Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[N:2](=[CH:4][C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[OH:3].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:19]1[O:20][C:5]([CH:4]=[N:2][OH:3])([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[O:17][CH2:18]1
Reactant: O=C(C=NO)CC(=O)OCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(CC1(C=NO)OCCO1)OCc1ccccc1
Yield: 94 %

Procedure:
In a two liter flask fitted with a Dean Stark water separator and a condenser were placed 186.5 g. (0.85 mole) of benzyl oximino-acetoacetate [1.1], 62 g. (1 mole) of ethylene glycol, 800 ml. of benzene (reagent grade) and 2 g. (10.5 mmole) of p-toluenesulfonic acid monohydrate. The reaction mixture was boiled at reflux until 15 ml. of water was removed (3 hours). The benzene solution was washed once with saturated sodium bicarbonate solution and once with brine. After drying over anhyrous sodium sulfate, the benzene solution was evaporated, leaving 212 g. (94% yield) of benzyl oximino-acetoacetate ethylene ketal [2.1] as a light yellow oil ! Its NMR spectrum was consistent with the assigned structure. Generally, the product was used as such in subsequent reactions but one of the isomers can be crystallized2 from toluene-petroleum either (b.p. 30°-60° C.); m.p. 52° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1([CH3:35])[CH2:34][O:33][CH2:32]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][C:31]2([CH3:35])[CH2:34][O:33][CH2:32]2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CC1(CBr)COC1
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC2(C)COC2)c1OC
Temperature: 80 °C
Yield: 19.5 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile (7 mL) was added potassium carbonate (111 mg, 0.80 mmol) and 3-(bromomethyl)-3-methyloxetane (132 mg, 0.80 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 19%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:26](=[O:28])=[O:27]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])=[C:13]([CH:14]=1)[C:26]([OH:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of 1-benzyloxy-2,3,4-trifluorobenzene (19.89 g, 83.6 mmol) in anhydrous THF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 42.6 mL, 85.2 mmol) at −78° C. under nitrogen atmosphere. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice (20.0 g, 454.5 mmol). The mixture was stirred overnight at ambient temperature. The reaction was quenched with 10% aqueous HCl (300 mL). The mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 5% sodium hydroxide (300 mL). The aqueous layer was acidized to pH 1 with concentrated HCl (aq.) and extracted with ethyl acetate (200 mL×3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (white solid, 19.33 g, 82% yield). 1H NMR (400 MHz, CDCl3): δ 14.01 (s, 1H), 7.42 (6H, m), 5.16 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1>C(O)C>[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 231.7 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate obtained in Example (125a) (4.31 g, 10.8 mmol) was dissolved in ethanol (25 mL). A 4 N hydrochloric acid/dioxane solution (25 mL, 100 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain 4.22 g of the title compound as a pale pink amorphous solid (quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)=[C:34]=[O:35]>ClCCl>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])[CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[O:44][CH3:45]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.20 mmol) (Aldrich), followed by the addition of 5-isocyanato-1,2,3-trimethoxy-benzene (33 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3,4,5-trimethoxy-phenyl)-amide (Yield 35 mg, 44.9%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (4.04 g, 33.08 mmol), in acetonitrile (50 ml) was added K2CO3 (10.1 g), followed by N-(2-chloroethyl)morpholine hydrochloride (6.16 g). The reaction mixture was heated to reflux overnight, additional N-(2-chloroethyl)morpholine hydrochloride (0.6 g) and K2CO3 (0.5 g) were added and the mixture was refluxed for another 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was treated with DARCO®, filtered and the solvent was stripped. The residue was partitioned between saturated NaHCO3 (150 ml) and ethyl acetate (300 ml). The layers were separated and the organic layer was washed with 1N NaOH, dried over MgSO4, filtered and stripped to afford, as an amber oil, 6.41 g of 4-[2-(4-morpholinyl)ethoxy]benzaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:6](=[O:8])[CH:7]=1.C[N:23]1CCOCC1.ClC(OC)=O>C(Cl)Cl>[OH:1][C:2]1[CH2:3][C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:23])=[O:21])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:6](=[O:8])[CH:7]=1
Reactant: O=C(O)CCCCC1(c2ccccc2)CC(O)=CC(=O)O1
Reactant: CN1CCOCC1
Agent: COC(=O)Cl
Solvent: ClCCl
Product: NC(=O)CCCCC1(c2ccccc2)CC(O)=CC(=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 50 mL reaction flask was added 1.2 mmol of 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid (±), 2.4 mmol of 4-methylmorpholine, and 10 mL of CH2Cl2. The reaction was cooled to 0° C. and 2.4 mmol of methyl chloroformate in 3 mL of CH2Cl2 was added. The reaction was stirred at 0° C. for 2 hours. Ammonia was bubbled into the vessel for 10-15 minutes and the reaction allowed to stir for minutes at 0° C. The reaction was poured into ethyl acetate and 1N HCl, the aqueous layer extracted with ethyl acetate, dried over MgSO4, and concentrated. The crude solid was triturated using CH2Cl2 to afford 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid amide (±) as a solid (m.p. 173-174° C.). 1H NMR (DMSO-d6) δ 0.8-1.0 (m, 1 H), 1.1-1.3 (m, 1 H), 1.3-1.5 (m, 2 H), 1.8-2.0 (m, 4 H), 2.9 (ABq, 2 H), 4.8 (s, 1 H), 6.6 (s, 1 H), 7.2 (s, 1 H), 7.2-7.5 (m, 5 H), 11.4 (s, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#Cc1ccccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 19 h
Yield: 72.4 %

