Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:15])[CH2:10][CH2:11][N:12]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: NC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1(c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 75 %

Procedure:
A solution of 4-(4-chlorophenyl)piperdin-4-yl amine hydrochloride (0.030 g, 0.1058 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.016 g, 0.1058 mmol) and triethylamine (0.074 ml, 0.5289 mmol) in n-butanol (1.0 ml) was heated to 100° C. for 2 days. Concentration and purification by SCX-2 Isolute column (2 g), eluting with 1M NH3/MeOH, followed by silica column chromatography (20% methanol in DCM) gave a white solid (0.026 g, 74%). LC-MS (LCT2) m/z 328 [M+H+], Rt 2.59 min.
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:11][CH:10]=1
Reactant: IC1CCOCC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1ccc(SC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-Iodotetrahydropyran (9 g, 42.45 mmol) was added to a stirred suspension of 4-bromobenzenethiol (7.296 g, 38.59 mmol) and potassium carbonate (10.67 g, 77.18 mmol) in DMF (15 mL) and the reaction stirred at ambient temperature for 3 hours. The mixture was diluted with Et2O and washed with water (×2) and brine (×1). The organic extracts was dried (MgSO4) and concentrated in vacuo. Petroleum ether was added to the residue and the resultant precipitate removed by filtration. The filtrate was concentrated in vacuo to give the sub-title compound as a light yellow oil (9.0 g, 85% Yield). 1H NMR (400.0 MHz, CDCl3) δ 1.63-1.73 (m, 2H), 1.89-1.93 (m, 2H), 3.23-3.30 (m, 1H), 3.45 (td, 2H), 3.99 (dt, 2H), 7.31 (d, 2H) and 7.45 (d, 2H) ppm.
Reaction SMILES: C(O)C.[CH:4]1([N:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[C:12]([CH3:29])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[CH:4]1([N:10]2[C:14]3[C:15](=[O:16])[NH:17][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][C:13]=3[C:12]([CH3:29])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccccc1C(=O)Nc1c(C)nn(C2CCCCC2)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 10 h
Yield: 72.3 %

Procedure:
To a 2 ml ethanol solution of 100 mg (0.28 mmol) of the compound obtained in Example 9, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at 90° C. for 10 hours. Then, the reaction mixture was brought to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 68.5 mg (72%) of the captioned compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CN(C=O)C.[CH3:10][C:11]1([CH3:23])[O:16][C:15](=[O:17])[CH:14]=[C:13]([CH2:18][C:19](=[O:22])[CH2:20]Cl)[O:12]1>C(OCC)(=O)C>[CH3:10][C:11]1([CH3:23])[O:16][C:15](=[O:17])[CH:14]=[C:13]([CH2:18][C:19](=[O:22])[CH2:20][N:1]=[N+:2]=[N-:3])[O:12]1
Reactant: CC1(C)OC(=O)C=C(CC(=O)CCl)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C=C(CC(=O)CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
195 mg (3.0 mmol) of sodium azide were added to 2 ml of a DMF solution containing 328 mg (1.5 mmol) of 2,2-dimethyl-6-(3-chloro-2-oxopropyl)-1,3-dioxin-4-one prepared in Example 1, followed by stirring at room temperature for 10 minutes. Afterward, the solution was poured into ice water, extracted with ether, and then dried with anhydrous magnesium sulfate. After ether was distilled off, the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=1:1), thereby obtaining 278 mg (yield 82%) of 2,2-dimethyl-6-(3-azido-2-oxopropyl)-1,3-dioxin-4-one.
Reaction SMILES: [ClH:1].[C:2]([O:6]C(=O)[C@H](CCCNCOC=N)NC(OC(C)(C)C)=O)(C)(C)[CH3:3].[C:26]([O:30][C:31](=[O:47])[C@H:32]([CH2:41][CH2:42][CH2:43][NH:44][C:45]#[N:46])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:29])([CH3:28])[CH3:27].C(OC(=O)[C@H](CCCNC#N)N)(C)(C)C>>[ClH:1].[C:26]([O:30][C:31](=[O:47])[C@H:32]([CH2:41][CH2:42][CH2:43][NH:44][CH:45]=[N:46][O:6][CH2:2][CH3:3])[NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNCOC=N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC#N)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@@H](N)CCCNC#N
Agent: Cl
Product: CCON=CNCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
By a method described above for the preparation of N2-(tert-butoxycarbonyl)-N5-(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride, 1.05 g (3.35 mmol) of N2-(tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester produced 0.95 g (75%) N2-(tert-butoxycarbonyl)-N5-(ethoxyiminomethyl)-L-ornithine tert-butyl ester hydrochloride (TLC, silica gel, methanol:dichloromethane/1:4, Rf=0.61) and 1.195 g (3.2 mmol) of N2-tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester produces 0.63 g (63%) N2-(tert-butoxycarbonyl)-N5-(iminoisopropoxymethyl)-L-ornithine tert-butyl ester hydrochloride (TLC, silica gel, methanol:dichloro methane/1:4, Rf=0.53). Mass Spectrum (CI) 360 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH2:23])=[NH:22])[C:16]3=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:27].[C:28]([OH:34])([C:30](F)(F)F)=O>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[NH:23][C:26]5[C:28](=[O:34])[CH:30]=[CH:6][CH:5]=[CH:4][C:3]=5[N:22]=4)[C:16]3=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:27]
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCN(CC(=N)N)C3=O)CC2)cc1C
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCN(Cc4nc5ccccc(=O)c5[nH]4)C3=O)CC2)cc1C

