Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:27]([Si:31]([CH3:41])([CH3:40])[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36](O)[CH2:35][CH2:34]1)([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:12][C@H:36]1[CH2:37][CH2:38][C@@H:33]([O:32][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:40])[CH3:41])[CH2:34][CH2:35]1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1O[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of methyl 5-chloro-2-hydroxybenzoate (2.07 g, 11 mmol) and diisopropyl azodicarboxylate (2.98 g, 14 mmol) (Aldrich) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added a mixture of trans-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol (3.2 g, 14 mmol) and triphenylphosphine (3.64 g, 14 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into water, extracted with ethyl acetate (3×). The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (5% EtOAc;hexanes) to give cis-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzoic acid methyl ester as a yellow oil (Yield 4.0 g, 90%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1)C.Cl>CN(C)C=O.O>[NH:15]1[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]([CH2:12][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14]1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]c2ccccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 131.9 %

Procedure:
NaCN (1.4 g, 29 mmol) was provided in absolute dimethylformamide (10 ml) in argon. At a bath temperature of 35° C. benzaldehyde (3 ml, 29 mmol) dissolved in absolute dimethylformamide (10 ml) was added in drops within 1.5 h and stirred for a further 0.5 h at this temperature. Gramine (10.1 g, 58 mmol) dissolved in absolute dimethylformamide (30 ml) was added in drops to this reaction solution within 2 h at an inside temperature of 70° C. The mixture was stirred a further 1 h at this temperature. For work up the vessel contents were placed in water (150 ml). The aqueous phase was acidified with 2N HCl to separate non-converted gramine as, a water-soluble hydrochloride. The aqueous phase was then extracted with chloroform (3×50 ml). The combined extracts were washed with NaHCO3 solution (50 ml) and dried over Na2SO4. The volatile constituents were then completely removed in a vacuum. The residue (9 g) obtained after distilling off the solvent was purified by column chromatography [silica gel 60 (300 g); cyclohexane/ethyl acetate 6:1 (1500 ml)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11].C(NC(C)C)(C)C>[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: OCC#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a mixture of 4-fluoroiodobenzene (710.0 mg, 3.82 mmol), bistriphenylphosphine palladium chloride (27.0 mg, 0.038 mmol), CuI (3.64 mg, 0.019 mmol) and propargyl alcohol (214.0 mg, 3.82 mmol), was added diisopropylamine (6.1 mL, 1.6 mL/mmol) under nitrogen atmosphere. The reaction mixture was stirred at r.t. for 6 h. After the completion of the reaction as confirmed by TLC, the crude product was extracted with ethylacetate (50 mL). The organic layer was washed with 10% HCl (20 mL), dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (silica gel, 2:8 EtOAc:Pet.Ether) to afford 3-(4-fluoro-phenyl)-prop-2-yn-1-ol (366.0 mg, 64%) as a viscous oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I.C(=O)([O-])O.[Na+].[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[NH:27][C:26]=2B2OC(C)(C)C(C)(C)O2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[NH:27][C:26]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:13])[NH:4][CH2:3][CH2:2][OH:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(NCCO)c1ccccc1I
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C(=O)NCCO)[nH]c2c1
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a suspension of N-(2-hydroxyethyl)-2-iodobenzamide (5.12 g, 17.5 mmol), sodium hydrogen carbonate (5.80 g, 69.8 mmol) and tetrakis(triphenylphosphine)palladium (2.00 g, 1.73 mmol) in 1,2-dimethoxyethane (70 ml) and water (35 ml) was added methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (7.50 g, 19.5 mmol) in five divided portions at 90° C., and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium is sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1-20:1) to give methyl 3-cyclohexyl-2-[2-(2-hydroxyethylcarbamoyl)phenyl]-1H-indole-6-carboxylate (7.40 g, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:31][CH3:32])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]Cl)=[CH:23][CH:22]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:33][NH2:34]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8](/[C:11](/[CH2:31][CH3:32])=[C:12](\[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][NH:34][CH3:33])=[CH:23][CH:22]=3)/[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(OC)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: CN
Solvent: CO
Product: CC/C(=C(\c1ccc(OC)cc1)c1ccc(OCCNC)cc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 1, step E described, 2-chloro-5-(1-(4-(2-chloroethoxy)phenyl)-1-(4-methoxyphenyl)but-1-en-2-yl)benzofuran (440 mg, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give the desired (Z)-product (Z and E isomer can be separated via column chromatography). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.01 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.51 (d, J=8.8 Hz, 2H), 6.45 (s, 1H), 3.92 (t, J=5.2 Hz, 2H), 3.83 (s, 3H), 2.88 (t, J=5.2 Hz, 2H), 2.50 (q, J=7.6 Hz, 2H), 2.45 (s, 3H), 0.92 (t, J=7.6 Hz, 3H); m/z=462[M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][CH:9]([NH2:11])[CH3:10])[CH2:4][CH3:5])[CH3:2].Cl.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](Cl)=[O:24])=[CH:15][CH:14]=1.C(N(CC)CC)C>O>[CH3:10][CH:9]([NH:11][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[CH:14][CH:15]=1)=[O:24])[CH2:8][CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: O=C(Cl)c1ccnc2ccccc12
Reactant: CCN(CC)CCCC(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)CCCC(C)NC(=O)c1ccnc2ccccc12

