Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1)[OH:19].O>CN(C)C=O>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:18]([OH:19])[CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:21][CH:22]=1)[CH3:27]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCc1ccc(C(O)CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
Into a solution of 2.9 g (0.0234 mol) of 4-hydroxy benzaldehyde dissolved in 100 mL dimethylformamide, 8.94 g (0.063 mol) of potassium carbonate in 20 mL dimethylformamide was added in 10 min. followed by slow addition of 5 g (0.0213 mol) of 2-bromo-1-(5-ethyl-pyridin-2-yl)-ethanol dissolved in 1000 mL dimethylformamide. Reaction mixture was stirred for 1 hr. at 25 to 30° C., heated at 80 to 90° C. for 14 hr. and poured into excess of water at 25° C. Product was extracted with diethyl ether. Subsequent concentration in vacuo of the organic layer and purification as described earlier yielded 3.97 g (67.5%) of the desired product. m.p. 80° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)=O.[F:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>C(O)C>[F:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][N:30]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C@@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)=[CH:5][CH:4]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C=O)cc2)C1
Reactant: NNC(=O)c1ccc(F)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C=NNC(=O)c3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
(S)-tert-Butyl 2-(4-formylphenyl)morpholine-4-carboxylate (120 mg, 0.41 mmol) and 4-fluorobenzohydrazide (64 mg, 0.41 mmol) were dissolved in ethanol (2 ml) and stirred for 2 h at room temperature. The solvent was evaporated and ether/ethanol (3:1) was added to precipitate the product. The crystals were filtered off to yield a white solid (101 mg, 58%). MS (ISP): 327.1 ([M-tBu+H]+).
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3]P(=O)(OC)OC.[OH-].[K+].[O:13]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14]1>O.C(O)C>[O:13]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:3][C:2](=[O:1])[CH3:10])[CH2:14]1
Reactant: COP(=O)(CC(C)=O)OC
Reactant: O=CC1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)C=CC1CCOC1