Procedure:
The title compound (18 mg) was prepared following the general procedures of Example 28 starting with 2-{(R)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-yl}-acetamidine (405 mg, 0.85 mmol). HRMS calculated for C27H30N4O4 474.5646. found (ESI, [M+H]+). found 475.2345. 1H NMR (400 MHz, CDCl3-d) 8 ppm 1.74-2.11 (m, 4H) 2.22-2.44 (m, 5H) 2.57 (d, J=8.03 Hz, 1H) 3.09 (d, J=6.53 Hz, 3H) 3.28-3.40 (m, 1H) 3.50 (t, J=8.28 Hz, 2H) 3.62-3.83 (m, 1H) 3.89-3.97 (m, 3H) 4.82 (br. s, 2H) 6.87 (d, J=8.53 Hz, 1H) 7.00-7.11 (m, 1H) 7.26-7.36 (m, 5H) 7.38-7.47 (m, 1H) 7.72-7.86 (m, 3H) HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.874 min.
Reaction SMILES: C(CC([O-])=O)#N.[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=[C:23]([C:21]#[N:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: N#CCC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1

Procedure:
[A] Synthesis of 1-benzyl-piperidin-4-ylidene)-cyanoacetate (2; FIG. 4). A solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (9400 mL), ethyl cyanoacetate (50.6 mL, 0.48 mol) and acetic acid (918.2 mL, 0.32 mol) was refluxed for 4 hr. The mixture was quenched with ice-water and extracted with diethyl ether. The combined extracts were washed with water, brine and dried over Na2SO4 to give ethyl (1-benzyl-piperidin-4-ylidene)cyanoacetate in quantitative yield. Rf=0.53 (hexane:AcOEt=1:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=O)=O.[Mg+2].CCN(CC)CC>>[CH2:12]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated aqueous NaHCO3 (200 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10%) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23%). Mass calculated for C14H22N2O2=250.34; found: [M+H]+=251.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:12]3[S:16][C:15]([C:17]([O:19]C)=O)=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:13]=3)[CH:10]=[N:11][C:6]2=[CH:5][CH:4]=1.[NH3:33]>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:33])=[O:19])=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:13]=3)[CH:10]=[N:11][C:6]2=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ccc(OC)nc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: COc1ccc2ncn(-c3cc(OCc4ccccc4C(F)(F)F)c(C(N)=O)s3)c2n1
Temperature: 130 °C
Reaction time: 10 h

