Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1.CO>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(N4CCCCC4)cc3)nc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1cc(-n2cc3c(n2)CCNCC3)ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(1-piperidinyl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 33) (70 mg, 0.18 mmol) in dioxan (1 ml) was added 4M hydrochloric acid in dioxan (2 ml). The resulting mixture was stirred at room temperature, under argon, overnight. The reaction mixture was diluted with methanol and then purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (D43). MS (ES+) m/e 297 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([NH:45][CH3:46])[CH:41]([F:47])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([N:45]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH3:46])[CH:41]([F:47])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1F
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CCN(C(=O)OC(C)(C)C)CC1F

Procedure:
4-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-Fluoro-4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (compound described in J. Med. Chem. 2008, 51, 4239-4252) following General Procedure C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(O)C>[CH2:13]([O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]2[NH:28][C:27]1[CH:29]=[CH:30][C:24]([O:23][CH2:22][CH:21]([OH:20])[CH2:31][OH:32])=[CH:25][CH:26]=1)[CH3:14]
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Reactant: Nc1ccc(OCC(O)CO)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Nc1ccc(OCC(O)CO)cc1

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate (2.0 g), absolute ethanol (30 ml) and 4-(2,3-dihydroxypropoxy)aniline (1.38 g) was boiled under reflux for 1 hour. The reaction mixture was hot filtered and the filtrate evaporated to dryness. The residue was triturated with dichloromethane and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica using ethyl acetate as the mobile phase to give ethyl 6-ethoxy-4-[4-(2,3-dihydroxypropoxy)anilino]-1,5-naphthyridine-3-carboxylate, m.p. 143°-145° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[OH:12])[CH2:9][CH3:10])(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[NH2:7][CH:8]([CH2:9][CH3:10])[C:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:12]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(=O)c1nc2ccccc2o1
Reaction time: 1 h

Procedure:
[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butyl ester (275 mg, 0.89 mmol) and MeCl2 (5 ml) were mixed and TFA (1 ml) was added at room temperature. After stirring for 1 hour, the solvent and excess TFA were removed under vacuum to produce 260 mg of 2-amino-1-benzooxazol-2-yl-butan-1-one TFA salt.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:17][CH:18]([CH2:23][CH3:24])[CH2:19][C:20](Cl)=[O:21].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[CH3:17][CH:18]([CH2:23][CH3:24])[CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:2][CH:3]=1)=[O:21]
Reactant: CCC(C)CC(=O)Cl
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCC(C)CC(=O)c1ccc(-c2ccccc2)cc1
Temperature: -7 °C
Reaction time: 18 h

Procedure:
To commercially available biphenyl (0.08 mole) and anhydrous aluminium trichloride (0.1 mole) dissolved in dry nitrobenzene (90ml), (+)-3-methylpentanoylchloride (0.1mole) the preparation of which is known and described in United Kingdom Patent Application No. 36211/75), is added in drops, the temperature being maintained at about -7° C. during the addition. The mixture is then stirred for about 18 hr. with cooling in an ice bath. It is then poured onto a mixture of ice, water and concentrated hydrochloric acid and stirred for 0.5 hr., and the nitrobenzene layer is separated. The nitrobenzene is removed by steam distillation and the residue is crystallised from a small volume of ethanol to constant melting point.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCC1CCOC1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH3:11].[C:12]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:11][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:15]1[CH:14]=[CH:13][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1c(C(F)(F)F)noc1N
Product: Cc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 78 %

Procedure:
N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared in the same manner as described in Example 2b from 5-amino-4-methyl-3-trifluoromethyl-isoxazole and 4-biphenylsulfonyl chloride in 78% yield. Purification was achieved by recrystallization from methanol/water to give a white solid, m.p. 139-140° C.
Reaction SMILES: C([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:7][CH2:6]1)(O)=O.C[C:36]1([CH3:44])[O:43][C:41](=[O:42])[CH2:40][C:38](=[O:39])O1.CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C>ClCCl>[CH2:36]([O:43][C:41]([CH2:40][C:38](=[O:39])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:9][CH2:10]1)=[O:42])[CH3:44]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1