Procedure:
2-[2'-(5"-nitrofuryl-2")vinyl]quinoline-4-carboxylic acid (α-methyl-δ-diethylaminobutyl)amide was prepared from 1.58 g (0.01 mol.) of diethylamino-4-aminopentane and 3.65 g (0.01 mol.) of 2-[2'-(5"-nitrofuryl-2")vinyl]quinoline-4-carboxylic acid chloride hydrochloride in 50 ml of water in the presence of triethylamine. The process was conducted as described in Example 5.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[N:16]=[N:15][CH:14]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:40])([CH3:41])[CH3:42])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])[N:16]=[N:15][CH:14]=1)[CH3:9]
Reactant: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Trifluoroacetic acid (0.063 mL) was added to a solution of {6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]pyridazin-4-yl}acetic acid ethyl ester (Example 183-(3); 9.0 mg, 0.014 mmol) in dichloromethane (0.36 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (6.5 mg, 87%).
Reaction SMILES: C(OC([NH:11][C:12]1([PH:20]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: CC(C)(C)CC(=O)N[PH](=O)C1(NC(=O)OCc2ccccc2)CCCN(N)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)CC(=O)N[PH](=O)C1(N)CCCN(N)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Palladium black (50.0 mg) was added to a solution of (3S, P (SR))-3-benzyloxycarbonylamino-1-amino(t-butylacetylamino)phosphinyl-2-piperidone (261.7 mg, 0.6166 mmol) in ethanol (15 mL), and the resulting mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:24])=[C:4]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:3]([CH3:24])=[C:4]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cccc(F)c3C)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(F)cccc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.9 %

Procedure:
In THF/methanol (2:1, 60 ml) was dissolved methyl (2-(3-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.21 g, 3.64 mmol). To the resulting solution was added 1N NaOH (20 ml). After stirring at room temperature for 17 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(3-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.10 g, 15%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.C(OC(O)C)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=2)[N:8]=1
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Solvent: CCOCCO
Solvent: O
Product: Cc1ccc2cc(-c3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methyl-6-phenylquinoline was prepared from 6-Bromo-2-methylquinoline by Suzuki coupling with phenylboronic acid and tetrakis(triphenylphosphine) palladium(0) in refluxing 2-ethoxyethanol. To a solution 6-Bromo-2-methylquinoline (8.9 g; 40 mmol) in 2-ethoxyethanol (100 ml) was added tetrakis(triphenylphosphine) palladium (1 g; 0.86 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Phenylboronic acid (5 g; 41 mmol) in ethoxyethanol (50 ml) was then added followed by aqueous sodium carbonate (8.4 g; 79 mmol) in water (50 ml). The reaction mixture was magnetically stirred and refluxed for 16 h. The cooled reaction mixture was extracted with chloroform (3×100 ml), washed with brine, dried over anhydrous magnesium sulphate and solvent concentrated. The residue with the solvent was filtered through a silica gel column and the colourless solution was evaporated. The residue was triturated with petroleum spirit (30-40° C.) and recrystallised from ether to give an off white solid, 5.5 g (63%); Mp 95° C. (DSC, onset). Elemental analysis: Found C, 87.60; H, 5.98; N, 6.32; C16H13N requires C, 87.64; H, 5.98; and N, 6.39%.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]3)=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[CH2:21][CH2:20]3)=[N:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a solution of 1-benzenesulfonyl-3-(1-methyl-4-piperazinyl)-1H-indazole (2.1 g, 5.89 mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.8 ml, 29.45 mmol) at room temperature. The reaction mixture was warmed to reflux for 2 hours, cooled to room temperature, and concentrated. The residue was diluted with ethyl acetate, filtered and purified via flash column chromatography (silica gel, ethyl acetate). Concentration of the product containing fractions gave an oil which solidified on standing. The product was washed well with heptane to give 1.5 g of a white solid, m.p. 112°-114° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2ocnc2c1
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 16.9 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 10.0 mmol), bromobenzene (471 mg, 3.0 mmol), t-BuOK (224 mg, 2.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 99 mg (51%) of 2-phenylbenzoxazole is obtained. Table I, entry 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:21][NH:22][C:23](=[S:24])[N:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: NNC(N)=S
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2n[nH]c(=S)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A mixture of 4,4′-dimethoxybenzil (13.6 g, 50 mmol) and 6.06 g of thiosemicarbazide (66.5 mmol) in 50 mL of glacial acetic acid were stirred at room temperature then refluxed overnight. The cooled reaction mixture was diluted with 150 mL of water and filtered. The solids were washed with water and dried. The crude product was heated with 55 mL of ethyl acetate, cooled, filtered and dried to give 10.1 g of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-thione, mp 228–232° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:10](C(O)=O)=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.N#N.Cl>N1C2C(=CC=CC=2)C=CC=1.O>[OH:1][C:2]1[C:3]2[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1c(-c2cccc([N+](=O)[O-])c2)oc2ncnc(O)c12
Agent: Cl
Agent: N#N
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cc3c(O)ncnc3o2)c1
Reaction time: 2 h

