Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[Cl:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33](=[O:36])[CH2:34]Br.C(=O)([O-])O.[K+]>CC(C)=O>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:17][CH:18]([C:19]3[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=3)[O:28][C:33]([OH:36])([C:32]3[CH:37]=[CH:38][CH:39]=[C:30]([Cl:29])[CH:31]=3)[CH2:34]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC(O)(c3cccc(Cl)c3)C2)cc1

Procedure:
from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine (pair of diasteromers A) with 3-chloro-phenacyl bromide and potassium hydrogen carbonate in acetone.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23](Cl)[N:22]=3)[C@@H:15]([CH3:40])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:43](B(O)O)([CH3:45])=[CH2:44]>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23]([C:43]([CH3:45])=[CH2:44])[N:22]=3)[C@@H:15]([CH3:40])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(C)B(O)O
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@@H]2C)n1
Temperature: 25 °C

Procedure:
A mixture of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl)}-4-methyl-1,3-oxazinan-2-one (Example 4, 16 mg, 0.026 mmol), isopropenyl boronic acid (22 mg, 0.26 mmol) and 1,1-bis(ditbutylphosphino)ferrocene palladium dichloride (2 mg, 0.0026 mmol) in aqueous potassium carbonate/THF (1 mL, 1 mL) was heated at reflux for 2.5 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-15% EtOAc in hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one. LCMS=625.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.85 (br s, 3H), 7.51 (m, 2H), 7.05 (m, 1H), 6.71 (d, J=11.9 Hz, 1H), 5.98 (br s, 1H), 5.35 (br s, 1H), 5.31 (br m, 1H), 4.32 (br m, 1H), 3.79 (s, 3H), 3.22 (br m, 1H), 2.28 (s, 3H), 1.89 (m, 2H), 1.27 (br m, 9H).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[F:11].C([Li])CCC.[CH2:17]([Sn:19](Br)([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>CCOCC>[F:11][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[Sn:19]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:17][CH3:18]
Reactant: CC[Sn](Br)(CC)CC
Reactant: Fc1oc2ccccc2c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC[Sn](CC)(CC)c1c(F)oc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis-(tetrafluoroborate (“Selectfluor®”) (13.11 g, 37.01 mmol) was added to a mixture of benzofuran-2-carboxylic acid (5.0 g, 30.84 mmol) and sodium bicarbonate (6.22 g, 74.0 mmol) stirred in 70 mL of pentane/water (2:5 by volume) at room temperature. After 1 hour at the pentane layer containing 2-fluorobenzofuran was separated from the mixture, and the water layer was extracted with pentane. The combined organic extract was dried through MgSO4, and then the solvent was evaporated to give 2-fluorobenzofuran (1.70 g) as a yellow oil. The 2-fluorobenzofuran (850 mg, 6.24 mmol) and potassium acetate (1.29 g, 13.11 mL) were stirred in of chloroform (3.5 mL) at room temperature, and a solution of bromine (2.05 g, 12.80 mmol) in of chloroform (1 mL), and added slowly into the reaction mixture. After stirring for 1 h at room temperature, the mixture was washed with 5% NaHSO3 then brine, dried through MgSO4, and the solvent was evaporated to give trans-2-fluoro-3-hydro-2,3-dibromo-benzofuran as a light-brown oil (1.70 g). trans-2-Fluoro-3-hydro-2,3-dibromo-benzofuran (1.66 g, 5.62 mmol) was dissolved in anhydrous ethanol (11 mL), and sodium ethoxide (420 mg, 6.18 mmol) was added. The mixture was stirred at RT for 5 min then brine was added, and the solution was extracted with pentane. The pentane layer was washed with water and with brine, dried through MgSO4, and then the solvent was evaporated to give 3-bromo-2-fluorobenzofuran as a light-brown oil (950 mg). Under nitrogen, 3-bromo-2-fluorobenzofuran (465 mg, 2.16 mmol) was dissolved in anhydrous ether (5 mL), and stirred at −78° C. under nitrogen. n-Butyllithium (1.6M, 1.50 mL, 2.38 mmol) was added followed after 5 min by triethylstannyl bromide (680 mg, 2.38 mmol). The mixture was then allowed to warm to room temperature and stirring was continued for a further 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound as a brown oil (370 mg), which was used directly without further purification for the next step.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH:8]([C:10](OC)=O)[C:7](=O)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].Cl.C([O-])(=O)C.[Na+].[C:22]1([NH:28]N)C=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(O)C>[CH2:1]([N:5]1[CH2:9][C:8]2[C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:7]=2[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: NNc1ccccc1
Reactant: CCCCN1CC(C(=O)OC)C(=O)C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCN1Cc2c([nH]c3ccccc23)C1=O