Procedure:
Combine 1-fluoro-2-nitro-benzene (5.00 g, 35.44 mmol), 2-amino-benzonitrile (4.19 g, 35.44 mmol), lithium hydroxide monohydrate (2.97 g, 70.87 mmol) and DMSO (50.0 ml). Stir the mixture at 55 ° C. for 19 hours then cool to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dry the precipitate under vacuum to give 6.14 g (72%) of an orange solid: mp 134–138°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:26])[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[NH:8]C=O.Cl>CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:26])[CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:16]=2)=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(NC=O)c(F)c2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of methyl 4-[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate (1.21 g, 3.39 mmol) in methanol (10 mL) was added conc. HCl (3.5 mL), and the resulting solution was stirred at rt for 16 h. The mixture was then concentrated, diluted with water, and the acidity was adjusted to pH ˜7 by slow addition of saturated aqueous sodium bicarbonate solution. The mixture was then extracted with dichloromethane, and the combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was then triturated with ethyl acetate/hexane to afford methyl 4-(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (998 mg, 89%). LC-MS ret. time 3.11 min, m/z 329.9 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.31 (s, 6H), 3.28 (s, 2H), 3.66 (s, 3H), 6.84 (t, 1H), 7.21-7.35 (m, 2H), 7.55 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[CH:3]=1.CCN(C(C)C)C(C)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>ClCCCl>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:2]2[N:7]3[N:8]=[C:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:10]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)=[C:6]3[N:5]=[C:4]([CH3:25])[CH:3]=2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (I-3A-4b; 109 mg, 0.280 mmol) and Argonaut™ PS-DIEA (97 mg, 0.38 mmol) in 1,2-dichloroethane (2.8 ml) was added piperazine-1-carboxylic acid tert-butyl ester (70.5 mg, 0.378 mmol). The mixture was stirred at room temperature for 19 hours, filtered, concentrated and then purified on a Biotage™ Flash 12M column using 0–35% ethyl acetate in hexanes as eluant to afford, after trituration from hexanes/methylene chloride, product 5A-1 (132 mg, 88%) as an off-white solid: +ESI MS (M+1) 538.4; 1H NMR (400 MHz, CD2Cl2) δ 7.48–7.32 (m, 6H), 7.22 (d, J=8.7 Hz, 2H), 6.13 (s, 1H), 3.73–3.61 (m, 8H), 2.56 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(=O)C>C(O)C.[Pt]=O>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)[C@@H](O)CC1CCCCC1
Yield: 95.2 %

