Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:20])=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:20][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[O:16][C:15](=[O:19])[CH:14]=1
Reactant: O=c1cc(O)c2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CO
Product: O=c1cc(O)c2ccc(O)cc2o1
Yield: 90 %

Procedure:
A 300 cc autoclave was charged with 7-benzyloxy-4-hydroxycoumarin (3 g, 3.7 mmol), prepared in accordance with Example 5, 5% Pd on carbon (0.18 g) and 85 mL of methanol and the autoclave was purged with N2. The autoclave was pressurized with H2 to a pressure of about 100 psi and maintained at that pressure. The exothermic reaction was carried out at ~50° C. for ~2 hrs. After the completion of hydrogenolysis, the reactor was flushed with N2 and the contents were transferred into a beaker using a long pipet. The mixture containing Pd/C was dried over MgSO4 and filtered through a frit. The filtrate was evaporated to dryness and finally dried overnight at 45° C. The purity of the material as determined by LC was 95%; yield ~90%. The product was characterized by NMR.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:17]1[CH:21]=[C:20]([CH2:22][C:23]([NH2:25])=[S:24])[N:19]=[CH:18]1>>[NH:17]1[CH:21]=[C:20]([CH2:22][C:23]2[S:24][C:2]3[CH2:11][CH2:10][C:9]4[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=4)[C:3]=3[N:25]=2)[N:19]=[CH:18]1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CCC1Br
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: O=[N+]([O-])c1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1CC2

Procedure:
Starting compounds: 2-bromo-7-nitro-1-tetralone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.[CH2:11](O)[CH3:12]>S(=O)(=O)(O)O>[CH2:11]([O:9][C:8](=[O:10])[CH2:7][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[N:4]1)[CH3:12]
Reactant: Cc1cn(CC(=O)O)nn1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cn1cc(C)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.0 g (14.2 mmol) (4-methyl-1H-1,2,3-triazol-1-yl)acetic acid are dissolved in 30 ml ethanol and 10 drops of conc. sulfuric acid are added. The reaction mixture is stirred at RT for 16 h. For working up, the mixture is concentrated in vacuo, ethyl acetate is added to the residue and the suspension is washed with half-concentrated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, the solvent is removed completely on a rotary evaporator and the solid is dried in vacuo.
Reaction SMILES: C(Cl)Cl.B(Cl)(Cl)Cl.[CH:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[S:20][C:21]([CH3:26])=[CH:22][C:23]=3[O:24]C)=[O:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1.O>C(Cl)Cl>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]([C:19]3[S:20][C:21]([CH3:26])=[CH:22][C:23]=3[OH:24])=[O:18])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COc1cc(C)sc1C(=O)c1ccc(C2CC2)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c(C(=O)c2ccc(C3CC3)cc2)s1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
In a nitrogen stream, a boron trichloride methylene chloride solution (1.0 M, 6.4 mL, 6.4 mmol) was added to a solution of (4-cyclopropylphenyl)-(3-methoxy-5-methylthiophen-2-yl)methanone (582 mg, 2.14 mmol) in methylene chloride (12 mL) at −15° C. and the reaction mixture was stirred for one hour. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methanol:methylene chloride (1:100)] to obtain the title compound (497 mg, 90%).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:64]1[CH:69]=[CH:68][N:67]([CH2:70][CH:71]2[CH2:73][CH2:72]2)[C:66](=[O:74])[CH:65]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:71]1([CH2:70][N:67]2[CH:68]=[CH:69][C:64]([N:13]3[CH2:14][CH2:15][CH:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:16])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)=[CH:65][C:66]2=[O:74])[CH2:72][CH2:73]1
Reactant: O=c1cc(Br)ccn1CC1CC1
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C2CCN(c3ccn(CC4CC4)c(=O)c3)CC2)cc1
Temperature: 100 °C

Procedure:
4-Piperidin-4-ylbenzoic acid methyl ester (0.40 g, 1.81 mmol), palladium(II) acetate (0.015 g, 0.069 mmol) sodium tert-butoxide (0.34 g, 3.44 mmol) and BINAP (0.06 g, 0.096 mmol) were added to a stirred solution of intermediate D3 (0.31 g, 1.37 mmol) in toluene (10 ml). The reaction mixture was heated at 100° C. for 16 hours in a sealed tube. After cooling to room temperature the mixture was diluted with EtOAc and then filtered through diatomaceous earth, after which the solvent was evaporated in vacuo. The crude residue was treated with a mixture of DCM/methanol and then filtered off. The filtrate was evaporated to dryness in vacuo to yield crude D37 (0.48 g, 100%) that was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([C:30](=O)[C:31]([F:34])([F:33])[F:32])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.[OH-].[Ca+2].[OH-].CN(C)C=O>COC(C)(C)C>[F:18][C:19]([F:36])([F:37])[C:20]1[CH:21]=[C:22]([C:30]([C:31]([F:34])([F:33])[F:32])=[CH:2][C:1]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: COC(=O)c1ccc(C(C)=O)c2ccccc12
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Agent: [Ca+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(C(=O)C=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)c2ccccc12
Reaction time: 10 h

