Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[N:7]([C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:41][C:40]=1[NH2:51])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:53](Cl)(=[O:56])[CH:54]=[CH2:55].O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:52])[N:7]([C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:46][CH2:47][O:48][CH2:49][CH2:50]2)=[CH:41][C:40]=1[NH:51][C:53](=[O:56])[CH:54]=[CH2:55])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:27]([Cl:37])=[C:28]([O:35][CH3:36])[CH:29]=[C:30]([O:33][CH3:34])[C:31]=2[Cl:32])[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:24])[CH3:25])=[O:16])[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3N)ncn2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)Nc1cc(N2CCOCC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(COCC[Si](C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1

Procedure:
To a solution of (2-amino-4-morpholin-4-yl-phenyl)-{6-[3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-ureido]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (80 g, 0.103 mmol) in DCM (5 mL) was added a solution of TEA (10 mg/mL, 1.2 mL, 0.12 mmol) and a solution of acryloyl chloride (10 mg/mL, 1 mL, 0.11 mmol) dropwise at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. Water (5 mL) was added to quench the reaction, and the reaction mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give crude product, which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].[F:27][C:28]([F:35])([F:34])[C@@H:29]([OH:33])[C:30](O)=[O:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:26][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([C:30](=[O:31])[C@H:29]([OH:33])[C:28]([F:35])([F:34])[F:27])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: CN1c2nc(C3=CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: O=C(O)[C@H](O)C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1c2nc(C3=CC4CN(C(=O)[C@H](O)C(F)(F)F)CC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclo-penta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (24-2, 0.79 g, 2.1 mmol, 1.0 equiv), (2S)-3,3,3-trifluoro-2-hydroxypropanoic acid (24-3, 0.30 g, 2.1 mmol, 1.0 equiv), EDC (0.40 g, 2.1 mmol, 1.0 equiv), HOBT (0.32 g, 2.1 mmol, 1.0 equiv) and triethylamine (0.58 mL, 4.2 mmol, 2.0 equiv) were added to anhydrous DMF (13.6 mL) and stirred at RT. After 18 h, the contents were partitioned between ethyl acetate (50 mL) and saturated NaHCO3 (20 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (2×20 mL). The combined organics were washed with H2O (5×20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a dark red oil. Purification by normal-phase chromatography (0-60% EtOAc:Hex) afforded 24-4 as a white solid. MS m/z (M+H): calculated=509.1276; observed=509.1281.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH2:25][C:26]([NH:1][C:2]2[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ncccc1N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ncccc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry CH2Cl2 (20 mL) was added to methyl 3-aminopicolinate (116) (0.421 g, 2.77 mmol). The solution was purged with nitrogen. Triethyl amine (1.16 mL, d=0.726, 8.31 mmol) was added to the solution via syringe. Phenylacetyl chloride (117) (0.805 mL, d=1.169, 6.09 mmol) was added to the solution via syringe. The mixture was stirred overnight at room temperature under nitrogen. The mixture was then stirred at 40° C. for 6 h. More triethyl amine (0.50 mL, 3.6 mmol) was added and, an hour later, more phenylacetyl chloride (0.400 mL, 3.02 mmol) was added. The mixture was stirred an additional hour and allowed to cool to room temperature. The reaction was quenched with water (20 mL), and the aqueous layer removed. The organic layer washed with water (3×15 mL), and dried with MgSO4. Silica gel was added and the slurry rota-evaporated to dryness. The resulting silica was chromatographed on silica (40 g, Davisil, grade 643, mesh 200-450) and eluded with EtOAc-hexanes (2:1, 400 mL). The appropriate fractions were collected (Rf =0.35). The solvent was rota-evaporated to yield the title compound (118) as a yellow oil, which, upon drying, precipitated out as a yellow solid (0.4463 g, 59.6%); Rf =0.35. 1H NMR (CDCl3) δ3.78 (s, 2, benzyllic), 3.97 (s, 3, CH3O--), 7.38 (m, 6, phenyl & H-5), 8.39, (dd, J1 =0.6, J2 =3.9, 1, H-4), 9.10 (dd, J1 =8.4, J2 =8.3, 1, H-6), 10.96 (s, 1, NH); MS (m./z) 270 (M+, 35), 211 (35), 179 (85), 153 (40), 147 (65), 119 (40), 94, (40), 91 (100).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:6]2[N:11]=[C:10]([C:12]([NH:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)=[O:14])[CH:9]=[N:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cncc(N2CCCC2)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCC2)n1

