Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:25])[N:15]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:16]4=[N:17][C:18]=3[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26](OC)=[O:27].N1CCCN2CCCN=C12>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:25])[N:15]4[CH2:24][CH2:23][N:22]([CH:26]=[O:27])[CH2:21][CH2:20][C:16]4=[N:17][C:18]=3[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC=O
Reactant: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCNCC2
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: O=CN1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1

Procedure:
A solution of 8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (0.1 g, 0.3 mmol), methyl formate (22 mg, 1.2 mmol), and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (2.1 mg, 0.015 mmol) in toluene (3 mL) was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated potassium bisulfate (5 mL). The solution was extracted with ethyl acetate (3×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 362 (M+H+); 1H NMR (300 MHz, CDCl3) δ 8.27-8.23 (m, 1H), 8.20-8.18 (d, J=6.24 Hz, 1H), 7.79-7.78 (m, 1H), 7.62-7.59 (m, 1H), 7.38-7.32 (m, 2H), 7.29-7.26 (m, 1H), 7.14-7.07 (m, 1H), 4.57-4.49 (m, 2H), 3.94-3.84 (m, 2H), 3.75-3.65 (m, 2H), 3.28-3.19 (m, 2H). mGluR5 PAM EC50: +++. Fold shift at 10 μM: ++.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>C1(CCN)CCCCC=1.C(O)C>[C:5]1([CH2:6][CH2:26][NH:23][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:21][CH2:2][CH2:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: NCCC1=CCCCC1
Solvent: CCO
Product: O[C@H](CNCCC1=CCCCC1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-(1-cyclohexenyl)ethylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=411.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:23]([C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:33])=[C:24]=[O:25]>C1(C)C=CC=CC=1>[CH:1]1([N:7]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[C:24]([NH:23][C:26]2[C:27]([CH3:33])=[CH:28][CH:29]=[CH:30][C:31]=2[CH3:32])=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)N(c1c2ccccc2nn1-c1ccccc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 2-isocyanato-1,3-dimethyl-benzene ([28556-81-2]) in toluene for 72 h under reflux conditions to give the title compound as yellow oil. MS: m/e=439.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3=[O:23])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+].C=O.C(O)(=O)C.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:26])[CH2:19][C:18]3=[O:23])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3=O)cn2)c1=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C(=O)C1
Reaction time: 4 h
Yield: 60.3 %

Procedure:
To a solution of 1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)piperazin-2-one (332e) (500 mg, 1.32 mmol) in methanol (20 mL) was added Na(OAc)3BH (2.0 g, 13.2 mmol), formaldehyde (30% aq., 8 mL), and acetic acid (2.7 mL, 45 mmol). The mixture was stirred for 4 h. The pH of the reaction mixture was adjust to 11˜13 by adding NaOH (1M). It was then extracted with methylene chloride three times. The combined organic exact was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica-gel column eluting with 50:1 methylene chloride/methanol to afford 332f as a gray solid (312 mg, 60%). MS: [M+H]+ 393. 1H NMR (500 MHz, CDCl3) δ 8.61 (d, J=2.5 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.45 (dd, J=9 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 3.64 (m, 2H), 3.53 (s, 3H), 3.22 (s, 2H), 2.74 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O-:11].[Na+].S([O-])([O-])=O.[Na+].[Na+].[C:19](=[O:21])=[O:20]>CC1(C2C=CC=CC=2)C2C(=CC=CC=2)CC1>[OH:11][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C=O
Reactant: [O-]c1ccc2ccccc2c1
Agent: CC1(c2ccccc2)CCc2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O

Procedure:
204 parts of technical sodium β-naphtholate melt containing 100 parts of sodium-β -naphtholate and 100 parts of sodium sulfite is stirred at 250° to 260° C. with 150 parts of methylphenylindan for fifteen minutes. The undissolved sodium sulfite is allowed to settle and the hot solution of sodium β-naphtholate in methylphenylindan at 260° C. is pumped into a stirred autoclave which has been preheated to 255° C. The autoclave is closed and at an internal temperature of 255° C. dry carbon dioxide is pressed in up to a pressure of 5 atmospheres. Carboxylation and processing are carried out analogously to Example 1. 34 parts of 2-hydroxynaphthalene-3-carboxylic acid having a melting point of 212° to 215° C. is obtained (60% of theory based on β-naphthol used up).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:18]3[CH:23]=[C:22]([O:24][S:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)(=[O:27])=[O:26])[CH:21]=[N:20][CH:19]=3)[NH:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cncc(OS(=O)(=O)N3CCCC3)c2)cc2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Oc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Chloro-2-[5-(pyrrolidine-1-sulfonyloxy)-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester is dissolved in DCM (2 mL), and the mixture is cooled to 0° C. TFA (2 mL) is added and the mixture is stirred at room temperature for 1 h. Saturated sodium bicarbonate is then added and the mixture is extracted with DCM. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford pyrrolidine-1-sulfonic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester as an oil which is taken onto the next step without further purification. MS (ESI) m/z 376.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1)[CH3:2]
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: CCc1ccccc1N
Product: CCc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 51.7 %