Procedure:
A mixture of methyl 4-acetyl-1-naphthalenecarboxylate (5.36 g, 23.5 mmol), 1-[3,5-bis(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (7.28 g, 23.5 mmol), calcium hydroxide (1.40 g, 18.9 mmol), N,N-dimethylformamide (16 mL) and tert-butyl methyl ether (32 mL) was boiled with provision of the apparatus comprising a ten-plate Oldershaw column and decanter described in Example 1, Step A for removal of the tert-butyl methyl ether/water azeotrope. As the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Tert-butyl methyl ether was removed by gradually draining the decanter trap until the pot temperature was 85° C. To maintain this temperature, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from beginning heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 10 h. During this time period no additional calcium hydroxide was added to the reaction mixture.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:32][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:13])[CH2:8]2
Reactant: NC1CCCCC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NC1CCCCC1

Procedure:
5-Cyclohexylamino-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and cyclohexylamine. Mass spectrum (ES) MH+=419.
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[C:19]([Cl:21])[C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([Cl:22])[CH:4]=1.[CH3:23][C:24]1[N:29]=[C:28]2[N:30]=[C:31]([CH2:33][CH3:34])[NH:32][C:27]2=[C:26]([CH3:35])[CH:25]=1>>[C:9]([CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:7][C:6]1[C:19]([Cl:21])=[CH:20][C:3]([CH2:2][N:30]2[C:28]3=[N:29][C:24]([CH3:23])=[CH:25][C:26]([CH3:35])=[C:27]3[N:32]=[C:31]2[CH2:33][CH3:34])=[CH:4][C:5]=1[Cl:22])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(Oc1c(Cl)cc(CBr)cc1Cl)c1ccccc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cc(Cl)c(OC(C(=O)OC)c2ccccc2)c(Cl)c1
Yield: 66.4 %

Procedure:
The product of Step E (0.126 g, 0.31 mmol) was used to alkylate 0.050 g (0.29 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine according to the procedure described for Step B of Example 2, which after purification afforded 0.096 g (68%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[NH:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[H-].[Na+]>CN(C)C=O>[C:24]([O:23][C:21]([N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[CH3:1])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 2-methyl-3-nitrobenzyl chloride (1.07 g) in dimethylformamide (30 ml) was added dropwise to a solution of di-t-butyl iminodicarboxylate (1.38 g) and sodium hydride (content, 60%; 0.30 g) in dimethylformamide (30 ml) at 0° C. Following 1-h stirring at room temperature, the temperature of the mixture was raised to 80° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to give 1.49 g of the titled compound (yield, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([N:13]=[C:14]=[S:15])[CH2:6][CH2:5]2.CO[CH:18](OC)[CH2:19][NH2:20]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([N:13]1[CH:18]=[CH:19][NH:20][C:14]1=[S:15])[CH2:6][CH2:5]2
Reactant: Fc1cc2c(cc1F)CC(N=C=S)CC2
Reactant: COC(CN)OC
Solvent: CN(C)C=O
Product: Fc1cc2c(cc1F)CC(n1cc[nH]c1=S)CC2
Temperature: 85 °C
Yield: 38.2 %

Procedure:
A mixture of (-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.49 g, 2.2 mmol), prepared as in Example 10, and 2,2-dimethoxyethylamine (0.23 g, 2.2 mmol) in DMF was heated at 85° C. under argon for 2.5 hours. The solvent was removed under reduced pressure and the residue was dissolved in 2 to 3 mL of ethanol and 20 mL of 4N hydrochloric acid. The solution was heated at 85° C. for approximately 48 hours and cooled giving a crystalline material. The material was isolated by filtration and dried. Purification by column chromatography on silica gel (elution: 3% methanol/methylene chloride) gave (-)-6,7-difluoro-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.225 g, 0.84 mmol), m.p. 200°-205° C. [α]D25 -77.9° , (C=0.6, 2:1 CHCl3 /CH2OH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)/[CH2:5]2.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5]/[C:6](=[CH:14]\[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)/[C:7]2=[O:13])=[CH:3][C:2]=1[N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1
Reactant: COc1cc2c(cc1Br)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCN(C)CC1)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Temperature: 110 °C