Procedure:
To a suspension of 2.90 g of 6-(1-pyrrolidinyl) pyrazine-2-carboxylic acid in 45 ml of tetrahydrofuran, 2.30 ml of triethylamine and 2.00 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 1.40 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 1 hour at room temperature, and then refluxed for 12 hours, The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from dimethylsulfoxide affording 1.63 g of the desired compound as yellow needles. The obtained crystal was consistent with that of (a)
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])=[C:9]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)[CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].[C:29]([OH:32])(=[O:31])[CH3:30]>C1COCC1.[Zn]>[C:29]([OH:32])(=[O:31])[CH3:30].[NH2:1][C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])=[C:9]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)[CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N=[N+]=[N-])c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(N)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-azido-1-methyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in the previous step, 13.6 mg, 0.0362 mmol) and zinc (9.5 mg, 0.15 mmol) in 1 mL of THF was added acetic acid (0.20 mL). The resulting mixture was stirred at RT for 3 h under Ar. The solid was removed by filtration on Celite and the filtrate was concentrated in vacuo to give a light brown oil. The mixture was triturated with DCM (2×4 mL). The solvent was removed by filtration and the solid was dried in vacuo to give 13.5 mg (91%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.27 (s, 1H), 7.70 (s, 1H), 7.43 (d, 1H, J=7.3 Hz), 7.29 (s, 1H), 5.81 (m, 1H), 2.11-2.37 (m, 4H), 1.91 (s, 3H), 1.59-1.84 (m, 4H), 1.71 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[ClH:7].[F:8][C:9]([F:16])=[C:10]([F:15])[C:11]([F:14])([F:13])[F:12]>C(#N)C>[Cl-:7].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([C:9]([F:16])([F:8])[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: Cl
Reactant: Cn1ccnc1
Reactant: FC(F)=C(F)C(F)(F)F
Solvent: CC#N
Product: C[n+]1ccn(C(F)(F)C(F)C(F)(F)F)c1
Product: [Cl-]
Yield: 97 %

Procedure:
1-Methylimidazole (10 mmol) was dissolved in acetonitrile (20 mL) in a 100 mL high pressure reactor, and HCl (ether solution, 10 mmol) was added slowly. After sealing the reactor and removing air, 1,1,2,3,3,3-hexafluoropropylene (20 mmol) was added and stirring was carried out at room temperature (20° C.) for 2 hours. Pressure inside the reactor, which was initially maintained at room temperature at about 60 psig by 1,1,2,3,3,3-hexafluoropropylene, decreased as the reaction occurred. When the pressure did not decrease any more, reaction product was taken from the reactor and the solvent was removed under reduced pressure. The reaction product 1-methyl-3-(1,1,2,3,3,3-hexafluoropropyl)imidazolium chloride was obtained as white solid. Yield of the obtained ionic liquid was calculated by the following Equation 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:25](Cl)(Cl)=[O:26]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([C:25]([NH:10][CH2:9][C:8]#[CH:5])=[O:26])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C#CCNC(=O)N1CC(c2ccc(F)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(4fluorophenyl)-1-(diphenylmethyl)azetidine (17) (0.38 g) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of 20% phosgene in toluene (1.4 mL). The mixture was stirred for 90 minutes then concentrated in vacuo. To the concentrate was added dichloromethane (5 mL) and to this solution at 0° C. was added, dropwise, with stirring propargylaminc (0.3 mL). The mixture was stirred for 18 hrs at room temperature, diluted with dichworomethane (20 mL), washed (water, brine), dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash column chromatography (50% ethyl acetate hexane) and then crystallised from diisopropyl ether to give 3-(4-fluoropenyl)-N-(2-propynyl)azetidine-1-carboxamide (19) (0.14 g), m.p. 141° C. (diisopropyl ether). Found: C, 67.32; H, 5.65; N, 11.93. C13Hi3FN2O requires C, 67.23; H, 5.64; N, 12.06%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1CN
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-1-Benzyl-4-methyl-3-aminomethylpyrrolidine (1000 mg) was dissolved in methanol (10 mL). While this solution was chilled in an ice water bath, benzaldehyde (0.50 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium cyanoborohydride (184 mg) was added and the mixture was stirred at room temperature for 1.5 hours, followed by addition of a second portion of sodium cyanoborohydride (123 mg) and then further stirring for 5.5 hours. To the resulting mixture, a 2 mol/L aqueous solution of sodium hydroxide (5 mL) was added and the mixture was refluxed for 2 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was extracted with toluene (2×30 mL). The toluene layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give cis-1-benzyl-3-benzylaminomethyl-4-methylpyrrolidine as a pale yellow oil (690 mg).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:3][CH2:2][C:1]([OH:5])=[O:4]
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]cc(CCC(=O)O)c2c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Acrylic acid (16.5 mL, 240.6 mmol) was added to a solution of 5-methyl-1H-indole (10.5 g, 80.2 mmol) in acetic acid (20 mL) and acetic anhydride (20 mL) and the mixture was stirred at room temperature for 1 week. Aqueous sodium hydroxide (4N, 100 mL) was added and the mixture was washed with ethyl acetate. The aqueous fraction was acidified to pH 1 with hydrochloric acid (5M) and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (7 g, 43%). 1H NMR (360MHz, CDCl3) δ7.85 (1H, br s), 7.38 (1H, s), 7.24 (1H, d, J 8.3 Hz), 7.02 (1H, dd, J 8.3, 2.3 Hz), 6.97 (1H, d, J 2.3 Hz), 3.09 (2H, t, J 7.6 Hz), 2.76 (2H, t, J 7.6 Hz), and 2.46 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH2:5][CH3:6].[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:11]([NH:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1)=[O:13])[CH2:5][CH3:6]
Reactant: Cn1ccc(N)n1
Reactant: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 77.5 %

