Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]1([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]1)=[O:15].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:19])([CH2:20][NH:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([F:22])([F:23])[F:24])=[O:15]
Reactant: Nc1c(C(=O)NCC2(C(F)(F)F)CO2)cnn1-c1ccc(F)cc1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: Nc1c(C(=O)NCC(O)(CNCc2ccccc2)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-amino-1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-pyrazole-4-carboxamide (15.3 g) in dioxane (250 ml) was added benzylamine (5.76 ml). The mixture was stirred at room temperature for 16 hours and then for a further 4 hours to ensure the reaction was complete. The orange solution was concentrated in vacuo to give an orange oil (which still contained some solvent). The oil was dried on the vacuum line to give the title compound (20.50 g) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:17])[N:6]([CH2:13][C:14]([OH:16])=[O:15])[C:7]2=[O:12].[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:15][C:14](=[O:16])[CH2:13][N:6]1[C:5](=[O:17])[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7]1=[O:12]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1cccc2c1C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Yield: 41.4 %

Procedure:
To a solution of 2-(4-methoxy-1,3-dioxoisoindolin-2-yl)acetic acid (30 mg, 0.128 mmol) in DCM (3 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (53.6 mg, 0.128 mmol), EDC (73.4 mg, 0.383 mmol) and DMAP (15.58 mg, 0.128 mmol) were added, and the mixture was reacted overnight at room temperature. The solvent was removed, and the resulting crude was purified by flash chromatography on silica gel (DCM:MeOH=98:2) recovering the title compound (33.7 mg, 0.053 mmol, 41% yield). MS/ESI+ 637.34 [MH]+; [αD]=−12.96, c=0.25 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.85 (dd, 1H), 7.54 (d, 1H), 7.46 (dd, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.95 (dd, 1H), 7.08 (t, 1H), 5.99 (dd, 1H), 4.36 (s, 2H), 3.99 (s, 3H), 3.94 (dd, 1H), 3.90 (dd, 1H), 3.38 (dd, 1H), 3.22 (dd, 1H), 1.07-1.36 (m, 1H), 0.50-0.68 (m, 2H), 0.24-0.45 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][NH2:11].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:9][C:5]1[CH:6]=[C:7]([NH:11][CH3:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CN
Reactant: Nc1ncc(F)cc1Br
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: CNc1cc(F)cnc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59.7 %

Procedure:
2-Amino-3-bromo-5-fluoropyridine (1.127 g, 5.90 mmol) and BrettPhos Precatalyst (0.141 g, 0.177 mmol) were mixed under an argon atmosphere. Methylamine (2.0 M in THF, 4.43 ml, 8.85 mmol) and lithium bis(trimethylsilyl)amide (1.0 M in THF, 14.75 ml, 14.75 mmol) were added slowly via syringe, and the reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with a 9:1 mixture of DCM to MeOH. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with acetone in DCM to yield the title compound (0.497 g, 3.52 mmol, 59.7% yield) as a tan solid. M+1: 142.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:26]([Si:30]([CH3:48])([CH3:47])[O:31][CH:32]1[CH2:37][CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH2:33]1)([CH3:29])([CH3:28])[CH3:27].C([O-])(=O)C.[K+].O>CC#N>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:35]3[CH2:36][CH2:37][CH:32]([O:31][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:47])[CH3:48])[CH2:33][CH:34]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: CC1(C)OB(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1H-benzimidazol-2-yl(4-((3-chloro-2-pyrazinyl)oxy)phenyl)methanone (0.50 g, 1.4 mmol), tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexen-1-yl)oxy)silane (0.68 g, 2.0 mmol), potassium acetate (1.0 g, 11.0 mmol), and bis[di-tert-butyl(phenyl)phosphane]dichloropalladium (0.066 g, 0.11 mmol) were taken up in 24 mL of 3:1 MeCN:water. The mixture was purged with nitrogen and heated to 100° C. After 18 hours, the mixture was diluted with 30 mL of water and extracted three times with 25 mL of 9:1 chloroform:isopropanol. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 25% EtOAc/hexanes) afforded 1H-benzimidazol-2-yl(4-((3-(4-((tert-butyl(dimethyl)silyl)oxy)-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[CH3:14]O>>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C(C)=O)cc1
Temperature: -10 °C
Yield: 74 %

