Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:36]([N:43]1[CH:47]=[CH:46]N=C1)(N1C=CN=C1)=[O:37].[CH:48](N)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:36](=[O:37])[NH:43][CH:47]([CH3:46])[CH3:48])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Reactant: CC(C)N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)NC(C)C)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12
Reaction time: 0.75 h

Procedure:
To a solution of 91 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 2 mL of anh. THF were added 57 mg of NaH at −10° C. The suspension was stirred for 45 min allowing the temperature to reach 0° C. 171 mg of 1,1′-carbonyldiimidazole were added at −10° C. and the mixture stirred for 30 min at rt. 0.178 mL of isopropyl amine was added at 0° C. and the reaction mixture stirred overnight at rt. After quenching with sat. NaHCO3 and extracting with DCM, the organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by prep. TLC using chloroform/MeOH/NEt3 70/30/1 to yield 45 mg of rac-isopropyl-carbamic acid (1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as yellowish oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].[C:9](=[S:11])=[S:10].[CH2:12](Br)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>O.CO>[C:15]1([C:13]2([OH:14])[CH2:12][S:10][C:9](=[S:11])[N:1]2[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: S=C=S
Reactant: NCCC(=O)O
Reactant: O=C(CBr)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCN1C(=S)SCC1(O)c1ccccc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To 250 ml of a methanol solution containing 44 g (0.5 mol) of β-aminopropionic acid and 28 g (0.5 mol) of potassium hydroxide, was added 30 ml (0.5 mol) of carbon disulfide under cooling (at 5° C. or below) and the mixture was stirred for 2 hours. A methanol solution containing 100 g (0.5 mol) of phenacyl bromide was added dropwise under cooling at 5° C. or below and after the completion of the addition the mixture was stirred at room temperature for 2.5 hours. 220 ml of water was added and the alcohol was distilled off under reduced pressure. The residue was acidified with hydrochloric acid (at pH of about 3 or 4) under cooling with ice with stirring and the crystals thus-deposited were collected and washed with water to obtain 116 g of 4-phenyl-3-(2-carboxyethyl)-4-hydroxythiazolidine-2-thione. Melting point of the compound was 132° C. The crystals were dissolved in 500 ml of glacial acetic acid and refluxed by heating for 30 minutes. After cooling, 1 liter of water was added to the mixture and the crystals thus-deposited were collected by filtration to obtain 89 g (yield 65%) of the desired compound. Melting point of the compound was 134° to 136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=C[CH:27]=1.Cl.N1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](Cl)=[O:40]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:40])[C:34]4[CH:27]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: c1ccncc1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80mg, 0.236 mmol) was dissolved in dichloromethane (2.0 mL). Pyridine (2.0 mL) was added followed by 2-pyridinecarbonyl chloride hydrochloride (63 mg, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzamide (84 mg, 0.189 mmol). 1H NMR (CDCl3-d) δ 2.12 (m, 4H), 3.67 (m, 2H), 4.03 (s, 3H), 4.14(m, 2H), 5.00 (m, 1H), 5.37 (s, 1H), 7.04(s, 1H), 7.09 (s, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.50 (m, 1H), 7.92 (m, 1H), 8.33 (s, 1H), 8.70(d, J=8.2 Hz, 1H), 10.62 (s, 1H). LC/MS: MH+=445.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10](=[O:38])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@@H:19]([C:22]([C:35](=[O:37])[NH2:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)C)(C)(C)C.Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl.O1CCOCC1>[CH3:6][NH:7][CH2:9][C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@@H:19]([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:35]([NH2:36])=[O:37])[CH2:18]1)=[O:38]
Reactant: CN(CC(=O)NCCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)NCCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of ({5-[(S)-3-(carbamoyldiphenylmethyl)pyrrolidin-1-yl]pentylcarbamoyl}methyl)methylcarbamic acid tert-butyl ester (23.47 g, 43.7 mmol) in DCM (60 mL) was added 4 N HCl in dioxane (100 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was dissolved in water (100 mL) and this solution was washed with DCM (4×60 mL). The aqueous phase was then made basic with 20% aqueous potassium carbonate and extracted with DCM (4×60 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was then dissolved in water (50 mL) containing TFA (2.5 eq) and purified by HPLC to obtain 17.5 g of the title compound as a bis(trifluoroacetate) salt. MS m/z [M+H+] calc'd for C26H36N4O2 437.3; found 437.5.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH2:13])=[O:12])[CH2:8]1.[CH2:19]=[O:20]>>[OH:20][CH2:19][NH:13][C:11]([N:9]1[CH2:8][CH:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10]1)=[O:12]
Reactant: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: C=O
Product: O=C(NCO)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 65 °C
Reaction time: 60 h
Yield: 30.5 %

