Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:10]([OH:22])[C:11]([NH:13][O:14]CC1C=CC=CC=1)=[O:12])=O)(C)(C)C>[Pd].C1COCC1>[NH2:8][C@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:10]([OH:22])[C:11]([NH:13][OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: N[C@H](CC1CCCCC1)C(O)C(=O)NO
Reaction time: 1 h

Procedure:
A solution of Example 106A (0.33 g, 0.82 mmol), and 10% palladium on charcoal (0.13 g) in THF (8 mL) at room temperature was stirred for 16 hours under an atmosphere of hydrogen gas, filtered, and concentrated. The concentrate was dissolved in saturated HCl/dioxane (5 mL), stirred for 1 hour, concentrated, treated with diethyl ether, then concentrated to provide the desired product.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14]1.[Cl-].[NH4+].Cl>O.C1COCC1>[C:1]1([C:7]([CH2:8][CH2:9][CH:10]=[CH2:11])=[C:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCC(=O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=C1C=CC=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 L round bottomed flask was charged with 1-phenyl-4-penten-1-one (49.1 g, 307 mmol), THF (200 mL), and a stir bar, and cooled in an ice bath. Cyclopentadienyl magnesium chloride (330 mL of approximately 1 M solution in THF, 330 mmol) was added dropwise over 1 hour. The pale red solution was stirred overnight while warming to room temperature. The solution was then refluxed for 4.5 hours, during which time the red color intensified. After being stirred overnight at room temperature again, the solution was acidified by first adding 5.5 g of ammonium chloride in 100 mL of water, and then adding 50 mL of 1 M HCl. The product was extracted with pentane, and the pentane extracts were collected, washed with water, and dried over sodium sulfate. Elution through silica with heptane and concentration under vacuum afforded 38.6 g (55% isolated and purified yield) of the product 6-phenyl-6-(3-butenyl)fulvene as a red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:34]=[CH:33][C:32]2[C@H:31]3[N:22]([CH2:23][C@@H:24]4[C@H:29]([CH2:30]3)[N:28]([S:35]([CH2:38][CH2:39][CH2:40]Cl)(=[O:37])=[O:36])[CH2:27][CH2:26][CH2:25]4)[CH2:21][CH2:20][C:19]=2[CH:18]=1.C(N(CC)CC)C.Cl>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:34]=[CH:33][C:32]2[C@H:31]3[N:22]([CH2:23][C@@H:24]4[C@H:29]([CH2:30]3)[N:28]([S:35]([CH2:38][CH2:39][CH2:40][N:12]3[CH2:13][CH2:14][N:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[CH2:10][CH2:11]3)(=[O:37])=[O:36])[CH2:27][CH2:26][CH2:25]4)[CH2:21][CH2:20][C:19]=2[CH:18]=1
Reactant: COc1ccc2c(c1)CCN1C[C@H]3CCCN(S(=O)(=O)CCCCl)[C@H]3C[C@@H]21
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN1C[C@H]3CCCN(S(=O)(=O)CCCN4CCN(c5ccccc5OC)CC4)[C@H]3C[C@@H]21
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1.8 g of 4-(2-methoxyphenyl)piperazine, 1.8 g of (8aR,12aS,13aS)-3-methoxy-12-(3-chloropropane-sulfonyl)-5,6,8a,9,10,11,12,12a,13,13a-decahydro-8H-isoquino[2,1-g][1,6]naphthyridine and 1 ml of triethylamine in 10 ml of DMF was stirred at 90° C. for 16 hours. The temperature was then raised to 120° C. for 8 hours and stirring continued. After cooling, the solution was acidified with 2N hydrochloric acid and then washed with ethyl acetate, the aqueous portion basified with aqueous ammonium hydroxide and extracted further with diethylether. The solvent was then dried over sodium sulfate and evaporated under reduced pressure. The residue was flash chromatographed on silica gel, eluting with ethyl acetate, to give (8aR,12aS,13aS)-3-methoxy-12-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propanesulfonyl}-5,6,8a,9,10,11,12,12a,13,13a-decahydro-8H-isoquino[2,1-g][1,6]naphthyridine, a compound of formula (I).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[K].[CH2:10]=[CH:11][CH3:12]>C1(C)C(C)=CC=CC=1>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:11]([CH3:12])[CH3:10])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)cc1
Reactant: C=CC
Agent: [K]
Solvent: Cc1ccccc1C
Product: Cc1ccc(CC(C)C)cc1
Temperature: 205 °C
Yield: 36.9 %