Procedure:
Dimethyl (2-oxopropyl)phosphonate (32.06 g, 193 mmol) is added to a chilled (ice-bath) solution of potassium hydroxide (10.83 g, 193 mmol) in water (30 ml) and ethanol (170 ml) and the mixture is stirred. Tetrahydrofuran-3-carboxaldehyde (50% wt. % solution in water, 25 ml, 138 mmol) is added dropwise and the reaction mixture is stirred at 5° C. for 10 minutes. The cooling bath is removed and the mixture is stirred at room temperature for 7 hours. Most of the solvent is removed in vacuo, water (100 ml) and diethyl ether (200 ml) are added, the mixture is poured into a separating funnel and the organic phase collected. The aqueous phase is extracted three times with diethyl ether, and the organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane to give 4-(tetrahydrofuran-3-yl)-3-buten-2-one as a pale yellow liquid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:16][CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[N:18]1([CH2:24][CH2:25][C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1(N=C=NC2CCCCC2)CCCCC1>>[N:18]1([CH2:24][CH2:25][C:26]([O:1][C:2]2[C:7]3[C:8]4[CH2:16][CH2:15][S:14][C:9]=4[C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Cc1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
Following a procedure similar to that described in Example 8 hereinabove, 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c] [1]benzopyran is reacted with methyl magnesium bromide to give 1,2-dihydro-9-hydroxy-4,4,7-trimethyl-4H-thieno-[2,3-c] [1]benzopyran. The benzopyran is then reacted with β-piperidinopropionic acid and dicyclohexylcarbodiimide to yield the desired ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:25]=1[CH3:26].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: Cc1c(I)cnn1-c1ccccn1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccn4)c3C)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (30.0 mg, 0.12 mmol), 2-(4-iodo-5-methyl-1H-pyrazol-1-yl)pyridine (51.0 mg, 0.18 mmol), copper (I) iodide (6.8 mg, 0.036 mmol), and tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.012 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.033 ml, 0.24 mmol). The mixture was sparged with argon for 3 minutes and heated to 60° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-[(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)ethynyl]pyrazolo[1,5-a]pyridine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[C:19]([C:29](=[O:43])[NH:30][CH2:31][C:32]3[C:33](=[O:42])[NH:34][C:35]([CH3:41])=[CH:36][C:37]=3[CH2:38][CH2:39][CH3:40])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:41][C:35]1[NH:34][C:33](=[O:42])[C:32]([CH2:31][NH:30][C:29]([C:19]2[C:20]3[CH:21]=[CH:22][N:23]([CH:26]([CH3:27])[CH3:28])[C:24]=3[CH:25]=[C:17]([O:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)=[O:43])=[C:37]([CH2:38][CH2:39][CH3:40])[CH:36]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)cc2c1ccn2C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN2CCNCC2)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a stirred solution of 4-(2-{1-isopropyl-4-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-carbamoyl]-1H-indol-6-yloxy}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (280 mg, 0.472 mmol; prepared following the procedure of Example xx) in dichloromethane (15 mL) was added TFA (1.5 mL) at room temperature and then stirred for 3 h at room temperature. Reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and washed the resulting aqueous layer with diethyl ether (2×15 mL). The aqueous layer was basified with (pH˜8) with saturated aqueous NaHCO3 solution and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine solution (2×25 mL) and concentrated. Purification by preparative HPLC afforded 1-isopropyl-6-(2-piperazin-1-yl-ethoxy)-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (48 mg, 20%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (t, 3H), 1.42 (d, 6H, J=6.8 Hz), 1.57 (m, 2H), 2.14 (s, 3H), 2.45-2.2 (m, 4H), 2.68 (t, 2H), 2.75 (t, 4H), 4.15-4.19 (m, 2H), 4.35 (d, 2H), 4.78-4.72 (m, 1H), 5.91 (s, 1H), 6.73 (d, 1H), 7.03 (s, 1H), 7.24 (s, 1H), 7.42 (d, 1H), 8.12 (t, 1H), 11.58 (bs, 1H). LCMS (ES+): m/z=494.57[M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=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.[CH3:42][S:43][CH2:44][C:45](O)=[O:46]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:45](=[O:46])[CH2:44][S:43][CH3:42])=[N:6][CH:7]=1
Reactant: CSCC(=O)O
Reactant: Nc1ccc(Br)cn1
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: CSCC(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.7 %

Procedure:
(1 g, 5.78 mmol) 5-Bromopyridin-2-amine was dissolved in DMF (40 ml) and HATU (2.64 g, 6.94 mmol, 1.2 equiv.) was added. After 15 minutes at room temperature Hunig's Base (6.0 ml, 34.7 mmol, 6 equiv.) and 2-(methylthio)acetic acid (736 mg, 6.94 mmol, 1.2 equiv.) were added. The mixture was stirred for 72 hours at room temperature. The reaction mixture was evaporated and extracted three times with saturated Na2CO3 solution and three times with ethyl acetate. The organic layers were extracted three times with 1N HCl solution and evaporated to dryness. The crude product was suspended in pentane, filtered and the solid evaporated to dryness. The desired N-(5-bromo-pyridin-2-yl)-2-methylsulfanyl-acetamide (312 mg, 21% yield) was obtained as a yellow solid, MS: m/e=258.9/260.8 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1N
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: CC#N
Product: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 62.2 %

Procedure:
A mixture of 3-propanoyl-4-chloro-8-(2-methylthioethoxy)quinoline (0.60 g, 1.9 mmol) and o-toluidine (0.25 g, 2.3 mmol) in acetonitrile was heated to 55° C. and stirred for 3.5 h. The solvent was evaporated and the residue was partitioned between methylene chloride and a 10% sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; CH2Cl2 :EtOAc 60:40) gave 0.45 g (61%) of the title compound.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:9][CH2:10]Cl)[CH2:6][CH2:7]Cl.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>>[CH2:4]([N:5]([CH2:9][CH2:10][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:6][CH2:7][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:3][O:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCO
Reactant: ClCCN(CCCl)CCCl
Agent: Cl
Product: COCCOCCN(CCOCCOC)CCOCCOC