Procedure:
To a solution of 3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoic acid (4.75 g, 14.4 mmol) and 3-amino-1-methyl-1H-pyrazole (2.04 g, 21 mmol) in DMF (25 mL) was added HATU (8.53 g, 22.4 mmol) then DIPEA (7.0 mL, 40 mmol) and the resulting mixture was stirred for 16 hours. The mixture was partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, washed with 1N citric acid (30 mL), water (30 mL), saturated sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL) then dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with 50% ethyl acetate in isohexane, to give the title compound as a colourless oil (4.57 g).
Reaction SMILES: C(O[C:5]1[CH:19]=[CH:18][C:8]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH3:28])[CH:6]=1)(=O)C.Cl.[OH-:30].[Na+]>>[OH:30][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:8]2[CH:18]=[CH:19][CH:5]=[CH:6][C:7]=2[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH3:28])=[O:17])=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: CC(=O)Oc1ccc(NC(=O)c2ccccc2)c(CCC2CCCCN2C)c1
Agent: Cl
Agent: [Na+]
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc(O)cc1

Procedure:
4'-Acetoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide suspended in 1 N sodium hydroxide is stirred until solution takes place. The pH of the aqueous solution is adjusted to 9 with 6 N hydrochloric acid and an oil precipitates which is extracted with ethyl acetate. The product isolated by removal of the ethyl acetate solvent is crystallized from ethanol to provide analytically pure 4-hydroxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-benzanilide, m.p. 178.5°-182.5° C. (corr.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:7])[OH:6].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:6])[OH:7])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCC[PH](=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCC[PH](=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g of 3-aminopropylphosphinic acid in 200 ml of water is cooled to 5°, and the pH adjusted to 9.5 with 2 molar sodium hydroxide solution. To this mixture is added 6.8 g of benzyl chloroformate whilst maintaining the pH and temperature. After the addition is complete the mixture is stirred for 3 hours at pH 9.5 at room temperature and left to stand overnight. The mixture is then extracted with 100 ml of ether and the aqueous layer stirred at 5° with an equal volume of chloroform. The mixture is acidified to pH 2, the chloroform layer separated, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The oily product is triturated with ether to give a white solid, 3-(N-benzyloxycarbonylamino)propylphosphinic acid, m.p. 53°-55°, 31P-NMR: δ =+36.6 ppm (CDCl3).
Reaction SMILES: [C:1]([CH:5]1[CH2:9]SC[C:6]1=O)([O:3][CH3:4])=[O:2].C[O-].[Na+].CI.[CH3:16][S:17]([CH3:19])=[O:18]>O>[C:1]([C:5]1([CH3:9])[CH2:19][S:17](=[O:18])[CH2:16][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: CS(C)=O
Reactant: COC(=O)C1CSCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)C1(C)CCS(=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of 4.65 g (29.0 mmol) of 4-carbomethoxytetrahydro-3-thiophenone in 20 ml of dry DMSO cooled in a cold-water bath at 12° C. under argon was added 1.73 g (32.0 mmol) of sodium methoxide. The mixture was stirred 30 minutes and a solution of 4.97 g (35.0 mmol) of methyl iodide in 1 ml of dry DMSO was added dropwise. The mixture was stirred overnight at room temperature, than diluted with water (60 ml) and extracted with methylene chloride (3×75 ml). The extract was washed with water (50 ml) and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 5.4 g of an oil. The oil was flash chromatographed on silica gel eluting with 3:1 hexane:ether to give 1.49 g (30%) of the product as an oil; NMR (deuteriochloroform): δ 3.76 (S, 3H), 3.70 (m, 1H), 3.50 (dd, 1H), 3.30 (dd, 1H), 2.83 (d, 1H), 1.46 (S, 3H).
Reaction SMILES: [C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][SH:28])([O:3][CH2:4][CH3:5])=[O:2].[CH2:29]=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)C>[N:31]1([CH2:29][S:28][CH2:27][C:7]2[NH:8][C:9]([CH3:26])=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:6]=2[C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: C=O
Reactant: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CSCN2CCCCC2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-2-mercaptomethyl-1,4-dihydropyridine (mg 300), formaldehyde (37%); μl 90) and piperidine (μ87) in ethanol (ml 3) is stirred at 40° C. under nitrogen atmosphere, for 24 hrs. After evaporation at reduced pressure the residue is purified by chromatography (SiO2 9 g eluent diisopropyl ether/ hexane 60/40) to give 2-(N-piperidinylmethylthiomethyl)-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[OH:9])=[O:2].[Br:13]N1C(=O)CCC1=O>>[Br:13][C:7]1[CH:6]=[C:5]([CH2:10][C:11]#[N:12])[CH:4]=[C:3]([CH:1]=[O:2])[C:8]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1ccc(O)c(C=O)c1
Product: N#CCc1cc(Br)c(O)c(C=O)c1
Yield: 80.6 %

