Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC(=O)C1CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 1.0000 M of potassium tert-butoxide in tetrahydrofuran (26.7 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.53 mL, 0.0280 mol) in tetrahydrofuran (50 mL, 0.6 mol). The reaction was warmed to rt and then cooled at 0° C. again. To the reaction mixture was a solution of methyl 3-oxocyclobutanecarboxylate (3.26 g, 0.0254 mol) in tetrahydrofuran (20 mL, 0.3 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product (3.12 g, 81.12%). LCMS calculated for C8H10NO2(M+H)+: 152.1; Found: 152.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=[O:9])=[CH:4][CH:3]=1.[C:12]([OH:17])(=[O:16])[CH:13]([CH3:15])O.B(F)(F)F.CCOCC>CCOCC.O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]2[O:17][C:12](=[O:16])[CH:13]([CH3:15])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(O)C(=O)O
Reactant: O=CCOc1ccc(Cl)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1OC(COc2ccc(Cl)cc2)OC1=O
Reaction time: 24 h

Procedure:
To a solution of 17.05g (0.07 mole) of 4-chlorophenoxyacetaldehyde in 100 ml of ether was added 9.0g (0.1 mole) of lactic acid dissolved in 50 ml of tetrahydrofuran. To the clear solution was added 15g (0.105 mole) of boron trifluoride etherate. After 24 hours at ambient temperature, the reaction mixture was washed with aqueous sodium bicarbonate, dried, concentrated, and purified by silica chromatography. The first fraction that emerged from the column was 2-(4-chlorophenoxymethyl)-5-methyl-1,3-dioxolan-4-one, the transisomer, having a melting point of 37°-40°. The second fraction was the cis isomer which melted at 53°-55°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10]C(C)(O)C)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[K+].O>C1(C)C=CC=CC=1.CCOCC>[C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=1)[NH2:1])#[CH:10]
Reactant: Cc1ccc(C#CC(C)(C)O)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: C#Cc1ccc(C)c(N)c1
Temperature: 25 °C