Procedure:
Charged into autoclave are 212 g of para-xylene, 3.9 g of metallic potassium and 63 g of propylene and the mixture is maintained at a temperature of 205° C. for 3.5 hours under stirring. Conversion of xylene is 34.2%. As a result of the reaction there are obtained 82 g of para-methylisobutylbenzene. The yield is 71.2% by weight (the balance being represented by heavier alkylaromatics). 80 g of paramethyl-isobutylbenzene recovered by rectification from the alkylation products are subjected to a catalytic conversion in a mixture with 150 g of ethylene at a temperature of 485° C., space velocity of 210 hr-1 on a catalyst consisting of the following components, percent by weight: 16.1 of Cr2O3 ; 7.2 WO3 ; 0.2 K2O; 76.5 SiO2. As a result of the conversion there are obtained (g): H2 -0.2; CH4 -0.4; C2H6 -0.9; C3H6 -0.8; C3H8 -0.1; C4H8 -8.4; hydrocarbons C5 -C6 -0.2; toluene-0.9; xylenes-1.1; styrene-0.5; methylstyrene-17.1; high-boiling products-0.4. Conversion of methyl-isobutylbenzene is 31.1%. The yield of methylstyrene is 68.5% by weight as calculated for the converted methyl-isobutylbenzene. The total yield of isobutylene and methylstyrene is 82.5% by weight as calculated for the converted methyl-isobutylbenzene and ethylene and 59.1% by weight for the converted xylene, propylene and ethylene. The methylstyrene recovered by rectification contains 98% of the para-isomer.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[OH:13].[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCOC(C)=O>C1COCC1>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[O:13][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(C)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)ccc1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
To a ice cooled suspension of sodium hydride (60%, 1.3 g, 78.3 mmol) in THF (100 mL) is added a solution of 2-hydroxy-5-methylbenzoic acid methyl ester (10 g, 60 mmol) in THF (20 mL) and it is stirred at 0° C. Then a solution of methanesulfonyl chloride (8.2 g, 72 mmol) in THF (20 mL) is added dropwise. The reaction mixture is stirred at RT for 18 h. Then the reaction mixture is cooled in an ice bath and slowly ice is added to quench the reaction. EtOAc is used to extract. Brine is added to the aqueous phase and re-extracted with EtOAc. The combined organic phase is washed with water, brine, dried over NaSO4 and MgSO4, and concentrated to give the title compound as an oil. It is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[CH3:25][S:26]([O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]3[CH:21]=[C:2]([Cl:1])[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:17][CH:16]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCO)cc1
Solvent: O
Solvent: ClCCl
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol), triethylamnine (293 mg, 2.90 mmol) and methansulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water, and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title compound as white solids.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[C:9]=1[Cl:18])(C)(C)C.FC(F)(F)C(O)=O>>[Cl:18][C:9]1[C:10]([O:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=1[NH2:7]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(Cl)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N)c(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101012.8 %

Procedure:
To 6.01 g (0.021 mmol) of (2-chloro-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester was added 15 mL of trifluoroacetic acid. The reaction was stirred for 3 hours at room temperature, then concentrated in vacuo. The residue was made basic with a saturated solution of sodium bicarbonate, then extracted three times with dichloromethane. The combined dichloromethane layers were dried with magnesium sulfate and concentrated in vacuo to give 3.98 g of the title compound, which was used as is in the following example.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH2:45][CH2:46][OH:47].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:47][CH2:46][CH2:45][C:36]3[CH:37]=[CH:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:35]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: OCCc1ccc2ccccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc3ccccc3c2)cc1
Reaction time: 18 h
Yield: 10.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(naphthalen-2-yl)ethanol (36.8 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.014 mL, 0.085 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2-(naphthalen-2-yl)ethoxy)phenyl)pyridin-3-yl)acetic acid (2.7 mg, 4.54 μmol, 10.64% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.92-7.80 (m, 4H), 7.57-7.46 (m, 3H), 7.21 (d, J=8.4 Hz, 1H), 7.10-6.93 (m, 3H), 5.83 (s, 1H), 4.45-4.26 (m, 2H), 3.45-3.24 (m, 3H), 2.80 (t, J=11.2 Hz, 1H), 2.43 (s, 3H), 2.17 (br. s., 1H), 2.05 (s, 3H), 1.99-1.91 (m, 1H), 1.48 (br. s., 1H), 1.37-1.27 (m, 1H), 1.17 (d, J=13.9 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=11.7 Hz, 1H), 0.84 (s, 3H), 0.60 (s, 3H). LCMS (M+H)=595.5.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][C:3]=2[CH3:12])[CH:17]=1
Reactant: Cc1ncc2ccccc2c1Br
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C#N)c(-c2c(C)ncc3ccccc23)c1
Temperature: 100 °C
Yield: 67.1 %