Procedure:
To a solution of 152 (120 mg, 0.3009 mmol) and 4-methylpiperazine (60.1 mg, 0.6105 mmol) in toluene was added cesium carbonate (197.2 mg, 0.6015 mmol). The reaction was degassed and purged with nitrogen for 10 min. Pd2(dba)3 (13.7 mg, 0.0150 mmol) and BINAP (28.0 mg, 0.0451 mmol) was added and again degassed and purged with nitrogen for another 10 min. The reaction was heated to 110° C. overnight under sealed conditions. The reaction was diluted with chloroform and filtered through celite Bed. The organic layer was concentrated to get the crude compound 155 which was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound at 25% ethyl acetate in hexane as pale yellow coloured solid (E)-6-methoxy-5-(4-methylpiperazin-1-yl)-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H inden-1-one 155.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34]([OH:36])=O)[C:17]=3[N:18]=[C:19]([CH3:21])[N:20]=2)[CH2:3][CH2:2]1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:23]([CH3:33])=[C:22]([C:34]([NH:37][CH:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[O:36])[C:17]=3[N:18]=[C:19]([CH3:21])[N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c18) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH4+].[Cl-]>C(Cl)Cl.O1CCOCC1>[O:11]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:3][CH:4]=2)[NH:8]1
Reactant: Nc1ccc2c(c1)NC(=O)C2
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1Cc2ccc(NC(=O)c3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-amino-1,3-dihydro-indol-2-one (0.15 g, 1.0 mmol) in 2:1 CH2Cl2-1,4-dioxane mixture (30 ml) is added triethylamine (0.30 g, 3.0 mmol) and benzoyl chloride (0.14 g, 1.0 mmol). The reaction is stirred for 2 hours at room temperature, and then a saturated aqueous solution of NH4Cl is added. The precipitate is collected and washed with water to give crude N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide. To a solution of this benzamide (20 mg, 0.079 mmol) and 1H-pyrrole-2-carbaldehyde (7.6 mg, 0.079 mmol) in ethanol (2 ml) is added 2 drops of piperidine. It is stirred at 80° C. for 4 hours and then cooled to room temperature. The precipitate is collected by vacuum filtration, washed with a small amount of cold ethanol and purified by HPLC(C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give the desired compound as an orange solid: 1H NMR (DMSO-d6) δ 6.34 (s, 1H), 6.80 (s, 1H), 7.33 (s, 1H), 7.39 (d, 1H, J=8.4 Hz), 7.53 (t, 2H, J=7.8 Hz), 7.57 (s, 1H), 7.59 (s, 1H), 7.61 (s, 1H), 7.64 (s, 1H), 7.96 (d, 2H, J=7.8 Hz), 10.29 (s, 1H), 10.94 (s, 1H), 13.23 (s, 1H); LC-MS: 330.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[N-:23]=[C:24]=[O:25].[K+].O>C(O)(=O)C>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:24]([NH2:23])=[O:25])=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [N-]=C=O
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(N)=O)cc2)n1

Procedure:
Dissolved 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (75 mg, 0.26 mmol) in acetic acid (1.0 mL), then added potassium isocyanate (0.01 ml, 0.33 mmol), water (0.1 ml), and stirred at RT for 18 hours. Concentrated and purified by reverse phase HPLC (Gilson, acidic mobile phase), extracted into CH2Cl2 washed with NaHCO3 and H2O. Product began to crash out of CH2Cl2 layer, transfered to round bottom flask, concentrated to yield 1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)urea as off-white solid. MS m/z=337 [M+1]+. Calc'd for C17H16N6O2: 336.35.
Reaction SMILES: [N:1]1([C:7]2[C:8]([CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:24].CO>>[ClH:24].[NH:15]1[CH2:16][CH:13]([C:8]2[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2N2CCCCC2)C1
Agent: Cl
Solvent: CO
Product: c1cnc(N2CCCCC2)c(C2CNC2)n1
Yield: 99 %

Procedure:
A solution of 3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (74) (191 mg, 0.6 mmol) in 4N HCl/MeOH (13 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give (75) (150 mg, 0.59 mmol, yield 99%). ESI-MS (M+1): 219 calc. for C12H18N4 218
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>O>[CH2:12]([N:16]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:13][CH2:14][CH3:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCN
Solvent: O
Product: CCCCN1C(=O)c2ccccc2C1=O
Temperature: 200 °C
Yield: 95 %

