2[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=2)=[C:2]([N:1]2[CH2:28][CH2:29][CH2:30][C:31]2=[O:32])[C:3]([CH3:20])=[C:4]([Cl:19])[CH:5]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cc(F)cc(F)c1
Reactant: O=C(Cl)CCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.1 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.34 mmol) and pyridine (0.041 mL, 0.51 mmol) in methylene chloride (2 mL) was added 4-chlorobutanoyl chloride (0.042 mL, 0.37 mmol). The reaction was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated to dryness under reduced pressure. The resulting residue was treated with 1.0 M potassium tert-butoxide in tetrahydrofuran (0.84 mL, 0.84 mmol) in tetrahydrofuran (2 mL) at room temperature for 2 hours. The reaction was quenched with aq. NH4Cl, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to give the desired product (15 mg, 12%), LCMS calculated for C19H17ClF2NO2 (M+H)+: m/z=364.1. found: 364.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:4][CH2:3]1.[O:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:26][C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)[CH2:16][CH2:15]2)[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(c2ccccc2N2CCNCC2)CC1
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(c2ccccc2N2CCN(Cc3ccoc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a mixture of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (30 mg, 0.11 mmol) produced in Example (3c), furan-3-carbaldehyde (21 mg, 0.22 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (119 mg, 0.559 mmol), followed by stirring for 1 hour and 50 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was filtered through Celite. The solvent was distilled off by nitrogen stream to the filtrate. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[2-(4,4-dimethylcyclohexyl)phenyl]-4-furan-3-ylmethylpiperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled off by nitrogen stream. Hexane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant hexane solution was removed and the resulting solid was dried to give 31 mg of the title compound as colorless crystals.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:24]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:23](=[O:30])[C@@H:22]([CH2:31][C:32]([NH2:34])=O)[S:21][C@H:20]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[C:19]=2[CH:45]=1.N1C=CC=CC=1>CCOCC>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:24]([CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:23](=[O:30])[C@@H:22]([CH2:31][C:32]#[N:34])[S:21][C@H:20]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[C:19]=2[CH:45]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(N)=O)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)CN1C(=O)[C@@H](CC#N)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
Trifluoroacetic anhydride (441 mg, 210 mmol, 296 μL) was added to a solution of trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetamide (98 mg, 210μmol) and pyridine (2.1 mL) at 0° C. After 1.5 h, the reaction mixture was diluted with ether, washed with water (2×) and 0.5 N aqueous hydrochloric acid, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by flash column chromatography (methylene chloride) to give 88 mg (93%) of the title compound as a white solid.