Procedure:
A mixture of 0.74 g of methyl 5-(5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B7b) and 200 ml of a saturated solution of ammonia in methanol was stirred in an autoclave at 130° C. for 10 h. The reaction mixture was allowed to cool down to room temperature and concentrated to about half of the volume. The precipitated solid was filtered, dissolved in 4 ml methanol/DMSO (1:1) and purified by preparative HPLC (water/acetonitrile, elution gradient 9/1 to 1/9 (v/v)). After lyophilization the obtained solid was crystallized with dichloromethane/n-hexane to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.O1CCCC1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Br:12])=[CH:14][CH:15]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Nc1ccc(Br)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)Nc2ccc(Br)cc2)c1
Reaction time: 72 h
Yield: 80.5 %

Procedure:
A mixture of 3-cyanophenyl isocyanate (3.76 g, 26.1 mmol) and 4-bromoaniline (4.5 g, 26.1 mmol) in 1:1 tetrahydrofuran:chloroform (100 mL). After 72 h at ambient temperature, product was isolated by filtration, the filtrate was washed with cold chloroform and air dried to give 6.6 g of N-(3-cyanophenyl)-N′-(4-bromophenyl)urea (21 mmol).
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in the ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (about 3 L). The filtrate was concentrated and the residue was purified over silica gel (7:1 to 3:1 Hexanes/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle, washed with hexanes (about 1000 mL) and dried to afford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[NH2:15].[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1.O>C(#N)C>[CH:16]1([CH2:21][C:22]([NH:15][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:5][C:4]=2[CH3:14])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Reactant: O=C(Cl)CC1CCCC1
Solvent: CC#N
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 20 %

Procedure:
2,6-Dimethyl-4-morpholin-4-yl-phenylamine (0.50 g) and cyclopentylacetyl chloride (0.53 mL) were dissolved in acetonitrile (5 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. Water (25 mL) was added and the product was extracted with ethyl acetate (3×25 mL). The organic phases were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 0.138 g (20%) of the title compound as an off-white solid. LC-MS-TOF (m/z) 317 (MH+); tR=1.93, (UV, ELSD) 95%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.76 (m, 2H), 2.07 (s, 6H), 2.11 (m, 1H), 2.25 (d, 2H), 3.05 (dd, 4H), 3.71 (dd, 4H), 6.63 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=O)[CH3:26])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: COc1ccc(CCC(C)=O)cc1
Product: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-methoxy-phenyl)-butan-2-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH2:23])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1.[C:28]1([C:34]2[N:35]=[C:36]([C:39](O)=[O:40])[S:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH:23][C:39]([C:36]4[S:37][CH:38]=[C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:35]=4)=[O:40])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1
Reactant: COCCN1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Solvent: O
Product: COCCN1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4nc(-c5ccccc5)cs4)nc3c2)CC1

Procedure:
The title compound was prepared according to amide synthesis general method B, utilizing 2-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 4-phenylthiazole-2-carboxylic acid (1.5 eq). Addition of water to the crude reaction did not precipitate the product, therefore it was concentrated, triturated with hot MeCN, MeCN/EtOAc/MeOH mixture, and EtOAC/MeOH sequentially. The resulting pale yellow solid was lyophilized with a MeCN/water/HCl mixture and subsequently purified on prep HPLC. MS Calcd for C30H30N6O2S2: 570.19. Found (M+H)+ m/z=571.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N-methyl propargylamine (23.3 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (15.6 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 8 h to give (Z)-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 41%).
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([CH:20]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]2[CH2:19][C:18](=[C:20]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Reactant: Clc1ccc(C(Br)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(=C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1