Procedure:
A 10-gallon stainless steel reactor equipped with a turbine blade impeller, cooling coil, distilling condenser, azeotropic separator, thermocouple probe and means to maintain a nitrogen atmosphere, was charged with 15.335 kg (103.53 moles) phthalic anhydride. N-butylamine (7.663 kg, 104.57 moles) from a pressure vessel was slowly added to the reactor which was at room temperature, e.g., about 25° C. The resulting exothermic reaction between the amine and phthalic anhydride was continued until the temperature in the reactor rose to 90° C., at which time addition of amine was complete. The reaction mixture was then heated, with removal of water, for a 5 hour period until the temperature of the mixture reached 200° C. The reaction mixture then was maintained at 200° C. for 2 hours. The resulting product was vacuum distilled at a temperature ranging from 150°-155° C. and at a pressure of 20 mm, to afford a liquid which solidified. The melting point of the solid was about 34° to 35° C. and was produced at a 95% yield.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:16]=[C:15]3[N:11]([CH2:12][CH2:13][S:14]3)[CH2:10]2)=[CH:7][CH:8]=1.Cl.Cl>O>[CH:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[N:16]=[C:15]3[N:11]([CH2:12][CH2:13][S:14]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Temperature: 40 °C
Yield: 121.7 %

Procedure:
A mixture containing 11.39 kg of L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (35.9 mol), 61 l of water, 3.77 l sodium hydroxide 19.5 molar aqueous solution (73.5 mol) and 16.61 kg of tetramisole hydrochloride (69 mol) was warmed up to 40° C. The homogeneous mixture was adjusted to pH 4.2 with hydrochloric acid and cooled at 15° C. After 18 hours the precipitate was filtered off, washed and dried under vacuo at 50° C., yielding 17.15 kg of levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield: 95%); αD20 =65.1° (c5, 1N HCl); mp. 127.9°-129.4° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:26])[C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:9]([CH3:17])[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C@H:4]([C:27](=[O:44])[NH:28][C@:29]2([C:34](=[O:43])[NH:35][S:36]([C:39]3([CH3:42])[CH2:41][CH2:40]3)(=[O:38])=[O:37])[CH2:31][C@H:30]2[CH:32]=[CH2:33])[CH2:3]1.[C:45](OC(N[C@@H]([C@H](CC)CC(C)CCC=C)C(N1C[C@H](O)C[C@H]1C(O)=O)=O)=O)(C)(C)C.C(OC(NC([C@H](C)CC(C)CCC=C)C(N1C[C@H](O)C[C@H]1C(O)=O)=O)=O)(C)(C)C>>[CH2:17]([C@H:9]([CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:27](=[O:44])[NH:28][C@:29]1([C:34](=[O:43])[NH:35][S:36]([C:39]2([CH3:42])[CH2:40][CH2:41]2)(=[O:38])=[O:37])[CH2:31][C@H:30]1[CH:32]=[CH2:33])=[O:26])[CH3:45]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Reactant: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C

Procedure:
The same procedure was used as described for the preparation of tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate but (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid was used as starting material instead of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.42 (d, J=4.02 Hz, 1H) 8.83 (d, J=8.53 Hz, 1H) 6.24 (m, 1H) 5.81 (m, 1H) 5.57 (m, 1H) 5.05 (m, 5H) 4.32 (m, 3H) 3.59 (m, 2H) 1.92 (m, 8H) 1.25 (m, 21H) 0.84 (m, 8H) MS: MS m/z 653.4 (M++1)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].[CH3:13]OS(OC)(=O)=O.[Br-].C([O-])(O)=O.[Na+]>O.C(Cl)Cl>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12]
Reactant: O=c1ccoc2ccc(O)cc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2occc(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A mixture of 6-hydroxychromone (4.5 g; 27.7 mmol), CH2Cl2 (150 ml), water (150 ml), dimethylsulphate (4 ml; 41.5 mmol), benzyltributylammmonium bromide (2 g; 5.5 mmol) and NaHCO3 (1.67 g; 41.5 mmol) was stirred for 24 hours at ambient temperature. The organic phase was decanted, washed with water, a dilute solution of ammonium hydroxide and with 1N HCl, it was dried over MgSO4 and evaporated. It was purified by chromatography, eluting with ethyl acetate/petroleum ether (50/50) to give 6-methoxychromone (4 g; 83%) as a brown solid.