Procedure:
A mixture of 0.639 g (0.0024 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide and 6 ml of 37% formaldehyde solution were heated on a water bath at 65° C. for 1 hr, at which time dissolution was complete. The solution was stirred at room temperature for approximately 60 hr. The reaction mixture was divided into two 15 ml centrifuge tubes each extracted three times with ether. The combined extracts were dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness. The residue weighing about 1.5 g was dissolved in ether, washed 5 times with 3 ml of water each time. The ether layer was again dried over magnesium sulfate and evaporated to dryness. The residue was triturated with hexane and ether to give 0.213 g (30.5%) of white powder, m.p. 113°-115° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]S(=O)(=O)[CH:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:11]=2[CH:28]=1)=[O:5])[CH3:2]>C(Cl)(Cl)(Cl)Cl.C(O)(C)(C)C.O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:12]1[C:11]2[CH:28]=[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=[CH:9][C:10]=2[NH:17][C:16](=[O:18])[CH2:15][CH:14]=1
Reactant: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)S(=O)(=O)CCC(=O)N2
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)=CCC(=O)N2
Reaction time: 0.5 h

Procedure:
93.1 g of 8-(ethoxycarbonylamino)-6-(2-chlorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine 5,5-dioxide are dissolved at 80° in a mixture of 1.3 l of carbon tetrachloride, 1.3 l of t-butanol and 33.5 ml of water. After cooling to 35°, the mixture is treated rapidly with 212 g of potassium t-butylate (in three portions) while cooling strongly. The temperature thereby rises to 45°-50°. After the reaction has faded away, the cooling bath is removed and the mixture is stirred for a further 30 minutes. The mixture is poured on to ice and extracted several times with chloroform. The organic solvents are evaporated and the residue is chromatographed on 310 g of silica gel. The desired product is eluted with toluene/chloroform (1:3). After recrystallization from ethyl acetate/petroleum ether, there is obtained ethyl 5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H-1-benzazepine-7-carbamate of melting point 241°.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([NH:6][C:7]1([O:12][CH3:13])[CH2:10][NH:9][C:8]1=[O:11])=[O:5])[CH3:3].C(N(CC)CC)C.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O.C1COCC1>[C:21]1([CH2:27][C:28]([N:6]([C:7]2([O:12][CH3:13])[CH2:10][NH:9][C:8]2=[O:11])[C:4](=[O:5])[C@@H:2]([CH3:3])[NH2:1])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC1(NC(=O)[C@@H](C)N)CNC1=O
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1(N(C(=O)Cc2ccccc2)C(=O)[C@@H](C)N)CNC1=O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
In 2 ml of DMA is dissolved 0.28 g of the 3-(D-alaninamido)-3-methoxy-2-oxoazetidine obtained in Example 16, and 0.30 g of triethylamine is added. To the solution is added a solution of 0.233 g of phenylacetyl chloride in 2 ml of THF under ice-cooling and the mixture is stirred at room temperature for an hour. The mixture is concentrated under reduced pressure and the residue is extracted with ethyl acetate. The extract is purified by silica gel column chromatography to obtain 0.22 g of 3-(N-phenylacetyl-D-alaninamido)-3-methoxy-2-oxoazetidine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1)[CH3:5])[CH3:2].N1C=CC=CC=1>O1CCOCC1>[CH:12]#[C:11][C:10]1[CH:13]=[CH:14][C:7]([OH:6])=[CH:8][CH:9]=1.[CH:1]([O:3][CH2:4][CH3:5])=[CH2:2]
Reactant: C=Cc1ccc(OC(C)OCC)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C#Cc1ccc(O)cc1
Product: C=COCC