Procedure:
To the mixture thus obtained, 51.6 g of tris(2-chloroethyl)amine hydrochloride (0.215 mole) are added. The mixture is then heated at the reflux temperature of the 2-methoxyethanol (125° C.) for 12 hours and then the solvent is removed by distillation under reduced pressure. The excess sodium 2-methoxyethanolate is neutralized by the addition of 11.6 cm3 aqueous HCl (10 N). The sodium chloride is filtered off and the solution is distilled.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13]C)[CH:8]=2)[N:3]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([Cl:27])[CH:19]=1)([OH:17])=[O:16]>>[Cl:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[N:3]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Reactant: COc1ccc2nc(Cl)cc(F)c2c1
Product: O=C(O)c1ccc(-c2cc(F)c3cc(O)ccc3n2)c(Cl)c1

Procedure:
Followed Scheme 2, B conditions starting with 2-chloro-4-fluoro-6-methoxyquinoline (Intermediate 7) and 4-carboxy-2-chlorophenylboronic acid. 1H NMR (MeOD 400 MHz): δ 8.20 (d, J=1.2 Hz, 1H), 8.10 (dd, J=8.0, 1.6 Hz, 1H), 8.02 (d, J=9.2, 1.2 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.52-7.45 (m, 2H), 7.47 (d, J=2.4 Hz, 1H). MS (ESI): m/z 317.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:25][C:26]([F:34])([F:33])[CH2:27]OS(C)(=O)=O)(=O)=O>CN(C=O)C.O>[F:33][C:26]1([F:34])[CH2:27][O:13][C:11]2=[CH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]2[CH2:25]1
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: CS(=O)(=O)OCC(F)(F)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cc3n(n2)CC(F)(F)CO3)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (4 g, 22.47 mmol) in DMF (30 mL) was added K2CO3 (12.4 g, 89.88 mmol) and 2,2-difluoropropane-1,3-diyl dimethanesulfonate (9 g, 33.7 mmol) at room temperature and then stirred for 16 h at 60° C. The progress of the reaction was monitored by TLC. Thereafter, the reaction mixture was diluted with cold water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulphate and concentrated to get the crude product. Purification by column chromatography over silica gel (eluent 5-10% ethyl acetate in petrol ether) yielded 6,6-difluoro-2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (3.2 g, 56%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:26]=4)[CH2:21][CH2:20]3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 58 was prepared from 1-(4-chloro phenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propan amide according to the procedures described in Scheme 10: ESMS m/e: 482.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].[C:12](O)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O>[C:12]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(=O)O
Reactant: CCCCCC(CO)CCC
Solvent: O
Product: CCCCCC(=O)OCC(CCC)CCCCC
Yield: 98 %

Procedure:
158.3 g 2-propylheptanol (1 mol) and 116.2 g caproic acid (1 mol) were heated for 4 h to 220° C. on a water separator together with 0.27 g Fascat® 2001 (Sn oxalate: 0.1% by weight, based on the composition as a whole). After the separation of water had stopped, the crude product was distilled in an oil pump vacuum through a 250 mm Vigreux column (T=111-126° C.). 251.4 g of a colorless oil were obtained: OHV=<1, AV=<0.1.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[C:2]=[O:3].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][OH:27].N1C=CC=CC=1>O1CCCC1>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][O:27][C:2]([NH:1][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:3]
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(N=C=O)c1)OC(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1NC(=O)OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.9 %