Procedure:
A solution of 0.280 g (1 mmol) of 1-[bromo(phenyl)methyl]4-chlorobenzene, 0.120 g (0.5 mmol) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate (Example 22, Step 1) and 0.12 mL (0.7 mmol) of diisopropylethylamine in 10 mL of acetonitrile was heated at 40° C. for 18 h. The solution was concentrated and the residue was dissolved in 20 mL of ethyl acetate. This solution was washed with 10 mL water and the aqueous layer was washed with a second aliquot of 20 mL ethyl acetate. The organic extracts were washed with brine, combined, and concentrated. The residue was dissolved in acetonitrile and purified by reverse phase chromatography (Waters Xterra C18, 19 mm×50 mm) using a gradient of acetonitrile-water-triethylamine (30:70:1 to 60:40:1) to afford the title compound; 1NMR (CDCl3) δ 3.74 (s, 3H), 3.88 (m, 2H), 4.24 (m, 2H), 4.55 (s, 1H), 6.70-6.86 (m, 3H), 7.21-7.43 (m, 911); Mass Spectrum: m/e=440 (M+1 35Cl) and 442 (M+1 37Cl).
Reaction SMILES: [CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16](C3N=CC(O)=CN=3)[CH:17]=2)C1)[CH2:2][CH2:3]CCCCCCC.C(C1C=CC2N=C(C3C=CC(O)=CC=3)SC=2C=1)CCCCCCC.[C:51]1([CH3:70])[CH:56]=[CH:55][C:54]([S:57]([O:60]CCCC2C=CC=CC=2)(=[O:59])=[O:58])=[CH:53][CH:52]=1>>[C:51]1([CH3:70])[CH:52]=[CH:53][C:54]([S:57]([O:60][CH2:3][CH2:2][CH2:1][CH2:11][CH2:19][CH:18]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:58])=[O:59])=[CH:55][CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2)cc1
Reactant: CCCCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Agent: CCCCCCCCc1ccc2nc(-c3ccc(O)cc3)sc2c1
Product: Cc1ccc(S(=O)(=O)OCCCCCC2CCCCC2)cc1
Yield: 62.4 %

Procedure:
An objective product was prepared in the same manner as in Example 2 except that 2-(2-decylindan-5-yl)pyrimidine-5-ol was changed to 4-(6-octylbenzothiazole-2-yl)phenol and 3-phenylpropyl p-toluenesulfonate was changed to 5-cyclohexylpentyl p-toluenesulfonate (Yield: 62.4%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[OH-].[Na+].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(OCC)C.O>[C:16]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: C=C(C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mechanically stirred mixture of L-proline (42.0 grams, g), NaHCO3 (148 g), H2O (680 milliliters, ml) and diethyl ether (280 ml) was maintained in an ambient temperature bath at pH 10.5-10.7 (adjusted by the addition of concentrated aqueous NaOH), then treated portionwise over 20 minutes with a solution of redistilled methacryloyl chloride (40 ml) in diethyl ether (20 ml). Additional concentrated aqueous NaOH was added as needed to keep the pH at 10.5-10.7. Upon addition of all of the methacryloyl chloride (and pH stabilization), the mixture was stirred for 20 minutes at ambient temperature. The resulting immiscible phases were separated and the aqueous phase was extracted with two 250 ml portions of diethyl ether. The combined organic extracts were washed with H2O (50 ml), and the aqueous extract was added to the aqueous phase which phase was then acidified to pH 1 with concentrated aqueous HCl and then extracted with four 250 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with about 100 ml of brine (saturated aqueous sodium chloride solution) and then dried over Na2SO4. The resulting solution was filtered and concentrated in vacuo to about 230 ml and then heated to boiling, diluted with hexane (80 ml) and allowed to cool. Upon cooling, the desired N-methacryloyl-L-proline spontaneously crystallized as chunky white prisms (51.3 g). The concentrated mother liquor yielded a second crop of crystals (4.26 g) when crystallized as described above. A portion of the first crop was recrystallized twice from ethyl acetate to give an analytical sample, m.p. 102°-104.5° C., having the following spectral characteristics:
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.N1C=CC=CC=1.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl>[C:37]([O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Reaction time: 20 h

Procedure:
To a solution of dehydro-aripiprazole (1.2 g, 2.7 mmol) in dichloromethane (30 mL) was added pyridine (1 mL), followed by pivaloyl chloride (0.66 mL, 5.4 mmol). The reaction mixture was stirred for 20 hours, then washed with water and dried over MgSO4. After evaporation the residue was co-evaporated with toluene and then further purified on silica eluting with ethyl acetate. After evaporation of the product containing fraction, Compound-316 (0.53 g) was obtained as a colourless oil.