Procedure:
To a solution of poly(p-hydroxystyrene) (4.0 g) obtained in above (2) and ethyl vinyl ether (1.5 g) in a mixed solvent (35 ml) of pyridine and 1,4-dioxane, a catalytic amount of p-toluenesulfonic acid was added and reacted with stirring at room temperature for 24 hours. The reaction mixture was poured into H2O (1 liter) and a white solid was precipitated. The polymer was filtered, washed with H2O and dried under reduced pressure to afford 5.0 g of the desired product as a white powder having Mw 10000 (GPC with polystyrene calibration). The polymer was found to have p-(1-ethoxyethoxy)styrene unit and p-hydroxystyrene unit in a molar ratio of ca. 1:1 based on 1HNMR.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[S:12])[NH2:11])=[CH:2]1.Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[S:12][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:11]=2)=[CH:2]1
Reactant: NC(=S)c1c[nH]c2ncccc12
Reactant: O=C(O)C(=O)CBr
Solvent: CCO
Product: O=C(O)c1csc(-c2c[nH]c3ncccc23)n1
Reaction time: 16 h
Yield: 99.3 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine-3-carbothioic acid amide (2.53 g, 14.37 mmol), bromopyruvic acid (2.4 g, 14.37 mmol) in ethanol (50 mL) was refluxed for 2 h. The solution was left at room temperature for 16 h and precipitated solid was filtered to give 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazole-4-carboxylic acid (3.5 g, 100%) as a yellow solid MS 246 (M+1).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:32])[C:19]2[CH:24]=[N:23][CH:22]=[C:21]3[S:25][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:27][C:20]=23)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.CS(C)=O.ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:19]2[C:20]3[C:21]([S:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH:27]=3)=[CH:22][N:23]([CH3:1])[CH:24]=2)=[O:32])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc2c(C(O)c3ccc(Cl)cc3)cncc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)C1C=C2C(=CN(C)C=C2C(=O)c2ccc(Cl)cc2)S1
Temperature: 78 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a stirred solution of oxalyl chloride (0.023 mL, 0.26 mmol) in anhydrous dichloromethane (1 mL) at −78° C. was added DMSO (0.045 mL, 0.63 mmol). After 15 minutes, a solution of Example 237G (0.07 g, 0.21 mmol) in anhydrous 1:4 DMSO/dichloromethane (5 mL) was added dropwise. The reaction was stirred 1 hour at 78° C. then treated with triethylamine (0.15 mL, 1.05 mmol). After 5 minutes, reaction was allowed to warm to room temperature over 1 hour. The reaction was quenched with water (2 mL) and partitioned between EtOAc (50 mL) and sat. aq. NaHCO3 (50 mL). The organic layer was washed with 50% sat. aq. NaHCO3 (2×50 mL), brine (1×50 mL), dried (Na2SO4), filtered, and concentrated. The product was dried in a desiccator to yield the title compound as a white solid (0.07 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][OH:21])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][O:21][S:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=4)(=[O:39])=[O:40])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCC1CN(C2CCN(c3ccc(Cl)cc3)CC2)CCO1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CN(C3CCN(c4ccc(Cl)cc4)CC3)CCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of {4-[1-(4-chlorophenyl)-4-piperidinyl]-2-morpholinyl}methanol obtained from step (vi) (125 mg, 0.384 mmol) in dichloromethane (CH2Cl2) (2 mL) was added triethylamine (0.240 mL, 1.72 mmol) followed by 3-nitrobenzenesulfonyl chloride (127.5 mg, 0.575 mmol) and the reaction mixture kept on stirring at room temperature overnight. The volatiles were removed in vacuo, residue dissolved in chloroform, washed sucessively with saturated aqueous sodium hydrogen carbonate (NaHCO3) and water (H2O). The organic layer was dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography to give the subtitled compound (163 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[N:14]=[C:13]([CH2:15][CH3:16])[C:12]([CH3:17])=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](OCC)=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19].N1CCCCC1.C(O)(=O)C>C(O)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:28](=[O:29])[O:1][C:2]3[C:3]([CH:4]=2)=[CH:6][CH:7]=[C:8]([N:10]2[N:14]=[C:13]([CH2:15][CH3:16])[C:12]([CH3:17])=[N:11]2)[CH:9]=3)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: CCc1nn(-c2ccc(C=O)c(O)c2)nc1C
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCc1nn(-c2ccc3cc(-c4ccc([N+](=O)[O-])cc4)c(=O)oc3c2)nc1C
Yield: 55 %

Procedure:
50.6 g (200 mmols) of the Na salt of 2-hydroxy-4-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-benzaldehyde, 41.8 g (200 mmols) of ethyl 4-nitrophenylacetate and 2 ml of piperidine are refluxed in 250 ml of ethanol for 4 hours. After the mixture has been cooled, it is neutralised with glacial acetic acid, and the residue is washed with ethanol and water, and dried: 46.3 g (61.5%). Recrystallisation from toluene yields 41.4 g (55%) of 3-(4-nitrophenyl)-7-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-coumarin in the form of a pale yellow crystalline powder of melting point 278°-279° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:17]([NH2:21])[CH:18](C)C.[C-]#N.[Na+]>>[O:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:18][C:17]#[N:21])[C:8]1[CH:15]=[CH:14][CH:13]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC(C)CN
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Product: N#CCc1ccccc1Oc1ccccc1