Procedure:
Proceeding as in Reference 9, but substituting 3-formyl-4-hydroxyphenylacetonitrile (1 g, 6.2 mmol) and N-bromosuccinimide (1.7 g, 9.3 mmol), gave 3-bromo-5-formyl-4-hydroxyphenylacetonitrile (1.2 g).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][CH2:4][C@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H]1CN
Yield: 100 %

Procedure:
A mixture of (R)-tert-butyl 2-(azidomethyl)azetidine-1-carboxylate (17 g, 80 mmol), 10% Pd/C (2 g) and MeOH (150 mL) was stirred under 45 psi hydrogen for 1 hour. The catalyst was filtered off and the filtrate was concentrated to give (R)-tert-butyl 2-(aminomethyl)azetidine-1-carboxylate (14.9 g, yield 100%). LRMS (M+H+) m/z 187.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([O:31][CH2:32][CH2:33][NH:34][CH3:35])[CH:25]=[C:26]([Cl:30])[C:27]=1[O:28][CH3:29]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:34]([CH3:35])[CH2:33][CH2:32][O:31][C:24]3[CH:25]=[C:26]([Cl:30])[C:27]([O:28][CH3:29])=[C:22]([Cl:21])[CH:23]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCOc1cc(Cl)c(OC)c(Cl)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCOc1cc(Cl)c(OC)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, N-[2-(3,5-dichloro-4-methoxy-phenyloxy)-ethyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([OH:8])[CH3:7].[Br:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(#N)C>O>[Br-:9].[O:12]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][N+:3]1[CH:4]=[CH:5][S:1][C:2]=1[CH:6]([OH:8])[CH3:7]
Reactant: CC(O)c1nccs1
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CC#N
Product: CC(O)c1scc[n+]1CC(=O)c1ccccc1
Product: [Br-]
Reaction time: 4 h
Yield: 42.9 %

Procedure:
1-(2-Thiazolyl)ethanol (0.71 g, 5.49 mmole), 2-bromo-1-phenyl-1-ethanone (1.09 g, 5.47 mmole), and acetonitrile (0.6 mL) were combined and heated with stirring at 130 C. for 4 hr. After cooling, water (20 mL) was added and the mixture was filtered and extracted twice with ether. The aqueous layer was treated with active carbon and filtered to give a clear solution which was concentrated in vacuo to 1.52 g of residue, which was crystallized from acetonitrile/ether and recrystallized twice from methanol/acetonitrile/ether to give 0.77 g of the title compound as prisms, mp 157-158 C; calc'd for C13H14NO2SBr: C 47.55, H 4.33, N 4.26; found: C 47.52, H 4.32, N 4.14.