Procedure:
Into a 40 mL screw-top vial with a stirbar was added 3 (500 mg, 2.25 mmol), 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (776 mg, 2.70 mmol, 1.2 eq) (prepared according to procedure in J. Am. Chem. Soc., 127, 10539, (2005)), and K3PO4 (1.004 g, 4.73 mmol. 2.1 eq) in a 10:1 mixture of 1,4-dioxane:H2O (10 mL/1 mL). To the solution was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (31.9 mg, 2 mol %), the vial capped and the contents heated to 100° C. for 4 hrs. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL). The solid was filtered and the filtrate washed with water (2×30 mL), brine, followed by drying over Na2SO4, and concentrating to a yellow oil. The crude product was purified using Biotage MPLC system (25S column size, 0-30% ethyl acetate/heptane, over 30CV, then 30% isocratic for 10CV) giving white solid as the product (455 mg, 1.51 mmol, 67%). 1H NMR (CDCl3, 400 MHz): δ 9.34 (s, 1H), δ 8.30-8.27 (dd, 1H), δ 8.13 (s, 1H), δ 8.08-8.05 (m, 1H), δ 8.00-7.98 (d, 1H), δ 7.64-7.61 (m, 2H), δ 7.17-7.15 (m, 1H), δ 3.99 (s, 1H), δ 2.51 (s, 3H); LRMS (m/z): 303 (M+H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:23][C:22](=O)[O:21]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:33]=[CH:32][CH:31]=[C:28]([C:29]#[N:30])[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G48) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light brown solid (92 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:34]C(=O)C)[C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:14]=2)=[CH:5][C:4]=1[F:38])#[N:2].[OH-].[Na+].[CH2:41]1COCC1>O>[F:38][C:4]1[CH:5]=[C:6]([CH:9]([OH:34])[C:10]2[N:11]([CH3:41])[CH:12]=[N:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Reaction time: 1 h

Procedure:
Acetic acid (4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl ester (as described in Step C above) (1.26 g, 4.59 mmol) and NaOH (5.5 mL, 5.5 mmol) were dissolved in THF (15 mL) and H2O (25 mL). After 1 h, the reaction was diluted with satd. NaHCO3 solution, extracted with CH2Cl2 (3×), dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:2](P(OC)(=O)OC)=[CH:3][CH:4]=[CH:5][CH:6]=1.C1(C2C=CC=CC=2)C=CC(P(OC)(=O)OC)=CC=1>>[C:1]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COP(=O)(OC)c1ccccc1-c1ccccc1
Agent: COP(=O)(OC)c1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
After electrolysis, the crude electrolyte contains 3.5% of educt, 27.6% of dimethyl biphenyl-2-phosphonate and 32% of dimethyl biphenyl-4-phosphonate (in % by area), and is worked up analogously to Example 4. Distillation gives 1.25 g of biphenyl and 19.44 g (81%) of a mixture of the products. The current efficiency is 46%.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[O:24]C)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[CH:10][C:9]=1[CH3:20])([CH3:3])[CH3:2].B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[CH3:14][C:13]1[CH:12]=[C:11]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH:10]=[C:9]([CH3:20])[C:8]=1[O:7][C:6]1[CH:21]=[CH:22][C:23]([OH:24])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(Oc2c(C)cc(-c3nn[nH]n3)cc2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2nn[nH]n2)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-[4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-2H-tetrazole (26 mg, 0.077 mmol) in 6 ml of chloroform at RT was added boron tribromide (1M in dichloromethane, 0.12 ml, 0.12 mmol). The reaction was stirred for 20 hours at RT, then additional boron tribromide (1M in dichloromethane, 0.3 ml) was added, and the reaction was stirred at RT for 6 hours. Water (10 ml) was added, and the reaction was stirred for 1 hour at RT, then extracted with ethyl acetate (3×15 ml), dried, and concentrated. The white solid residue was triturated with dichloromethane (2×0.3 ml) and dried in vacuo to afford the title product of Example 1. MS (APCI−) Calc.: 324.4, Found: 323.3 (M−1).
Reaction SMILES: [C:1](O)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Pd:13].[N+]([O-])([O-])=O.[Pd+2].[N+]([O-])([O-])=O>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1)([OH:8])=[O:7].[Pd:13]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: O=[N+]([O-])[O-]
Product: O=Cc1ccc(C(=O)O)cc1