Procedure:
A solution of 4-(3-amino-4-methylphenyl)-2-methylbut-3-yn-2-ol (509 mg, 2.7 mmol) in toluene (2 mL) was treated with potassium hydroxide (1.0 g, 18 mmol) at reflux for 20 min. After cooling to rt, water and ether were added, and the layers were partitioned. The organic phase was acidified with 4 N hydrochloric acid in dioxane (700 μL). The volatile materials were removed in vacuo providing a yellow/brown solid. The solid was taken up in ether and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated carefully to avoid loss of the moderately volatile product. Desired 5-ethynyl-2-methylaniline was isolated as an oil in quantitative yield, contaminated with 10% ether by mass. 1H NMR (400 MHz, CDCl3): 6.99 (d, 1H), 6.85 (dd, 1H), 6.81 (d, 1H), 3.61 (br s, 2H), 2.98 (s, 1H), 2.16 (s, 3H); GCMS for C9H9N: 131 (M+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.[N:13]12CCCN=[C:19]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2.O.[C:25](=[O:28])([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.C(Cl)Cl>[O:28]1[C:25]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]([N:10]2[CH2:9][CH2:8][N:7]3[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]3[CH2:11]2)=[N:13]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: OCC1CCC2CNCCN2C1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: OCC1CCC2CN(c3noc4ccccc34)CCN2C1
Temperature: 35 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A stirred solution of alcohol-amine title product of Example 6 (179.4 g, 1.05 mol), 3-chloro-1,2-benzo[d]isoxazole (194.2 g, 1.26 mol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 197.9 g, 1.30 mol) in pyridine (400 ml) was heated at 100° C. for 18 hours. After cooling to 35° C., water (3 liters), methylene chloride (2.5 liters) and, finally, saturated aqueous sodium carbonate (2 liters) were added, and the resulting biphasic mixture was vigorously stirred for 3 hours. The tan solid precipitate which formed during the stirring period was filtered, and the filter cake was washed first with water and then with hexane (1 liter of each) prior to being dried in vacuo. Trituration of the entire sample (216 g) with isopropyl alcohol (630 ml) followed by filtration and in vacuo drying afforded present title compound (154.5 g, 51% yield) as a light tan powder, sufficiently pure for use in the next step without further purification. TLC Rf (methylene chloride/methanol=9:1 in volume; iodoplatinate spray): 0.50.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1.C(N(CC)CC)C.[CH2:31]([Si:38](Cl)([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH2:46]([Si:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: C[C@]12CC[C@H](O)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Reactant: Cl[Si](Cc1ccccc1)(Cc1ccccc1)Cc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H](O[Si](Cc3ccccc3)(Cc3ccccc3)Cc3ccccc3)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of 15.7 g of 3β,7β-dihydroxy-15β,16β-methylene-5-androsten-17-one in 750 ml of methylene chloride is combined with 9 ml of triethylamine and 200 mg of dimethylaminopyridine and cooled to -20° C. Within 30 minutes, 19.4 g of tribenzylsilyl chloride in 10 ml of methylene chloride is added dropwise thereto. The reaction mixture is stirred for one hour at -20° C. and one hour at 0° C., diluted with methylene chloride, and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, and water. After drying over sodium sulfate, the mixture is concentrated under vacuum. Chromatography on silica gel with hexane-acetone yields 27.5 g of 3β-tribenzylsilyloxy-7β-hydroxy-15β,16β-methylene-5-androsten-17-one.
Reaction SMILES: O1CCCCC1[N:7]1[C:11](=[O:12])[CH:10]=[C:9]([CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:17][CH:16]([NH:31][C:32]([C:34]3[NH:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[C:15]2=[O:43])[O:8]1.Cl.O1CCCC1>CO>[OH:12][C:11]1[CH:10]=[C:9]([CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:17][CH:16]([NH:31][C:32]([C:34]3[NH:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[C:15]2=[O:43])[O:8][N:7]=1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2cc(=O)n(C3CCCCO3)o2)C1=O)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2cc(O)no2)C1=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a suspension of (3RS)-1,3-dihydro-1-[[2-(2-tetrahydropyranyl)-3-oxo-2,3-dihydroisoxazol-5-yl ] methyl]-3-(2-indolylcarbonylamino)-5-phenyl-1,4-benzodiazepine-2-one (212.9 mg) in methanol (4 ml) was added 2N hydrochloric acid under stirring at room temperature. Tetrahydrofuran (1 ml) was added thereto in order to gain a clear solution, which was stirred at the same temperature for 30 minutes. The reaction mixture was evaporated to dryness to afford yellow powder, which was washed with ether by stirring overnight, collected by filtration and dried to give (3RS)-1,3-dihydro-1-[(3-hydroxyisoxazol-5-yl)methyl]-3-(2-indolylcarbonylamino)-5-phenyl-1,4-benzodiazepine-2-one (149.1 mg) as yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][O:58][CH:59]1[CH2:64][CH2:63][CH2:62][N:61]([CH2:65][C:66]2[CH:71]=[CH:70][C:69]([CH2:72][NH:73][CH3:74])=[CH:68][CH:67]=2)[CH2:60]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:73]([CH2:72][C:69]3[CH:68]=[CH:67][C:66]([CH2:65][N:61]4[CH2:62][CH2:63][CH2:64][CH:59]([O:58][CH3:57])[CH2:60]4)=[CH:71][CH:70]=3)[CH3:74])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (30 mg, 0.16 mmol), HOBt (23 mg, 0.17 mmol), DIPEA (0.04 mL, 0.22 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (39 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20](Br)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
To a solution of (±)-3-benzyl-2-(1-bromo-2-methyl-propyl)-7-chloro-3H-quinazolin-4-one (a compound of Formula 105, 250 mg, 0.616 mmol) in DMF (3 mL) was added triethylamine (0.130 mL, 0.924 mmol) and imidazole (63.0 mg, 0.924 mmol) followed by tetrabutylammonium iodide (228 mg, 0.616 mmol). The resultant solution was heated to 90 ° C., stirred for 18 h and allowed to cool to room temperature. The reaction mixture was quenched with water (3 mL) and diluted with ether (10 mL). The aqueous layer was extracted with ether (10 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:1 hexanes:ethyl acetate) to provide 38 mg (16%) of the title compound as a yellow solid. MS(ES+) m/e 393.0 [M +H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:25]=2[F:24])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)c1cc(N)n(C[C@H]2CCCO2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(C[C@H]2CCCO2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of the product of Example 1C (7.8 g) and triethylamine (14.6 mL, 105 mmol) in THF (60 mL) at ambient temperature was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.3 mL, 35.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 3 h. The mixture was quenched with saturated, aqueous NaHCO3 (20 mL) and diluted with EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 40% hexanes/EtOAc) gave the title compound (11.0 g, 26.6 mmol). MS (DCI/NH3) m/z 414 (M+H)+.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.[OH-:12].[Na+]>Cl>[O:12]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[O:6][CH2:4][CH2:3][C:2]#[CH:1]
Reactant: C1=COCCC1
Reactant: C#CC(C)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: C#CCCOC1CCCCO1
Reaction time: 2.5 h