Procedure:
18.4 g of 4-hydroxy-6-(3-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylic acid are placed in ca. 200 ml of quinoline, and heated for 20 min to 200-220° C. under a constant stream of N2. Then, 0.7 g of Cu2O are added. After 2 hours, an additional 0.4 g of Cu2O is added. 1 hour later, another spatula tip of Cu2O is added and the temperature lowered. The next day, the reaction mixture is mixed with 0.5 litres of 2.5 M HCl, diluted with H2O, stirred, left to stand for 8 h and filtered by suction. The residue is washed with conc. ammonia and with a lot of H2O. The basic filtrate is acidified with conc. HCl, filtered by suction and washed with a lot of H2O. The crude product from the two residues is used directly without further working up m.p.: >300° C. IR: 3091 w, 2853w, 1670ss, 1593w, 1527s, 1496w, 1475w, 1373w, 1348s, 1297w, 1202m, 938m, 900m, 783w, 740w, 703w, 622w.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>O>[CH2:9]([O:8][C:6]([CH2:5][NH:4][CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])[CH3:10]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CCNCC(=O)OCC
Temperature: 25 °C

Procedure:
A 4.7M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until the completion of reaction was ascertained by TLC (19 h). After 19 h which it was partitioned with dichloromethane (3×100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.[H-].[Na+]>CN(C)C=O>[O:22]1[CH2:21][CH:20]1[CH2:18][N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: ClCC1CO1
Reactant: O=c1[nH]cc(-c2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(-c2ccccc2)cn1CC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 179 %

Procedure:
22 g of 4-phenyl-1(2H)-isoquinolone, 4.1 g of epichlorohydrin and 4.3 g of sodium hydride were added to 500 ml of dimethylformamide, and the mixture was stirred overnight at room temperature. Thereafter, the solvent was distilled off, and chloroform and water were added to the residue. The mixture was thoroughly shaked, and the chloroform layer was separated and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate to obtain 22 g (80% yield) of 2-(2,3-epoxypropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 148° C. as colorless needles.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9])#[N:2].OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:18]=[C:3]([CH:4]=[CH:5][C:6]=2[O:19][CH3:20])[C:1]([NH2:2])=[O:24])=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C#N)cc1C(=O)Nc1ccc(Cl)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
5-Cyano-N-(4-chlorophenyl)-2-methoxybenzamide (9.8 g) obtained in step D was dissolved in 80 mL of dimethyl sulfoxide, and the solution was cooled in a water bath. A solution prepared from 17.4 mL of a 30% aqueous solution of hydrogen peroxide and 9.5 g of potassium carbonate was added dropwise to the solution. After stirring for 1 hour, the mixture was poured into 800 mL of cold water. The precipitate formed was separated by filtration, washed with cold water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 10.3 g (99%) of 3-N-(4-chlorophenyl)-4-methoxyisophthalamide.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]Br.ClC1C=CC(C2C=CC=CC=2)=CC=1.C(OCCCC1C=CC=CC=1)(=O)CC([O-])=[O:27]>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:27]
Reactant: O=C([O-])CC(=O)OCCCc1ccccc1
Reactant: BrCCc1ccccc1I
Agent: Clc1ccc(-c2ccccc2)cc1
Product: OCCc1ccccc1I

Procedure:
The title compound was synthesized by a sequence similar to that for Example 87 except that 2-(2-iodophenyl)ethyl bromide and commercially available diethyl phenethyl malonate were used in lieu of the 4-chlorobiphenyl and phenylpropyl malonate respectively. The final product was recrystallized from chloroform to give a fluffy, white solid (mp: melts/softens over a broad range starting at 50° C.; the bulk of the sample melts at 189°-190° C.).
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]([S:11][CH3:12])=[NH:10])=[O:7])[CH:5]=[CH:4]N=[CH:2]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21]C(CN)=[CH:17][CH:16]=1>O1CCCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:4]([CH2:5][N:1]2[CH:2]=[N:10][C:9]([S:11][CH3:12])=[N:8][C:6]2=[O:7])=[CH:17][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: CSC(=N)NC(=O)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(SC)nc2=O)cc1
Yield: 53.9 %

Procedure:
A tetrahydrofuran solution (5.0 mL) of methyl 1H-imidazole-1-carbonylcarbamimidothioate (921 mg, 5.00 mmol) synthesized in Reference Synthesis Example 289 was refluxed and a tetrahydrofuran solution (5.0 mL) of 4-methoxybenzylamine (343 mg, 2.50 mmol) was added dropwise to the refluxed solution, followed by refluxing the resultant mixture for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain a compound. The obtained compound was used to obtain the title compound (355 mg, two step yield 48%) by synthesis in a similar manner to Reference Synthesis Example 291.