Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1ccc2ccn(Cc3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccc3ccn(Cc4ccccc4)c3c2)cc1
Yield: 70.9 %

Procedure:
Following the procedure described in Step 2 of Example 5, 1-benzyl-6-bromo-1H-indole (0.490 g, 1.71 mmol), was coupled to 4-trifluoromethylbenzeneboronic acid (0.376 g, 1.98 mmol), using tetrakis(triphenylphosphine)palladium (0.0663 g, 0.057 mmol) and sodium carbonate (0.733 g, 6.92 mmol) in water (3.5 mL), ethanol (2 mL) and toluene (10 mL). Purification by flash chromatography using 0-1% ethyl acetate in hexane as an eluant yielded the title compound as a yellow solid (0.426 g, 71%), mp: 83-85° C. 1HNMR (300 MHz, DMSO-d6): δ 7.9 (d, 3H, J=7.7 Hz), 7.8 (d, 2H, J=7.7 Hz), 7.7 (d, 1H, J=7.7 Hz), 7.6 (d, 1H, J=3.9 Hz), 7.4 (d, 1H, J=7.7 Hz), 7.2-7.4 (m, 5H), 6.55 (d, 1H, J=2.3 Hz), and 5.55 ppm (s, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH3:18][N:19]([CH3:24])[S:20]([N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:15])=[CH:6]1)(=[O:22])=[O:21]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(c1c[nH]c2ncccc12)C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cc(C(=O)C(F)(F)F)c2cccnc21
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of 107 mg (0.5 mmol) of 2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone in 2 mL of DMF was added 60% sodium hydride in mineral oil followed by 80 mg (0.56 mmol) of N,N-dimethylsulfamoyl chloride. The mixture stirred for 30 minutes and was then diluted with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 7 mL portions of brine, three 7 mL portions of saturated aqueous ammonium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was adsorbed onto silica gel and chromatographed on silica gel eluting with ethyl acetate-hexanes (10-100% gradient) to afford 88 mg (54%) of 3-(2,2,2-trifluoroacetyl)pyrrolo[2,3-b]pyridine-1-sulfonic acid dimethylamide as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)#[N:7].C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][CH2:2][CH2:3][CH2:4][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCCCBr)cc1
Yield: 69 %

Procedure:
1,3-Dibromopropane (1.02 L, 10 mol) was added to a stirred suspension of p-cyanophenol (238 g, 2 mol), K2CO3 (276.4 g, 2 mol) in MeCN (2.7 L). The reaction mixture was refluxed for 4 h, filtered and concentrated. The residue was recrystallised from iso-propyl ether to give the sub-title compound in a 69% yield.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH3:40])[CH:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[O:24])=[CH:16][C:15]=3[CH:41]=2)=[CH:7][CH:6]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1COCC1.CC(C)=O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH3:40])[CH:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[O:24])=[CH:16][C:15]=3[CH:41]=2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 65 °C
Reaction time: 14 h
Yield: 88.3 %

Procedure:
In THF/acetone (1/1, 60 ml) was dissolved 7-(4-methoxymethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (650 mg). To the mixture was added 1N sulfuric acid (4.4 ml), and the mixture was stirred at 65° C. for 14 hours, cooled to room temperature and neutralized with saturated sodium bicarbonate solution. Under reduced pressure, the solvent was evaporated, and the residue was added to water. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(4-hydroxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 89) (530 mg).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([CH:33]=[CH2:34])=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:27]1([C:24]2[O:23][C:22]([C:21]3[C:16]([NH2:8])=[N:17][CH:18]=[C:19]([CH:33]=[CH2:34])[N:20]=3)=[N:26][N:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnc(-c3ccccc3)o2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-vinyl-pyrazin-2-yl]carbamate (138 mg, 0.3 mmol) in DCM (0.7 mL) at room temperature under an atmosphere of N2 was added TFA (338 mg, 228 μL, 3 mmol) and reaction mixture was stirred for 20 minutes. The reaction mixture was diluted with DCM and slowly quenched with satd. NaHCO3. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to yield 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-vinyl-pyrazin-2-amine (67 mg, 85%) as a yellow solid. LC/MS m/z 266.4 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[C:3]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:33][CH:32]=1
Reactant: CN1CCCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)CC1
Reactant: Cc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCCN(C)CC2)cn1

Procedure:
A mixture of 5-bromo-6-(4-methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 146.1, 74 mg, 0.150 mmol), (6-methylpyridin-3-yl)boronic acid (20.6 mg, 0.150 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon. Pd(PPh3)2Cl2 (5.3 mg, 0.0075 mmol) was added and the mixture was subjected to MW irradiation at 125° C. for 30 min. The RM was evaporated to dryness under reduced pressure and the residue was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative HPLC. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.55 min, m/2z=243.6 [M+2H]+, m/z=484.2 [M−H]−.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=[O:20])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[Sn](CCCC)(CCCC)CCCC>>[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=[O:20])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: O=C(Cc1cccc2ccccc12)Nc1ccsc1I
Product: Cn1ccnc1-c1sccc1NC(=O)Cc1cccc2ccccc12