Procedure:
To a dichloromethane (10 mL) suspension of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester (939 mg) obtained in Example 2, Meldrum's acid (317 mg), dimethylaminopyridine (293 mg), and EDCI (460 mg) were added at 0° C. The reaction mixture was diluted with dichloromethane, washed with 1 N hydrochloric acid and saturated brine, then dried over sodium sulfate, and then concentrated. A mixture of the residue and ethanol (10 mL) was heated to reflux for 4 hours and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate) to obtain the title compound (820 mg, 76%) as a yellowish-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[Cl:1])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1cc(C)cc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 33.9 %

Procedure:
A stirred, 0° C. solution of 1-chloro-3,5-dimethylbenzene (10.9 g, 77.2 mmol) and 4-chlorobenzoyl chloride (13.6 g, 77.2 mmol) in carbon disulfide (165 ml) was treated with aluminum chloride (11.4 g, 85.0 mmol) in portions over 15 minutes. The mixture was stirred 15 minutes at 0° C., 60 minutes at ambient temperature, 20 hours at reflux and 3 days at ambient temperature. The mixture was cooled to 0° C. and quenched by addition of ice (250 g) followed by concentrated hydrochloric acid (60 ml). The mixture was extracted twice with diethyl ether and the combined extracts were washed with water (3X), saturated aqueous sodium carbonate, and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness of 30° C. under vacuum. The residue was chromatographed in three approximately equal batches on silica gel (500 g) eluted with 97:3 (v/v) hexane-ethyl acetate using a preparative high performance liquid chromatograph to provide 7.3 g (34%) 1-(4-chlorobenzoyl)-2-chloro-4,6-dimethylbenzene, m.p. 84°-87° C. [IR (neat): 2100, 1660 cm-1 ; 60 MHz 'H NMR (CDCl3): 2.11 s (3H), 2.34 s (3H), 6.94 bs (1H), 7.04 bs (1H), 7.34 dm (J= 9 Hz, 2H), 7.70 dm (J=9 Hz, 2H)] and 3.4 g (16%) 1-(4-chlorobenzoyl)-4-chloro-2,6-dimethylbenzene, m.p. 41°-52° C. [IR (neat): 2100, 1660 cm-1 ; 60 MHz 'H NMR (CDCl3) 2.08 s (6H), 7.07 s (2H), 7.38 dm (J=9 Hz, 2H), 7.69 dm (J=9 Hz,2H)].
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:27][CH2:28][C:29]([O:31][CH2:32]/[CH:33]=[C:34](/[CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])\[CH3:35])=[O:30].ClCC([O-])=O>C(Cl)(Cl)Cl>[Cl-:27].[CH3:26][N+:24]([CH3:25])([CH2:28][C:29]([O:31][CH2:32]/[CH:33]=[C:34](/[CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])\[CH3:35])=[O:30])[CH2:23][CH2:22][CH2:21][NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Reactant: CC(C)=CCC/C(C)=C/COC(=O)CCl
Agent: O=C([O-])CCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC(=O)OC/C=C(\C)CCC=C(C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
A 36.86 g (0.100 mol) portion of N-octadecanoyl-N′,N′-dimethyl-1,3-diaminopropane and 100 ml of chloroform were put into a flask, and 23.30 g (0.101 mol) of geranyl chloroacetate was added thereto at 25° C. spending 5 minutes. The reaction mixture was stirred at 25° C. for 36 hours and then, after confirming by 1H-NMR that chloroacetate was mostly disappeared, the solvent was evaporated under a reduced pressure. The thus obtained viscous oil was dissolved in 200 ml of acetone and cooled to 5 to 10° C. to effect precipitation of a white precipitate. The supernatant solvent was discarded, and the precipitated was collected and dried under a reduced pressure to obtain the title compound (to be referred to as betaine ester (1) hereinafter) as a slightly brownish white solid. Yield 49.1 g (0.0819 mol; yield 81.9%). 1H-NMR (200 MHz, CDCl3): δ [ppm]
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[C:10]([NH:17][CH3:18])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26](Cl)(Cl)=[O:27].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([N:7]2[CH2:8][C:9]3[C:10](=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=3)[N:17]([CH3:18])[C:26]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(C)C(=O)N(C1CCCCC1)C2
Temperature: 0 °C
Yield: 51.9 %