Procedure:
3-Butyn-2-ol (1 mol) and dihydropyran (1.1 mol) are mixed and 2 drops of concentrated hydrochloric acid are added. The reaction mixture is allowed to stand 2 to 3 hours at room temperature and a few pellets of sodium hydroxide are added. After filtration, the product is distilled.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCN(C)CC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2 g, 8.23 mmol) and 1-methylpiperidin-4-one (1.86 g, 16.46 mmol) in methanol (20 mL), acetic acid (0.5 g, 8.23 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.622 g, 9.87 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the desired compound (0.9 g, 33%).
Reaction SMILES: [CH3:1]N(C)N=C1CCN(CC2C=CC=CC=2)CC1C.[CH:19]([N-:22][CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20].[Li+:26]>O1CCCC1>[CH3:1][Li:26].[CH:19]([NH:22][CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)[N-]C(C)C
Reactant: CC1CN(Cc2ccccc2)CCC1=NN(C)C
Reactant: [Li+]
Solvent: C1CCOC1
Product: CC(C)NC(C)C
Product: [Li]C

Procedure:
Subsequently, 6.1 g of the 1-benzyl-3-methyl-4-piperidone-N,N-dimethylhydrazone obtained above was dissolved in 30 ml of tetrahydrofuran. The solution were added dropwise to a solution of lithium diisopropylamide in tetrahydrofuran obtained from 23 ml of methyl lithium (1.2M ether solution), 3.8 ml of diisopropylamine and 30 ml of tetrahydrofuran at -8° C. over 15 minutes and the mixture was stirred at the same temperature for 2 hours. Thereafter, the reaction mixture was cooled to -60° C. and, to the reaction mixture was added 2.4 ml of methyl iodide. The temperature was gradually raised to 0° C. in 4 hours. The reaction mixture was poured into a mixed solvent of 120 ml of dichloromethane and 40 ml of water, and the dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1 V/V) to obtain 3.8 g of 1-benzyl-3,5-dimethyl-4-piperidone.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[O:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].Br[CH2:21][C:22]#[N:23]>O1CCCC1>[C:22]([CH2:21][CH2:19][C:12](=[O:11])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])#[N:23]
Reactant: N#CCBr
Reactant: CC(=O)CCCC(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCCC(=O)CCCC(=O)O
Reaction time: 1 h

Procedure:
To a solution of potassium hexamethyldisilazide (66 ml, 60 mmol) in dry tetrahydrofuran (140 ml) at -70° is added slowly 5-oxohexanoic acid (36 ml, 30 mmol). The resulting yellow suspension is stirred at -70° for 1 h and bromoacetonitrile (2.2 ml, 32 mmol) is added slowly. The reaction mixture is stirred at -70° for 1 h and then at room temperature for 0.5 h. The reaction is quenched by addition of 1N aqueous hydrochloric acid (100 ml). The aqueous layer is extracted twice with ether. Combined organic layer is dried, filtered and evaporated to obtain a dark oil which is purified by silica gel chromatography using 9:1 ether/hexane with 1% acetic acid as eluent to give 7-cyano-5-oxoheptanoic acid as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[C:17]([S:19](=[O:24])(=[O:23])[N:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH:32][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([S:19](=[O:24])(=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(Nc2ccc(I)cc2Cl)c1
Reactant: NOC1CCCCO1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(C(=O)NOC2CCCCO2)c(Nc2ccc(I)cc2Cl)c1
Reaction time: 0.5 h