Procedure:
4-Acetylbenzoic acid (1.00 g, 6.09 mmol) was suspended in methanol (10 mL). Hydrochloric acid (500 μL) was added. The reaction mixture was refluxed overnight. The resulting suspension was cooled to −10° C., filtered and the solid washed with cold methanol (3×2 mL) to provide methyl 4-acetylbenzoate as a white solid (799 mg, 74%). 1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=8.9 Hz, 2H), 8.01 (d, J=8.9 Hz, 2H), 3.95 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH3:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[S:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[C:17]([CH3:22])=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2c(C)ccc(Cl)c2s1
Reactant: Brc1ccccn1
Product: Cc1ccc(Cl)c2sc(CCC#Cc3ccccn3)nc12
Yield: 7.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (20 mg, 0.13 mmol) and 2-but-3-ynyl-7-chloro-4-methyl-benzo[d]thiazole (30 mg, 0.13 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 2.9 mg (9.3 μmol, 7%) of 7-chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>C1COCC1>[CH:33]([C:32]1[CH:31]=[C:30]([Br:29])[CH:37]=[CH:36][CH:35]=1)=[C:2]([CH3:4])[CH3:3]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=Cc1cccc(Br)c1
Temperature: -23 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of iso-propyltriphenylphosphonium iodide in dry THF (150 mL) under nitrogen at −23° C. was added 2.5 M n-butyl lithium in hexanes (13.4 mL, 33.6 mmol). The resulting solution was stirred 0.5 hours at −23° C., the cooling bath was removed, and the reaction was stirred 0.5 hours at ambient temperature to give a dark red homogeneous solution which was cooled to −23° C. To the solution was added neat 3-bromobenzaldehyde (3.73 mL, 32 mmol). The cooling bath was removed, the reaction was stirred at ambient temperature for 1 hour, quenched by adding excess saturated ammonium chloride, and partitioned between ether and brine. The organic layer was washed with saturated aqueous Na2S2O5, brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification on silica gel with hexanes gave the title compound (5.34 g, 79%) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:26])[NH:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[O:14])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[CH:23]1([CH2:22][NH:21][C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH2:12][O:11][C:9]2[N:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[O:26])[CH2:24][CH2:25]1
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
To a solution of 1.45 g 5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 18 ml THF and 5 ml water were added 2.3 ml aqueous NaOH (2 M) portionwise at 0° C. After 12 h the solution was neutralized with Amberlite IR-120 ion exchange resin, filtered and washed with methanol. The crude product obtained after evaporation of the solvents was used in the subsequent reaction. Yield: 1.50 g.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH:11][C:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:21]O)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>C1(C)C=CC=CC=1>[CH2:1]([Sn:5]1([CH2:6][CH2:7][CH2:8][CH3:9])[O:11][C:12]([C:13](=[O:14])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][O:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCC[Sn]1(CCCC)OCC(C(=O)c2ccccc2)(c2ccccc2)O1
Reaction time: 2 h
Yield: 40.7 %

Procedure:
In a 50 ml dry three-neck-flask 2.1 g (8.3 mmol) of dibutyltin oxide, 2.0 g (8.3 mmol) of 2,3-dihydroxy-1,2-diphenyl-propan-1-one [prepared according to H. J. Hageman, Macromolekulare Chemie, Rapid Communications (1981), 2(8), 517-521] and 20 ml of toluene are heated to reflux under argon flow. A small amount of water is distilled off the clear solution. According to the 1H-NMR-spectrum the conversion is complete after 2 h. The solution is concentrated and the crude product (4.0 g) is recrystallized from 15 ml of cyclohexane. The white crystals (2.3 g) are recrystallized from 10 ml of heptane and 3 ml of cyclohexane. 1.6 g of the title product is obtained as a white powder melting at 140-145° C. The structure is further confirmed by 1H-NMR and 13C-NMR-spectra.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30](=[O:31])[CH2:29][O:28][C:27]3[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccccn3)sc2n1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccccn3)sc2n1
Yield: 57 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-2-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyactic acid in a yield of 57%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:10]O.S1C2C(=[N:16]C=CC=2)C=C1CN>>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:10][NH2:16]
Reactant: OCc1cc2cccnc2s1
Reactant: NCc1cc2ncccc2s1
Product: NCc1cc2cccnc2s1