Procedure:
Using the procedure of example 1, 2-ethylaniline (98 mg) was reacted with compound 1f (100 mg) to provide compound 32 (44 mg, 52%). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=8.0 Hz, 1H), 8.21-8.18 (m, 3H), 7.51 (d, J=7.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.27 (m, 2H), 7.14 (d, J=5.2 Hz, 1H), 7.03 (dd, J=8.0 Hz, 4.8 Hz, 1H), 2.71 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of 1.146 g (3.1 mmol) of the product from Example 3 in 31 mL of DMF was added 0.137 g (3.42 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at 25° C. and then 0.42 mL (3.50 mmol) of benzyl bromide was added all at once. This reaction mixture was stirred for 10 hr at 55° C. and then poured into water and extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from EtOAc/Hexanes to provide 1.364 g (95%) of the desired product. 1H NMR(CDCl3): 7.7 ppm (dd, 2H, Ar), 7.1-7.4 (m, 5H, Ar), 6.9 ppm (dd, 2H, Ar), 4.5-4.7 ppm (AB quartet, 2H, CH2 --Ar), 3.9 ppm (s, 3H, OMe), 4.0 ppm (m, 1H, N--CH), 2.9 ppm (m, 1H, CH--CO2 --), 1.0-2.3 ppm (m, 17H, hydrocarbon protons).
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:10][C:11]1([CH3:34])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:34])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[CH2:12]1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a suspension of cyclopropanesulfonamide (610 mg, 5.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (200 mg, 5.0 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A31. A solution of 4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 1.0 mmol) and 1,1′-carbonyldiimidazole (320 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B31. Solution B31 was added to Solution A31 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (140 mg, 30%) as a white solid: MS (ESI) M+1=453.3.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:38]([C:39]#[N:40])=[C:37]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[N:36]=[C:35]([S:46][CH2:47][C:48]3[N:49]=[C:50]([C:53]4[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=4)[S:51][CH:52]=3)[C:34]=2[C:60]#[N:61])=[CH:29][CH:28]=1)=[O:22])[CH3:20])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.[ClH:62]>ClCCl.C(OCC)C>[ClH:59].[ClH:62].[NH2:8][C@H:9]([C:16]([NH:18][C@H:19]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[C:38]([C:39]#[N:40])=[C:37]([N:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)[N:36]=[C:35]([S:46][CH2:47][C:48]3[N:49]=[C:50]([C:53]4[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=4)[S:51][CH:52]=3)[C:34]=2[C:60]#[N:61])=[CH:31][CH:32]=1)=[O:22])[CH3:20])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 6 h

Procedure:
169 mg (0.192 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-histidyl-L-alaninate were dissolved in 3 ml dichloromethane, and 1.915 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 6 hours of stirring, the precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 75 mg (44% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][N:2]([C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19]Br)=[CH:14][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].C[Sn](C)(C)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][N:2]([C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:14][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6][CH3:7]
Reactant: CSCC[C@@H](C(=O)O)N(C)C(=O)c1ccc(C#CBr)cc1-c1ccccc1C
Reactant: C[Sn](C)(C)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CSCC[C@@H](C(=O)O)N(C)C(=O)c1ccc(C#Cc2cccnc2)cc1-c1ccccc1C
Yield: 25.3 %

Procedure:
Methyl N-[4-(bromoethyn-1-yl)-2-(2-methylphenyl)benzoyl]methionine (200 mg, 0.43 mmol), trimethyl-3-pyridyltin (89 mg, 0.37 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (15 mg, 0.02 mmol) were heated at 80° C. for 18 h. The mixture was evaporated and chromatographed (50% ethyl acetate in hexane) to give 43 mg of the title compound. MS m/e 459 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.60 (m, 1H), 1.86 (m, 1H), 2.1 (m, 8H), 3.68 (s, 3H), 4.63 (m, 1H), 5.97 (m, 1H), 7.30 (m, 6H), 7.63 (m, 1H), 7.83 (m, 1H), 7.99 (m, 1H), 8.59 (m, 1H), 8.78 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][C:12]=1[Cl:18])[CH3:8].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)#[N:21]>CN(C)C=O>[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)=[N:13][C:12]=1[Cl:18])[CH3:8]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Cl
Temperature: 5 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
96.7 mg (0.7 mmol) of potassium carbonate was added to a stirred solution of 2,6-dichloro nicotinic acid ethyl ester 0.15 g (0.7 mmol) in 10 ml of N,N-dimethyl-formamide (DMF) cooled to 5° C. This was followed by dropwise addition (over a period of 10 min) of 4-cyano phenol 80 mg (0.68 mmol) dissolved in 2 ml of DMF. The reaction mixture was allowed to stir at RT for 2 h, concentrated under reduced pressure and the residue was dissolved in 100 ml of ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane:ethylacetate (8:2) as eluants to afford 0.13 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 7.26 (1H, s), 7.38 (1H, s), 7.48 (2H, d), 7.96 (2H, d).
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][C:16]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].[F:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=S)[CH:29]=[CH:30][C:31]=1[F:32].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[O:24][C:3]([C:4]([NH:6][C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:14][CH2:15][C:16]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]4)=[N:11][CH:12]=3)=[O:5])=[N:1][N:2]=2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: Fc1ccc(N=C=S)cc1F
Reactant: COC(=O)C1(C)CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(F)c(F)c4)o3)cn2)CC1
Temperature: 45 °C
Yield: 79.6 %