Procedure:
1-n-Butyl-4-carbomethoxy-2,3-dioxopyrrolidine, 107 g., [Southwick and Owellen, J. Org. Chem. 25(1960)1133] is heated to boiling in a mixture of 600 ml. of a twenty percent aqueous hydrochloric acid solution and about 100 ml. of ninty-five percent ethanol. Solids dissolved in about ten minutes to give a yellow solution. After one hour of heating, the flask is cooled to about room temperature. Sodium acetate is then added to neutralize the reaction mixture to a pH of 4-5. In addition about 500 ml. of water is added during the neutralization to insure that most materials will remain in solution. Phenylhydrazine, 54 g., is then washed into the stirred mixture with methanol, 20 ml. The phenyl hydrazone starts to separate immediately, and is collected after 10 minutes of cooling and stirring. The material is dissolved in 200 ml. of acetic acid at 65° and treated with 100 ml. of concentrated hydrochloric acid. A strong exotherm takes the temperature up to about 110° which causes vigorous refluxing. Filtration of the cooled slurry yields 78 g. of the title compound, m.p. 215°-218° sinters at 210°. Dilution of the filtrate with water gives additional product, 7 g., m.p. after recrystallization from methanol: 216°-218°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[O:6]
Reactant: O=Cc1ccccc1CCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccccc1C=O)OCC

Procedure:
47.9 g (0.31 mol) of 2-chloromethylbenzaldehyde were heated to 160° C. together with 51.5 g (0.31 mol) of triethyl phosphite. Ethyl chloride distilled off during the course of this. The product was purified by fractional distillation.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:6]=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[Cl-].[Na+]>O1CCCC1>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@@H:7]1[CH2:8][C@H:4]([NH2:1])[CH:5]=[CH:6]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](N=[N+]=[N-])C1
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](N)C1
Temperature: 25 °C
Yield: 106.9 %

Procedure:
934 mg (3.90 mmol) of ((1R,4S)-4-azido-cyclopent-2-enyloxy)-tert-butyl-dimethyl-silane (35) were dissolved in 16 mL of tetrahydrofuran and 1.13 g (4.29 mmol) of triphenylphosphine were added. After the addition of 2 mL of water, the reaction mixture was stirred at room temperature, until the reaction was complete. Sat. sodium chloride solution was added, the layers separated and the organic layer was evaporated in vacuo. The crude product was purified by silica gel chromatography to yield 890 mg of the title compound (36). Rt=1.02 min (Method C). Detected mass: 214.3 (M+H+).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])[CH:11]=1)(=[O:24])[CH3:23]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1

Procedure:
reaction of androst-4-ene-3,17-dione with acetic anhydride to produce 3-acetoxyandrost-3,5-diene-17-one,
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=[O:37])[CH:26]([N:34]=[C:35]=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C.O.[OH-].[Li+]>ClCCl>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:35]([NH:34][C@H:26]([C:25]([OH:37])=[O:24])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:36])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccccc1)N=C=O
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Cn2ccc3cc(NC(=O)N[C@@H](Cc4ccccc4)C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A mixture of 1-(4-tert-butylbenzyl)-1H-indol-5-amine (0.233 g, 0.84 mmol) and 2-isocyanato-3-phenyl-propionic acid ethyl ester (0.10 g, 0.8 mmol) in 10 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in 2:1:1 THF/MeOH/Water (10 mL). Lithium hydroxide monohydrate (0.30 g, 7.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents were removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid. The solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption and concentrated to give the title compound as an off-white solid (0.15 g, 40%): MS (ESI) m/z 470; MS (ESI) m/z 468.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:8][C:5]1[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1nc(Cl)cnc1N
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccccc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 2-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C@H:10]([O:35][CH2:36][C@H:37]([OH:41])[CH2:38][O:39][CH3:40])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:43][CH2:44][CH2:45][O:46][CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=1[O:55][CH3:56]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:43][CH2:44][CH2:45][O:46][CH2:47][C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=3[O:55][CH3:56])=[CH:30][CH:29]=2)[C@H:10]([O:35][CH2:36][C@H:37]([OH:41])[CH2:38][O:39][CH3:40])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(O)cc1
Reactant: COc1ccc(F)cc1COCCCCl
Product: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2cc(F)ccc2OC)cc1