Procedure:
For reasons which are not understood, it has been found that hydrogenation of crude terephthalic acid with a catalyst comprising palladium deposited upon and reacted with a porous activated carbonaceous support from an organic solution of palladium nitrate gives a better reduction of 4-carboxybenzaldehyde (4-CBA) with decreasing palladium content of the catalyst in the 0.1 (wt)% to 0.6 (wt)% range. Preferably, the catalyst should have less than 0.3 (wt)% palladium content. This is also an economic advantage because less palladium is needed.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].CI.[C:31](=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH3:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OC)c1
Yield: 76.7 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.329 ml (5.181 mmol) of methyl iodide, there were added 85.5 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 4 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1 and 25/1) to obtain 159 mg (0.3975 mmol, 77%) of 2-methoxy-2'-hydroxy-5,5 '-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.96 (4H, m, 2CH2), 2.35 (2H, t, CH2), 2.36 (2H, t, CH2), 2.63 (2H, t, CH2), 2.66 (2H, t, CH2), 3.66 (6H, s, 2CH3), 3.87 (3H, s, CH3), 6.24 (1H, s, OH), 6.9-7.3 (6H, m, arom-H) MS (FAB): 400 (M+)
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:7]=[C:6]([S:20][CH3:21])[N:5]=1.[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C1COCC1.C(OC)(C)(C)C>[CH3:21][S:20][C:6]1[N:5]=[C:4]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:7]=1
Reactant: CSc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: OCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(OCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 40 °C
Yield: 78 %

Procedure:
Sodium hydride (30 mg, 1.23 mmol) was added to a mixture of 4-chloro-2-methylthio-6-(3-trifluoromethyl-phenyl)-pyrimidine (187 mg, 0.62 mmol) and 1-(2-hydroxyethyl)piperidine (120 μl, 0.92 mmol) in dry THF (6 ml). The mixture was heated at 40° C. for 2 h. After cooling, water and tert-butyl-methyl ether were added. The aqueous layer was extracted twice with tBuOMe. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 95/5) to yield the above titled compound: 190 mg (yield: 78%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[CH:21]=[C:20]([O:22]CC)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>Cl>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[CH2:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: CCOc1cc(NCCSCc2[nH]cnc2C)nc2ccccc12
Agent: Cl
Product: Cc1nc[nH]c1CSCCNC1=Nc2ccccc2C(=O)C1

Procedure:
2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline (1.69 gms) and concentrated HCl (30 mls) were refluxed together for 17 hours. The solution was evaporated to dryness, the residue dissolved in water and basified with potassium carbonate. The precipitated oil was separated by decantation, washed with water and crystallised from isopropanol-water to give 2[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-quinolone. m.p. 121°-124° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:16]O>S(=O)(=O)(O)O>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: CO
Reactant: O=C(O)Cc1ccc(C(=O)C2CC2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C(=O)C2CC2)cc1
Reaction time: 24 h
Yield: 68 %

Procedure:
Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid in methanol (100 mL) containing concentrated sulfuric acid (10 drops). Stir 24 hours. Add triethylamine (2 mL) and concentrate the solution. Dissolve the residue in water/ethyl acetate. Wash the organic phase with saturated sodium hydrogen carbonate solution, dry over anhydrous magnesium sulfate and concentrate. Purify by silica gel chromatography (400 mL silica gel, 20% ethyl acetate/heptane as eluent) to give the title compound (4.6 g, 68%).
Reaction SMILES: C([C:6]1[N:11]2[C:12]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:13]=3[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][CH2:16][C:10]2=[N:9][C:8](=[O:29])[CH:7]=1)(OCC)=O.[I-].[Li+]>N1C=CC=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:12]2[N:11]3[CH:6]=[CH:7][C:8](=[O:29])[N:9]=[C:10]3[CH2:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:13]=2[CH:24]=1
Reactant: CCOC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=c1ccn2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 32, 1-carboethoxy-9-chloro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one was heated in pyridine with lithium iodide to give 9-chloro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.