Procedure:
A mixture of 210 mg (0.79 mmol) of 5-cyclohexylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml of triethylamine in 10 ml of tetrahydrofuran was added dropwise to an ice-cooled solution of 0.5 ml (0.96 mmol) of phosgene (20% solution in toluene) in 5 ml of tetrahydrofuran. After 1 hour 15 ml of aqueous ammonium chloride solution and 10 ml of tetrahydrofuran were added to the resulting mixture. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and then evaporated. The residue was chromatographed on silica gel using diethyl ether/hexane (3:2) for the elution. Product-containing fractions were combined and evaporated to give 120 mg (52%) of 3-cyclohexyl-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])/[CH:9]=2)=[N:5][N:4]=[N:3]1.[Cl:35][C:36]1[CH:37]=[C:38]([S:43](/[N:46]=[C:47]2\[CH:48]=[C:49](Cl)[C:50](=[O:57])[C:51]3[C:56]\2=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[Cl:42].SC1N=CNN=1>>[NH:4]1[CH:1]=[N:2][C:6]([S:7][C:49]2[C:50](=[O:57])[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)/[C:47](=[N:46]/[S:43]([C:38]3[CH:39]=[CH:40][C:41]([Cl:42])=[C:36]([Cl:35])[CH:37]=3)(=[O:45])=[O:44])/[CH:48]=2)=[N:5]1.[CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:21])=[O:22])/[CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Agent: Sc1nc[nH]n1
Product: O=C1C(Sc2nc[nH]n2)=C/C(=N\S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
(E)-N-(3-(1H-1,2,4-triazol-3-ylthio)-4-oxonaphthalen-1(4H)-ylidene)-3,4-dichlorobenzenesulfonamide (13ag) was prepared according to the procedure for 13x except using 12g and 3-mercapto-1,2,4-triazole, affording 27.8 mg (29.9%) title compound as a yellow solid.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[O-:10][C:11]#[N:12].[K+].Cl.[OH-].[K+]>O1CCCC1.O>[C:11]([N:4]1[CH:5]2[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]2)[CH2:2][CH2:3]1)(=[O:10])[NH2:12]
Reactant: C1CN2CCC(CC2)N1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CCN2CCC1CC2
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
To a solution of 1,4-diazabicyclo[3.2.2]nonane (2.75 g) in a mixture of tetrahydrofuran (40 ml) and water (20 ml) was added potassium cyanate (2.65 g) at ambient temperature. The mixture was adjusted to pH 5.0 with concentrated hydrochloric acid and stirred at 50° C. for 40 minutes. The mixture was poured into 50% aqueous solution of potassium hydroxide. The resulted aqueous solution was extracted with chloroform. The extract was dried over anhydrous potassium carbonate and evaporated to dryness in vacuo. The crystalline residue was recrystallized from diethyl ether to give 4-carbamoyl-1,4-diazabicyclo[3.2.2]nonane (898.5 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]4[N:52]=[C:51](Cl)[N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH:59]5[CH2:64][C:63]([CH3:66])([CH3:65])[N:62]([O:67][CH:68]6[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]6)[C:61]([CH3:75])([CH3:74])[CH2:60]5)[N:48]=4)=[CH:42][CH:41]=3)([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[N:3]=1.[NH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]([OH:84])=[O:83]>>[C:82]([CH2:81][CH2:80][CH2:79][CH2:78][CH2:77][NH:76][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]4[N:52]=[C:51]([NH:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]([OH:84])=[O:83])[N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH:59]5[CH2:64][C:63]([CH3:66])([CH3:65])[N:62]([O:67][CH:68]6[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]6)[C:61]([CH3:75])([CH3:74])[CH2:60]5)[N:48]=4)=[CH:42][CH:41]=3)([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[N:3]=1)([OH:84])=[O:83]
Reactant: NCCCCCC(=O)O
Reactant: CC(C)(c1ccc(Oc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)cc1)c1ccc(Oc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)cc1
Product: CC(C)(c1ccc(Oc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)cc1)c1ccc(Oc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)cc1