Procedure:
To a suspension of methyl 1-(5-{[hydrazino(oxo)acetyl]amino}pyridin-2-yl)-4-methylpiperidine-4-carboxylate (Intermediate 109; 250 mg, 0.75 mmol) in anhydrous DMF (3 mL) was added 3,4-difluorophenylisothiocyanate (154 mg, 0.89 mmol) in anhydrous DMF (1 mL) and the resulting suspension heated to 45° C. for 1 hr. EDAC.HCl (172 mg, 0.89 mmol) was added and the reaction mixture heated to 85° C. for 2 hrs and then allowed to cool to ambient temperature. Water (15 mL) was added and the suspension was filtered, washed with water (2×10 mL) and ether (15 mL) then dried to give the title product as a yellow solid (282 mg, 0.597 mmol, 79.6%);
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)=[N+]=[N-].N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(OCC)(=O)C.[Pd]>[C:37]([NH:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of 14.92 g (35.5 mmol) of the azide 4 in 2000 mL of ethyl acetate was treated with 2 g of 10% palladium on carbon followed by hydrogenation at one atmosphere for 24 h. The flask was flushed with nitrogen, followed by sequential addition of 14.0 g (14.4 ml, 177.5 mmol) of pyridine and 9.1 g (8.4 mL, 88.8 mmol) of acetic anhydride. The mixture was stirred at ambient temperature for 72 h, followed by filtration through celite. The filtrate was extracted with water, 1N copper sulfate solution, dried and concentrated in vacuo to afford a tan solid. This material was purified by silica gel chromatography to afford 12.7 g (82%) of the product 5 as a powdery white solid, mp 153°-159° C.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O[C@H:29](COC1C=CC(C(C)(C)C)=CC=1)[CH2:30]NC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:29][CH3:30])[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: CCc1cccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)c1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M-15,.6), 237(16), 236 (100), 163 (5), 121 (21), 114 (6), 105 (5), 90 (6).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])[Br:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Cl)cc1C(=O)OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Yield: 120.8 %

Procedure:
18E (16.48 mmol) was dissolved in CCl4 (50 mL), and was added NBS (N-bromosuccinimide, 3.23 g, 18.13 mmol), followed by catalytic amount of BPO (benzoyl peroxide). The reaction mixture was refluxed for about 20 hours under stirring. When no more product was produced any more, the reaction mixture was cooled and filtered. To the filtrate was added NBS (1.6 g, 8.24 mmol) and catalytic amount of BPO. The reaction mixture was refluxed for additional 10 hours. After the reaction completed, the mixture was cooled and filtered. The filtrate was concentrated to give 6.4 g of a crude product (19A), which was used directly for the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:20])[CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1.CS(C)=O.[C-:25]#[N:26].[Na+].Cl[O-].[Na+]>O>[C:25]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:20])[CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1)#[N:26]
Reactant: CC(CCCC1CCCCC1)c1ccc(CCCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CS(C)=O
Product: CC(CCCC1CCCCC1)c1ccc(CCC#N)cc1

Procedure:
9 Grams of the 4-[p-(2-chloroethyl)phenyl]pentylcyclohexane, 100 ml of dimethyl sulfoxide ((CH3)2SO) and 23 g of sodium cyanide (NaCN) were stirred together at 140° to 150° C. for 2 hours. After the resulting mixture was cooled, a 10% aqueous sodium hypochlorite (NaClO) solution was added. Further, water was added thereto, and the precipitate was recrystallized from ligroin to obtain 4-[p-(2-cyanoethyl)phenyl]pentylcyclohexane. The melting point of this compound was 44° to 46° C.
Reaction SMILES: [C:1]([C:6]1[C:7]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[N:8][C:9](Cl)=[N:10][C:11]=1[CH3:12])([O:3][CH2:4][CH3:5])=[O:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>O1CCOCC1>[C:1]([C:6]1[C:7]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[N:8][C:9]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:10][C:11]=1[CH3:12])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1N1CCS(=O)(=O)CC1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc(N2CCNCC2)nc1N1CCS(=O)(=O)CC1

Procedure:
2.0 gm (0.006 mol) of 5-carbethoxy-2-chloro-4-(1,1-dioxido-thiomorpholino)-6-methyl-pyrimidine were added in small portions to a boiling solution of 5.2 gm (0.06 mol) of piperazine in 70 ml of dioxane, and the mixture was refluxed for 20 minutes. The reaction mixture was then poured into 150 ml of water, and the aqueous mixture was extracted with chloroform. The organic extract was washed with water, dried with sodium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from ethanol/petroleum ether. Yield: 1.7 gm (74% of theory); m.p. 154°-159°C.