Procedure:
This molecule was synthesized from N-(2-iodothiophen-3-yl)-2-(naphthalen-1-yl)acetamide and 1-methyl-2-(tributylstannyl)-1H-imidazole according to protocol E. The residue was directly purified by HPLC to yield N-(2-(1-methyl-1H-imidazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide. Method [7] Retention time 3.41 min by HPLC (MH+ 348). 1H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H), 7.87 (m, 3H), 7.51 (m, 6H), 6.91 (d, J=1.5 hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 4.15 (s, 3H), 3.68 (s, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:18]N(P(N(C)C)(N(C)C)=O)C.CI>C1COCC1>[CH3:18][O:3][C:4]1([CH3:17])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
A suspension of 60% NaH in mineral oil (160 mg, 4 mmol) in THF (5 mL) at room temperature was treated with a solution of Example 494A (430 mg, 2.00 mmol) in THF (5 mL), heated to 55° C. for 2 hours, cooled to room temperature, treated with HMPA (2.5 mL) and methyl iodide (0.50 mL), heated to 55° C. for 16 hours, cooled to room temperature, quenched with 10% aqueous citric acid, and extracted twice with diethyl ether. The combined extracts were washed sequentially with water, saturated NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10%-20% ethyl acetate/heptane to provide the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:23]([N:25]1[C:29]2=[N:30][C:31]([CH2:54][CH3:55])=[C:32]([CH2:41][NH:42][C:43]([C:45]3[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=3)[C:48](O)=[O:49])=[O:44])[C:33]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]2[CH:27]=[N:26]1)[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:23]([N:25]1[C:29]2=[N:30][C:31]([CH2:54][CH3:55])=[C:32]([CH2:41][NH:42][C:43]([C:45]3[CH:53]=[CH:52][CH:51]=[C:47]([C:48]([NH:22][CH2:21][C:17]4[CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][CH:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)[CH:10]=5)[CH:20]=[CH:19][CH:18]=4)=[O:49])[CH:46]=3)=[O:44])[C:33]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]2[CH:27]=[N:26]1)[CH3:24]
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CC4CCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59.3 %

Procedure:
To a solution of ({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine (0.0294 g, 0.10 mmol) in DCM (1 mL) was added 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.0452 g, 0.10 mmol), HBTU (0.0417 g, 0.11 mmol), and TEA (0.0303 mL, 0.20 mmol) and was stirred at room temperature for 17 h. The reaction was quenched with H2O (1 drop), concentrated by Glas-Col evaporator and re-dissolved in MeOH/DMSO (0.5/0.1 mL). The resultant mixture was purified using a Gilson HPLC (with 0.1% TFA), concentrated by GeneVac EZ-2 evaporator and basified with an amine cartridge to afford the title compound 0.0432 g (59.34%). LC-MS m/z 728 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.37-1.44 (m, 3 H) 1.46-1.54 (m, J=7.28, 7.28 Hz, 5 H) 1.81-1.98 (m, 5 H) 2.05-2.13 (m, J=12.55 Hz, 2 H) 2.68 (d, J=6.53 Hz, 2 H) 2.78-2.86 (m, 3 H) 2.88-2.97 (m, 2 H) 3.15 (q, J=7.61 Hz, 2 H) 3.43-3.51 (m, J=12.30 Hz, 2 H) 3.67 (t, J=11.54 Hz, 2 H) 4.03 (d, J=11.80 Hz, 2 H) 4.30-4.41 (m, 1 H) 4.47 (q, J=7.19 Hz, 2 H) 4.65 (s, 2 H) 4.71 (s, 2 H) 7.17 (d, J=7.53 Hz, 1 H) 7.33-7.53 (m, 6 H) 7.59-7.66 (m, 2 H) 8.05 (dd, J=7.91, 1.63 Hz, 2 H) 8.29 (s, 1 H) 8.39 (s, 1 H).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([NH:10][C:11]3[N:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([N:10]3[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][N:18]=4)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:22]4[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=4)[C:29]3=[O:30])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc2nsnc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1cccc2nsnc12
Yield: 7 %