Procedure:
The title compound is prepared from the reaction of 2,2-bis{4-[[2-chloro-4-[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl]oxy]phenyl}propane with 6-aminohexanoic acid.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23](Cl)=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1.O>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23]([N:1]3[CH2:4][CH2:3][C@H:2]3[C:5]([OH:7])=[O:6])=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 0.50 g of (S)-2-azetidine carboxylic acid in 15 ml of 10% aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethylchloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution washed with ether. The aqueous layer was cooled to 0° C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl)azetidine-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[Cl:38][C:39]1[CH:40]=[C:41]([CH:46]2[CH2:50][NH:49][CH2:48][CH:47]2[CH:51]([O:53][C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][N:55]=2)[CH3:52])[CH:42]=[CH:43][C:44]=1[Cl:45]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:49]2[CH2:50][CH:46]([C:41]3[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=3)[CH:47]([CH:51]([O:53][C:54]3[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][N:55]=3)[CH3:52])[CH2:48]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.165 g, 0.72 mmol) in 20 mL of CH2Cl2 was added (0.14 g, 0.94 mmol) of EDC, (0.10 g, 0.94 mmol) of HOBt and Et3N (0.11 mL, 1.1 mmol). After one hour at RT, was added 6-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VII-B-2, 0.26 g, 0.72 mmol). The mixture was stirred at RT over night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/H, 1:1) yielded 0.29 g (91%) of the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:25][C:26]([F:35])([F:34])[C:27](N1C=CN=C1)=[O:28]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:27](=[O:28])[C:26]([F:35])([F:34])[F:25])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CC(=O)c1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(Br)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
To a solution of 1-[4-bromo-3-(trifluoromethyl)phenyl]-1-ethanone (1.34 g, 5.65 mmol) in THF (30 ml) was added lithium bis(trimethylsilyl)amide (1.0 M THF solution, 6.8 ml, 6.8 mmol) at −78° C. The mixture was stirred at 0° C. for 15 minutes and the solution was again cooled to −78° C. N-trifluoroacetylimidazole (1.15 g, 6.78 mmol) was added to the solution at the same temperature. The resulting mixture was stirred at −78° C. for 15 minutes and at room temperature for 2.5 hours. The reaction was quenched with 2N HCl (100 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (200 ml), dried over MgSO4, and concentrated in vacuo to give 1.80 g (88%) of the title compound as a pale yellow solid.
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]=1)=O.[C:14]([O-])(=O)[CH3:15].[NH4+].[N+:19](C)([O-:21])=[O:20]>>[N+:19]([CH:14]=[CH:15][N:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=2)[CH:3]=[CH:4]1)([O-:21])=[O:20]
Reactant: CC(=O)[O-]
Reactant: C[N+](=O)[O-]
Reactant: N#Cc1ccc2[nH]cc(C=O)c2c1
Agent: [NH4+]
Product: N#Cc1ccc2c(ccn2C=C[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Combine 3-formyl-5-cyano-1H-indole (10.60 g, 63.32 mmol) and a solution of ammonium acetate (10.60 g) in nitromethane (660 ml). Heat to 90° C. After 2 hours, cool to ambient temperature to give a precipitate. Collect the precipitate by filtration, wash with 1:1 MeOH/water (500 ml), and dry to give the title compound: mp 247–251° C. MS (ACPI): m/e 214.0 (M+1).