Procedure:
Intermediate E was prepared from thieno[2,3-b]pyridine-2-ylmethanol (E-2) following similar procedures for synthesizing intermediate C from C-4, as described above. MS (m/z): 165 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:17])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Fc1cc(CBr)ccc1-c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
3′,4′-dichloro-2-fluoro-4-methyl-biphenyl (29 g, 0.114 mol), N-bromosuccinimide (21.2 g, 0.119 mol), benzoyl peroxide (1.4 g, 0.004 mol) were dissolved in acetonitrile (190 ml). The mixture was refluxed for 3 hours, then cooled, mixed with a solution of sodium sulphite (2.2 g) in water (54 ml), stirred for 30 minutes and then allowed to rest to separate the phases. The lower aqueous phase was separated and extracted with dichloromethane (29 ml). The upper phase was concentrated under vacuum, mixed with water (10 ml), and dichloromethane (58 ml) and stirred. The organic phases were separated and put together, washed twice with water (29 ml), and concentrated under vacuum. The compound 3′,4′-dichloro-2-fluoro-4-bromomethyl-biphenyl was isolated as an orange oil (35.7 g, 94% yield).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(NCC)C.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23](Br)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.[ClH:34]>C(OCC)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:34].[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([C:13]#[C:12][CH2:11][N:8]2[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]2)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C#CCN1CCC(C(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCOCC
Solvent: CCNCC
Product: CC(C)(C)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
4-tert-Butyl-1-(prop-2-ynyl)piperidine (prepared as described in Example 3; 37.3 g) and anhydrous diethylamine (800 ml) were added to 3,5-bistrifluoromethylbromobenzene [which may be prepared as described by E. T. McBee et al, J. Amer. Chem. Soc. (1950), 72, 1651; 61.0 g] and dichlorobis(triphenylphosphine)palladium (0.26 g), copper (I) iodide (0.26 g) and triphenylphosphine (0.26 g) were added with stirring, under an inert atmosphere, to the solution thus obtained. The reaction mixture was heated under reflux for 17 hours and then cooled and filtered. The filtrate was evaporated under reduced pressure (water-pump) and the residual oil thus obtained was dissolved in diethyl ether. A slight excess of a saturated solution of hydrogen chloride in anhydrous diethyl ether was then added, with stirring, to the ethereal solution. The resulting suspension was filtered and the solid residue was washed with diethyl ether and dried under vacuum, to give solid 1-(3,5-bistrifluoromethylphenyl)-3-(4-tert-butylpiperidino)prop-1-yne hydrochloride (72 g), which was then partitioned between a small excess of 2 N aqueous sodium hydroxide solution and diethyl ether. The ethereal layer was dried over anhydrous sodium sulphate and evaporated, to give 1-(3,5-bistrifluoromethylphenyl)-3-(4-tert-butylpiperidino)prop-1-yne in the form of an oil, which had the elementary analysis C: 61.7%; H: 5.8%; N: 3.5% (C20H23F6N requires C: 61.4%; H: 5.9%; N: 3.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[ClH:27]>C(#N)C.O1CCOCC1>[ClH:27].[NH:15]1[CH2:14][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=3)[N:12]=2)[CH2:16]1
Reactant: Cc1ccc(-c2noc(C3CN(C(=O)OC(C)(C)C)C3)n2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc(-c2noc(C3CNC3)n2)cc1[N+](=O)[O-]

Procedure:
To stirring suspension of tert-butyl 3-(3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (28) (1 g, 2.78 mmol) in acetonitrile (2 mL) was added 4 N HCl in dioxane (5 mL). The reaction was stirred at room temperature for 1 hour. The solvent was concentrated and the crude product was dried under high vacuum to yield 5-(azetidin-3-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole hydrochloride (29). MS m/z 261.4 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-].[Na+].NC(N)=N.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:19]([O:26][C:27]1[C:28]([Cl:37])=[C:29]([N:34]=[C:35]=[O:36])[C:30]([Cl:33])=[CH:31][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:26][C:27]1[C:28]([Cl:37])=[C:29]([NH:34][C:35]([NH:4][C:3](=[NH:5])[NH2:2])=[O:36])[C:30]([Cl:33])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N=C(N)N
Reactant: O=C=Nc1c(Cl)ccc(OCc2ccccc2)c1Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N=C(N)NC(=O)Nc1c(Cl)ccc(OCc2ccccc2)c1Cl