Procedure:
The procedure of Example 1 was repeated using 2-(2,1,3-benzothiadiazol-4-ylamino)nicotinaldehyde (1.0 eq.; prepared in Synthetic Example 1c)), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.; prepared in Synthetic Example 2) and LDA (1.5 eq.) to obtain 1-(2,1,3-benzothiadiazol-4-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield 7%). The target product was purified through flash column chromatography and recrystallization, mp 191–192° C./DMF.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:14]=3[N:13]=[C:12]2[NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[NH4+].[Cl-].OC1C2N=N[NH:44]C=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[C:1]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]([NH2:44])=[O:21])=[CH:19][C:14]=3[N:13]=[C:12]2[NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CCC[C@@H](n2c(NC(=O)c3cccc(C(F)(F)F)c3)nc3cc(C(=O)O)ccc32)C1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)N1CCC[C@@H](n2c(NC(=O)c3cccc(C(F)(F)F)c3)nc3cc(C(N)=O)ccc32)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 18 (50 mg, 0.1 mmol) and NH4Cl (7 mg, 0.11 mmol) in DMF (4 mL) were added hydroxybenzotriazole (15 mg, 0.11 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.11 mmol) and the mixture was stirred at room temperature for 14 h (completion of reaction monitored by TLC). The mixture was diluted with water and extracted with CH2Cl2 (3×20 mL). The combined organic phase was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (10% MeOH in CH2Cl2) to afford the title compound (Example 19). 1H-NMR (400 MHz, DMSO-d6): ∂ 13.0 (br s, 1H), 8.47 (d, J=7.2 Hz, 2H), 8.06-7.73 (m, 6H), 7.35 (s, 1H), 6.92-6.79 (m, 1H), 6.17-6.13 (m, 1H), 5.75-5.60 (m, 1H), 4.81-4.60 (m, 2H), 4.29-4.10 (m, 1H), 2.84-2.72 (m, 1H), 2.17-1.94 (m, 3H), 1.65 (s, 2H); MS calculated for C24H23F3N5O3 (M+H+) 486.17. found 486.3.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]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.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:22]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:21]=2[C:20]([F:37])([F:38])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(F)cc1C(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: Fc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2)c(C(F)(F)F)c1

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (9.8 mmol) and 2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydrol (123) (19.7 mmol) using the procedure described for compound (3) (2.31 g, 45%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[CH:11].C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][F:26]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][F:26]
Reactant: C#CCCOC1CCCCO1
Reactant: FCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: FCCCCCCCCC#CCCOC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of 3-butyn-1-yl tetrahydropyranyl ether (0.4815 g, 3.05 mmol) (prepared as in Example 1 above) in dry tetrahydrofuran (15 mL) at -78° C. is added n-butyllithium (3.05 mmol, 2.80 mL of 1.09M n-BuLi in hexane). The resulting yellow mixture is stirred for 1 hour at -78° C., warmed to -5° C. for about 5 min and then a solution of 8-bromo-1-fluorooctane (0.7716 g, 3.65 mmol, 1.2 eq.) in HMPA (10 mL) is added dropwise over 45 minutes (Hendry et al., J. Chem. Ecol., 1, 317, 1975). After the addition is completed, the reaction is allowed to warm to room temperature and stirred overnight. After quenching the solution by the dropwise addition of water (about 10 mL), the aqueous solution is extracted with pentane (4×50 ml) and the combined pentane extracts are washed with saturated sodium chloride (50 mL) and dried (MgSO4). The volatiles are removed in vacuo and the crude product is flash chromatographed using hexane/ethyl acetate (9:1, v/v) to give 12-fluoro-3-dodecyn-1-yl tetrahydropyranyl ether (0.526 g, 60%) as a clear colorless oil: Rf=0.60, hexane/ethyl acetate (7:3, v/v); IR (film) ν2850-3000 (alkane CH) and 1H-NMR (CDCl3) δ1.20-1.90 (m, 18H), 2.05-2.20 (m, 2H), 2.30-2.55 (m,2H), 3.30-3.95(m, 4, 4.42 (dt, J=48 Hz, 6 Hz, 2H), 4.60 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[CH2:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:34])[CH:29]=[CH:30][CH:31]=1)[CH3:25]
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: CCc1cccc(N=C=O)c1
Product: CCc1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-ethylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)#[N:2].S(Cl)([Cl:16])=O>>[C:1]([CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)#[N:2]
Reactant: N#CC=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: N#CC=Cc1ccc(C(=O)Cl)cc1

Procedure:
17.3 parts of 4-(2-cyanovinyl) benzoic acid are made into a paste in 80 parts of thionyl chloride and the mixture is refluxed for 15 minutes. Then the surplus thionyl chloride is eliminated under reduced pressure and the 4-(2-cyanovinyl) benzoyl chloride, which is thus obtained, is purified by being recrystallized in xylene. M.P.: 154° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[NH2:16][C:17]1[N:18]=[C:19](S(C)(=O)=O)[S:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[NH2:16][C:17]1[N:18]=[C:19]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[S:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: COC(=O)c1sc(S(C)(=O)=O)nc1N
Agent: Cl
Product: COC(=O)c1sc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N

Procedure:
Analogously to the preparation of Example 49A, 335 mg (1.42 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate hydrochloride and 3190 mg (2.84 mmol) of methyl 4-amino-2-(methylsulfonyl)-1,3-thiazole-5-carboxylate gave 158 mg (29% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.F[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]>>[CH2:1]([NH:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCN
Solvent: CO
Product: CCNc1ccccc1[N+](=O)[O-]
Temperature: 55 °C

Procedure:
To a solution of ethylamine in methanol (2.0 M, 150 mL, 300 mmol) was added 1-fluoro-2-nitrobenzene (8 mL, 75.7 mmol). The reaction mixture was placed in a sealed vessel and heated to 55° C. for 15 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (200 mL), washed with a saturated aqueous solution of sodium bicarbonate (80 mL), and dried over anhydrous sodium sulfate (50 g). After removal of solvent, ethyl-(2-nitro-phenyl)-amine (12.5 g, 75 mmol) was obtained as a brown oil. MS (ES) m/z 167.1.