Procedure:
A solution comprised of 2-(2-chloro-4-iodo-phenylamino)-4-dimethylsulfamoyl-benzoic acid, O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (1.25 molar equivalents), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.25 molar equivalents), and diisopropylethylamine (3 molar equivalents) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography; elution with dichloromethane affords the desired product. The product may be recrystallized with an appropriate solvent like methanol if further purification is necessary.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:24])=[C:7]([N:9]([CH2:18][C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:8]=1)[CH3:2].N1C=CC=CC=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:24])=[C:7]([N:9]([CH2:18][C:19]2[CH:23]=[CH:22][N:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:20]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(F)c(N(Cc2cc[nH]n2)c2ccc(C#N)cc2)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(F)c(N(Cc2ccn(-c3ccccc3)n2)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
To a mixture of Intermediate 264.1 (40 mg, 0.125 mmol), 4 A molecular sieves, TEA (70 uL, 0.25 mmol), pyridine (20 mg, 0.25 mmol), phenyl boronic acid (31 mg, 0.25 mmol) in CH2Cl2 was added Cu(OAc)2 (34 mg, 0.19 mmol). The reaction mixture was stirred at rt for 2 h, which was then diluted with EtOAc and washed with 0.5 N HCl, H2O, sat NaHCO3 and brine, dried over (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes, gradient) to afford 20 mg (45%) of Intermediate 264.2.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH2:23][CH2:24]Br.O>CN(C)C=O.C(N(CC)CC)C>[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH2:23][CH2:24][N:9]1[CH2:8][CH2:7][C:6]2([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]2)[CH2:11][CH2:10]1
Reactant: BrCCC1COc2ccccc2O1
Reactant: O=C1COC2(CCNCC2)CN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1COC2(CCN(CCC3COc4ccccc4O3)CC2)CN1

Procedure:
A solution of 1-oxa-4,9-diazaspiro[5.5]undecan-3-one (2.5 g.) and 3.0 g. of 2-(1,4-benzodioxan-2-yl)ethyl bromide in 40 ml of dimethylformamide and 10 ml of triethylamine was heated to 70° C. for 3 hours. The mixture was poured into water, extracted with methylene chloride, and the methylene chloride was extracted with aqueous HCl. The aqueous extract was made basic with ammonium hydroxide and extracted with methylene chloride and the methylene chloride layer was evaporated to give 9-[2-(1,4-benzodioxan-2-yl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, m.p. 139°-140° C. The base was converted to the HCl salt of 9-[2-(1,4-benzodioxan-2-yl)ethyl]-1-oxa-4,9-diazaspiro-[5.5]undecan-3-one by dissolution in methanolic HCl and precipitation with ether, m.p. 225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:27][N:26]=[N:25][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1.IC.[C:39](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[N:27]([CH3:39])[N:26]=[N:25][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2nnnn2C)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 48 h
Yield: 36.1 %

Procedure:
To 2.7 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1H-tetrazol-5-yl)methyl]benzenesulfonamide dissolved in 50 ml of DMF are added, at room temperature, 1.07 g of iodomethane and 1.04 g of potassium carbonate. After 48 hours at room temperature, the medium is poured into water and then extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) toluene/ethyl acetate mixture to give 1 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-tetrazol-5-yl)methyl]benzenesulfonamide (compound 152) 1H NMR δ in ppm (DMSO d6): 3.81 (s, 3H); 3.90 (s, 3H); 3.93 (q, 1H); 4.05 (m, 4H); 4.93 (d, 1H); 5.42 (d, 1H); 6.58 (s, 1H); 7.00 (d, 1H); 7.10-7.46 (unresolved complex, 7H). m.p.=180.8° C. and 0.71 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(2-methyl-2H-tetrazol-5-yl)methyl]benzenesulfonamide (compound 151) 1H NMR δ in ppm (DMSO d6): 3.81 (s, 3H); 3.89 (s, 3H); 4.13 (s, 2H); 4.26 (s, 3H); 4.77 (d, 1H); 5.25 (d, 1H); 6.57 (s, 1H); 6.86 (d, 1H); 7.11-7.47 (unresolved complex, 7H). m.p.=136.3° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[NH:21][CH3:22]>>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(F)ccc1OC2
Reactant: CNc1ccc(Cl)cc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)ccc1OC2)c1ccc(Cl)cc1Cl

Procedure:
Following Example 75, 8-fluoro-4H-thieno[3,2-c]chromene-2-carbonyl chloride and 2,4-dichloro-N-methylaniline gave 164bp. MS: (ESI+)=408.0