Procedure:
In analogy to the procedure described in example 1(e) the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-(4-hydroxy-phenyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was treated with the 2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene [example 11(α)] to yield the (3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 764 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:15].[H-].[Na+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CN(C)C=O>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:15]
Reactant: O=C1Nc2ccccc2C12CCCCC2
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2cccc(F)c2)c2ccccc2C12CCCCC2
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
Spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (1.0 g, 5 mmol) was dissolved in dimethylformamide (10 mL) and NaH (0.21 g, 5.5 mmol) was added and the mixture was stirred 30 minutes then 3-fluorobenzyl bromide (1.04 g, 5.5 mmol) was added. The mixture was stirred 2 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-20% ethyl acetate in hexane) to afford 0.8 g of 1′-(3-fluorobenzyl)spiro[cyclohexane-1,3′-indol]-2′(1′H)-one.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]1=[O:16].[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[NH:7][C:6]3=[O:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A mixture of 1-(3-bromopropyl)-2,4(1H,3H)-quinazolinedione (2.12 g), 1-diphenylmethylpiperazine (2.07 g), anhydrous potassium carbonate (3.1 g) and N,N-dimethylformamide (14 ml) was stirred for 2.5 hours at 100° C. After the reaction mixture was cooled to ambient temperature, to the mixture was added water and then stirred to give precipitates. The precipitates were collected by filtration and they were dissolved in hot chloroform containing a little quantity of methanol. The resultant solution was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crystal, which was washed enough with methanol and dried to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4(1H,3H)-quinazolinedione (1.6 g). This crystal was dissolved in 2N hydrochloric acid solution and then the solution was concentrated in vacuo to give a white crystal, which was washed with methanol, dissolved in water with warming and the solution was evaporated in vacuo. The resultant crystal was washed enough with methanol, to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4(1H,3H)-quinazolinedione.2HCl.0.7H2O (1.6 g).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH:2]12.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([Mg]Br)[CH:12]=[CH:13][CH:14]=1.C(OCC)(=O)C.Cl>O1CCCC1.[Cu]Cl>[OH:1][CH:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[CH:14]=1
Reactant: C1CC2OC2C1
Reactant: COc1cccc([Mg]Br)c1
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C2CCCC2O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of a mixture of 1,2-epoxycyclopentane (7.0 g) and copper(I) chloride (260 mg) in tetrahydrofuran (70 ml) was added 3-methoxyphenylmagnesium bromide (53.5 m mol) in tetrahydrofuran (60 ml) at -78° C. under N2. The mixture was stirred for 1 hour at 0° C. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid and then the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give 1-hydroxy-2-(3-methoxyphenyl)-cyclopentane (13 g).
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Br:16])=[N:7][NH:6][C:5]1=[O:17])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(#N)C>[CH2:1]([N:4]1[C:5](=[O:17])[N:6]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[N:7]=[C:8]1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Br:16])[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2ccc(Cl)cc2Br)n[nH]c1=O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCn1c(-c2ccc(Cl)cc2Br)nn(CC(=O)OC)c1=O

Procedure:
Of the compound from Example 164A, 9.78 g (about 23.32 mmol, purity 75%) were dissolved in 75 ml of acetonitrile. Then 3.55 g (25.65 mmol) of potassium carbonate and 2.46 ml (27.98 mmol) of methyl chloroacetate were added. The mixture was stirred under reflux for 5 hours. After cooling, it was filtered with suction. The filtrate was concentrated a little on a rotary evaporator and then diluted with 30 ml of ethyl acetate and washed with 30 ml each of 1M hydrochloric acid and of saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 2:1). This gave 7.1 g (79% of theory) of the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-[6′-methyl-4′-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 261) (0.570 g, 1.085 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.28 g, 55%). MS (ISP) 468.2 [(M+H)+]; mp 250° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[CH2:8][OH:9].[CH:26](OB(O)O)=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([C:11]1[N:10]([CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2=[N:6][C:7]([CH2:8][OH:9])=[C:2]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=[C:4]2[N:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: OB(O)OC=Cc1ccccc1
Reactant: CCCCc1nc2cc(Br)c(CO)nc2n1CC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCc1nc2cc(C=Cc3ccccc3)c(CO)nc2n1CC(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
5.08 g(0.0127 mole) of the compound obtained in step 7 of Example 1 was dissolved in 12 ml of dimethylformamide(DMF) and to the resulting solution were added 5.64 g(0.0381 mole) of styrylboric acid, 0.29 g(0.00127 mole) of palladium acetate, 0.67 g(0.00254 mole) of triphenylphosphine and 13 ml(0.0889 mole) of triethylamine. The resultant was stirred for 1 hour at 120° C., cooled, extracted with 300 ml of ethyl acetate and washed with 300 ml of water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified with column chromatography (methanol/methylene chloride=1:9) to obtain 4.58 g of the title compound(yield 85%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][C:6]2[N:7]=[N:8][N:4]([CH2:3][CH2:2][NH:1][S:44]([CH3:43])(=[O:46])=[O:45])[N:5]=2)=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCc2nnn(CCNS(C)(=O)=O)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 29.7 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.33 g), triethylamine (65 mg) and methanesulphonyl chloride (71 mg) in dichloromethane (15 ml) was heated under reflux for 2 hours and then evaporated. The residue was purified by chromatography on silica (6 g) using dichloromethane plus from 0 to 1% by volume of methanol as eluant. Appropriate fractions were combined and evaporated. The residual solid was recrystallized from ethyl acetate and dried to give the title compound (111 mg) as a hydrate, m.p. 245°-247° C. Found: C,46.23; H,5.02; N,13.82. C23H28Cl2N6O7S.H2O requires: C,46.26; H,5.19; N,14.08%.