Procedure:
14 mg of Ethyl 3-(3-isocyanato-4-methoxyphenyl)-2-isopropoxypropanoate was dissolved in 1 ml of tetrahydrofuran, and 10 mg of 2,4-dichlorobenzyl alcohol and 5 μl of pyridine were added thereto, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of nitrogen, and the residue was dissolved in 0.6 ml of ethanol, and 0.12 ml of 5N sodium hydroxide was added and stirred at room temperature for 1 hour. The reaction solution was diluted with 1 ml of water and 0.14 ml of 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was collected, and the solvent was removed under a stream of nitrogen. The residue was purified by HPLC using a reverse-phase column and a water-acetonitrile-trifluoroacetic acid elution solvent, to give 3.1 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:7][CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:14][CH2:13]2)[OH:9])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>C(OCC)C>[C:26]([O:9][CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:14][CH2:13]2)[CH2:7][O:6][CH2:5][CH2:4][N:2]([CH3:1])[CH3:3])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCOCC(O)c1ccc2c(c1)CCC2OC1CCCCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.5 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethanol, 8 ml of acetic anhydride and 0.64 ml of pyridine was stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/methanol=10/1) to obtain 1.9 g of oily 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethane (compound No. 295).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH:19]1[CH2:21][NH:20]1)#[N:18].C(N(CC)CC)C>C(OCC)C>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:20]2[CH2:21][CH:19]2[C:17]#[N:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: N#CC1CN1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: N#CC1CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
The same compound is also obtained when a solution of 1.15 g. diphenylacetyl chloride in 5 ml. anhydrous diethyl ether is added dropwise at 0° C. to a solution of 0.35 g. 2-cyanoaziridine and 0.6 g. triethylamine in 15 ml. diethyl ether and the reaction mixture then stirred for 1 hour at 0° C. and for 2 hours at ambient temperature. The precipitated hydrochloride is filtered off with suction (0.7 g.) and the ethereal filtrate is concentrated to a volume of about 10 ml. and shaken out twice with 5 ml. amounts of water. After evaporation of the ethereal phase, there is obtained 1.13 g. of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][N:4]=[C:3]1[C:14]([NH2:17])([CH3:16])[CH3:15].[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C(O)(=O)C>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[C:3]([C:14]([N:17]2[C:21](=[O:22])[C:20]3[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]2=[O:23])([CH3:15])[CH3:16])=[N:4][N:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)N
Solvent: CC(=O)O
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)N1C(=O)c2ccccc2C1=O
Yield: 81.3 %

Procedure:
2-[4-Methyl-5-(2-chlorophenyl)-1,2,4-triazol-3-yl]propan-2-amine (1.19 g) and phthalic anhydride (704 mg) were diluted with acetic acid (5 ml), followed by stirring under heating and refluxing for 22 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting residue was diluted with ethyl acetate (50 ml) and washed with a saturated aqueous sodium bicarbonate solution (30 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting solid was recrystallized from ethanol-water to obtain 1.47 g of 2-{1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-1-methylethyl}-1H-isoindole-1,3-(2H)-dione (white solid).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].Cl[C:21]([O:23][CH2:24][Cl:25])=[O:22]>N1C=CC=CC=1>[CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][N:8]([C:21]([O:23][CH2:24][Cl:25])=[O:22])[C:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)OCCl
Reactant: CCCCN1N=C(c2cc(Cl)cc(Cl)c2)NCC1=O
Solvent: c1ccncc1
Product: CCCCN1N=C(c2cc(Cl)cc(Cl)c2)N(C(=O)OCCl)CC1=O
Yield: 51 %

Procedure:
1-(n-Butyl)-3-(3,5-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one was acylated with chloromethyl chloroformate in a similar manner to the reaction described to make compound 14 except that pyridine was used as a base. The product 1-(n-butyl)-3-(3,5-dichlorophenyl)-4-(chloromethyloxycarbonyl)-4,5-dihydro-1,2,4-triazin-6-one was isolated in 51% yield.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=1[Br:25])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CCO.CCOC(C)=O.[Pt]>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Br:25])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1C(COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (9 g, 21.63 mmol) in EtOH (50 ml) and EtOAc (50 ml) was added Pt/C (1.5 g), attached with a balloon of H2. More Pt/C (500 mg) was added after 3 h. Then the reaction mixture was stirred at rt for another 2 h. The reaction mixture was filtered over celite, concentrated down to give product (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) and went to next step without purification. To a solution of (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) (21.63 mmol) in HOAc/THF (80 ml, 1:1) was added KSCN at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Then Br2 was added slowly, reacted at 0° C. The reaction was quenched by adding sat. NaHSO3, extracted by EtOAc, dried over MgSO4, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 65H (2.3 g, 24% over 2 steps).