Procedure:
Guanidine hydrochloride (7.8 g) is suspended in acetone (150 ml). A 50% aqueous sodium hydroxide solution (6.53 g) is added to the guanidine suspension. The mixture is stirred for one and one-half hours, after which 15 g anhydrous sodium sulfate are added and the reaction mixture stirred vigorously for an additional hour. The isocyanate obtained in Step 5 above (8.0 g) is dissolved and suspended in 50 ml acetone. This suspension is added to the reaction mixture over a period of one hour fifteen minutes. The reaction mixture is stirred overnight, filtered, and the filtrate evaporated in vacuo to a green oil. The green oil is triturated in 200 ml of H2O containing 5 drops of a 50% aqueous sodium hydroxide solution. The resulting suspension is stirred for three hours, filtered, and the solid washed with water and dried. After air drying overnight, there is obtained 12.9 g of a white powder which is dried in vacuo at 30°-35° C. for four hours, giving 9.47 g of white powder. The powder is dissolved in 50 ml of methanol. The methanol solution is filtered and the filtrate acidified with methanol/HCl. The acidified solution is evaporated in vacuo (30°-35° C.) to yield the hydrochloride salt as a light-colored oil, which is utilized without further treatment.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.CS[C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>>[CH3:15][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:7]=1)=[CH:19][N+:20]([O-:22])=[O:21])[CH3:14]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1cccc(OCCCN)c1
Product: CN(C)Cc1cccc(OCCCNC(=C[N+](=O)[O-])NCCCOc2cccc(CN(C)C)c2)c1
Yield: 61 %

Procedure:
3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (1.09 g) and 1,1-bis(methylthio)-2-nitroethene (413 mg) were heated as an intimate mixture on a steam bath for 90 minutes. The resulting oil was washed with ether and purified by column chromatography on silica using 2% 0.88 ammonia in methanol to give the title compound as a pale yellow oil (0.74 g). Rf 0.30, silica/2% 0.88 ammonia in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][CH2:11][O:12][C:13]([C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14].[Cl-].[NH4+]>O1CCCC1>[CH2:11]([O:12][C:13](=[O:14])[C@H:15]([NH:16][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:18][C:17]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:20])[CH3:10]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C

Procedure:
Under a nitrogen atmosphere, 4-chlorophenyl magnesium bromide (64.1 mL, 1 M tetrahydrofuran solution) was added dropwise at −40° C. into a tetrahydrofuran (300 mL) solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester (15 g) obtained in Example 4. After stirring for 1 hour at the same temperature, saturated ammonium chloride aqueous solution was added, and extraction with ethyl acetate was conducted. After washing the organic layer with brine, the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane→heptane/ethyl acetate), and the title compound (17.38 g) was obtained. The physical property values are as follows.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[CH3:28][O:29][CH2:30][C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH:6]=[CH:5][S:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (150 mg, 0.33 mmol) and methoxyacetic acid (31 mg, 0.34 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White solid (66 mg, 48%), MS (ISP) m/z=417.1 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[CH2:10]1[O:14][CH:11]1[CH2:12][CH3:13].[OH-].[Na+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]([OH:14])[CH2:12][CH3:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(O)cc1
Reactant: CCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(OCC(O)CC)cc1
Yield: 76.2 %

Procedure:
In a closed vessel 12.2g (0.1 mol) of p-ethylphenol, 7.2 g (0.1 mol) of 1,2-butylene oxide and 0.8 ml of a 50% aqueous solution of sodium hydroxide were heated at 140° to 145° C for 4 hours in the same way as in Example 1. The reaction mixture obtained was treated in the same way as in Example 1 to afford 14.8 g of 1-(p-ethylphenoxy)-butan-2-ol (compound No. 52) in a yield of 76.3%.