Procedure:
3-Phenoxybenzaldehyde, isobutylamine hydrochloride and sodium cyanide were reacted on a 0.3 molar scale using essentially the same procedure as that described in Example 1. The product, α-(N-isobutylamino)-3-(phenoxybenzeneacetonitrile, was obtained as a golden oil (43.5 g). Proton nuclear magnetic resonance spectrum (d6 -acetone; δ in ppm): 0.9 (6H, d of d); 1.74 (1H, m); 2.52 (2H, d); 5.02 (1H, s); 6.9-7.6 (9H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>ClCCl.C(C1C(C)=CC=C(O)C=1C(C)(C)C)(C)(C)C>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)Cl
Reactant: CO[Si](CCCN)(OC)OC
Agent: Cc1ccc(O)c(C(C)(C)C)c1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)NCCC[Si](OC)(OC)OC
Reaction time: 1 h
Yield: 71.6 %

Procedure:
77.4 g 3-(amino)propyltrimethoxysilane, 43.7 g triethylamine and 25 mg di-tert-butyl-p-cresol were dissolved in 500 ml dichloromethane under argon. 45.1 g methacryloyl chloride was slowly added dropwise within 1 h at −5° C., after which stirring was continued for a further 1 h at 0° C. The precipitated hydrochloride was filtered off and washed again with dichloromethane. The volatile components were removed at 40° C. under reduced pressure on the rotary evaporator. A yellow liquid with separated solid (hydrochloride) remained. The precipitation of the hydrochloride was completed by adding 150 ml diethyl ether, the precipitate was filtered off and the filtrate concentrated to small volume by introducing dry air at 40° C. on the rotary evaporator. The brownish liquid was freed from the remaining volatile components at 4 Pa (4×10−2 mbar) and the crude product (104.2 g) was distilled at a pressure of 0.06 Pa (6×10−4 mbar). The product had a boiling point of 123-125° C. 76.4 g product was obtained as a yellowish clear liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:44]([NH2:48])[CH2:45][CH:46]=[CH2:47].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:48][CH2:44][CH2:45][CH:46]=[CH2:47])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCN
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added but-3-en-1-amine hydrochloride (45 mg) and diisopropylethylamine (97 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used for Step B without purification. retention time: 2.11 min (method A). MS (ESI) (M+H)+ 689.20.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=O)[NH:2]1.[O-:14][C:15]#[N:16].[K+].Cl>C(O)(=O)C.O>[C:11]1(=[O:13])[CH:3]2[N:2]([CH2:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]2)[C:15](=[O:14])[NH:16]1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)N2Cc3ccccc3CC12
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a suspension of 53.1 g (0.30 mole) of 1,2,3.4-tetrahydroisoquinoline-3-carboxylic acid in 1000 ml glacial acetic acid was added quickly a solution of 48.6 g (0.60 mole) of potassium cyanate in 150 ml water. The mixture was stirred and heated on a steam bath at 90°-95° for 90 min and all solids dissolved. 3N hydrochloric acid (2400 ml) was added and the resulting solution was stirred and refluxed for 20 hr. The solution was filtered while hot through a coarse sintered glass funnel to remove mechanical impurities and the filtrate was stored in the refrigerator for 18 hrs to deposit 44 g of the crude product. Recrystallization from 1400 ml alcohol gave 29.9 g (49%) of the cyclized material, m.p. 225°-231°. Further recrystallization from alcohol gave the analytical sample, m.p. 227°-230°.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[CH2:12][C@@H:11]1[CH2:13]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>CN(C)C=O>[O:7]([CH2:13][C@H:11]1[CH2:12][O:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OC[C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.1 %

Procedure:
Add phenol (1.089 g, 11.572 mmol) to a slurry of sodium hydride (0.347 g, 14.465 mmol) in N,N-dimethylformamide (77.1 mL) and stir at room temperature for 40 minutes. Add 3-nitrobenzenesulfonic acid (R)-1-oxiranylmethyl ester (3.00 g, 11.572 mmol) and stir at room temperature for 16 hours (J. Org. Chem., 54, 1296-1304 (1989). Quench with saturated aqueous ammonium chloride (75 mL), dilute with water (75 mL) and extract with diethyl ether (3×300 mL). Combine the organic extracts, wash with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous ammonium chloride (200 mL), dry (magnesium sulfate), filter and purify (silica gel chromatography, eluting with 10:90 to 50:50 ethyl acetate:hexanes) to give the desired compound as a clear liquid (1.410 g, 81.1%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](O)(=[O:10])[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1
Yield: 90 %

Procedure:
Toluene (100 ml), phenol (8.94 g, 95 mmol) and acetic acid (6.05 g, 100 mmol) were added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (2.85 g, 15 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (2.40 g, 25 mmol) at room temperature, stirred and then added with silica gel. After continuing to stir for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, phenyl acetate (11.64 g, 90%) was isolated in distillation.