Procedure:
α(S)-Hydroxybenzene propanoic acid (4.99 g, 30 mmol) was hydrogenated at 4 bar in ethanol (175 ml) and acetic acid (10 ml) using platinum oxide (0.5 g) as catalyst. After filtration, evaporation of the solvent gave the sub-title acid (4.92 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH:17]3[CH2:19][CH2:18]3)[C:3]=12.[CH3:20][S:21]([CH2:24][CH2:25]O)(=[O:23])=[O:22]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:25][CH2:24][S:21]([CH3:20])(=[O:23])=[O:22])[N:15]=[C:16]([CH:17]3[CH2:19][CH2:18]3)[C:3]=12
Reactant: CS(=O)(=O)CCO
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(C3CC3)c12
Product: CS(=O)(=O)CCn1nc(C2CC2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound Ix was synthesized from 4-chloro-3-cyclopropyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(methylsulfonyl)ethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8].C(O)(=O)C.N1C=CC=CC=1>Cl>[CH2:7]([O:9][C:10](=[O:14])[C:11]([C:12]#[N:13])=[CH:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH3:8]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)(C)C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=CC(C)(C)C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
A mixture of pivaldehyde (5.00 g, 58 mmol), ethylcyanoacetate (6.60 g, 58.3 mmol), acetic acid (3.50 g, 58.3 mmol) and pyridine (4.60 g, 58.2 mmol) was heated at reflux for 1 h. A second portion of pivaldehyde (5.00 g, 58 mmol) was added. The refluxing of the mixture was continued for 18 h. After cooling, the mixture was poured into 1N aqueous HCl (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 1N aqueous HCl, dried (MgSO4) and concentrated to give a colorless oil. The oil was purified by flash chromatography on SiO2 using hexane-EtOAc (9:1) as the eluant to give 2-cyano-4,4-dimethyl-2-pentenoic acid ethyl ester as a colorless oil (7.69 g, 73% yield).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[C:7]3[C:12]([CH2:13][CH2:14][C:4]=2[C:3]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>CC(N(C)C)=O.O>[S:17]([NH:1][C:2]1[S:6][C:5]2[C:7]3[C:12]([CH2:13][CH2:14][C:4]=2[C:3]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:20])(=[O:19])[NH2:18]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1c(N)sc2c1CCc1ccccc1-2
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1c(NS(N)(=O)=O)sc2c1CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-4,5-dihydronaphtho[1,2-b]thiophene-3-carbonitrile (Example 93b) (250 mg, 1.11 mmol) in dimethylacetamide (5 mL) was added sulfamoyl chloride (385 mg, 3.33 mmol). The reaction mixture was stirred at room temperature under nitrogen for about 1 hr, then it was diluted with water and extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to give the crude product which was carried on for next step.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)=[O:7].[H][H]>CO.C(OCC)(=O)C>[CH3:28][Si:25]([CH3:26])([CH3:27])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:1])([CH3:30])[CH3:29])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=1)=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 99.5 %

Procedure:
Compound 17a (150 mg) was dissolved in methanol (35 ml) and ethyl acetate (35 ml). The obtained mixture was stirred for 30 minutes in a hydrogen atmosphere. After the reaction was over, the obtained reaction mixture was filtered through Cerite, and then washed with methanol. The solvent was distilled off from the filtrate, and the obtained residue was dried. Thus, Compound 20a (150 mg, quant.) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1)[NH2:6].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30](O)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH:13]4[CH2:17][CH2:16][CH2:15][O:14]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1cc(N)ccc1OCCC1CCCO1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCC1CCCO1
Yield: 98 %

Procedure:
Acylation of 3-methoxy-4-(2-(tetrahydrofuran-2-yl)ethoxy)aniline from step A with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid to generate the title compound in 98% yield was achieved via the procedure described in step C of Example 1. The crude product was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:16][C:17]([CH2:19]Cl)=[CH2:18].[CH3:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:14][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:12])[Cl:13])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:15][CH2:16][C:17](=[CH2:18])[CH2:19][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:22](=[O:23])[CH3:21])=[CH:25][CH:26]=1
Reactant: C=C(CCl)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(COc1ccc(C(C)=O)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.6 g of 1,3-dichloro-2-(2-chloromethyl-allyloxy)-5-(3,3-dichloro-allyloxy)-benzene and 686 mg of 4-hydroxyacetophenone are introduced into 25 ml of acetonitrile. 1.7 g of potassium carbonate and 50 mg of potassium iodide are then added and the mixture is stirred for 3 hours at 80° C. The reaction mixture is filtered and the filtrate is concentrated. After purification over silica gel, 1-(4-{2-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxymethyl]-allyloxy}-phenyl)-ethanone is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[ClH:28].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3c(F)cccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3c(F)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 106 %

Procedure:
A mixture of 1.2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-9-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.65 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.3 g of potassium carbonate and 50 ml of acetone is treated in the same manner as described in Example 56. The crude product thus obtained is converted to its hydrochloride and recrystallized from isopropanol. 1.7 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl-]-9-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][S:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24]>>[F:21][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([S:23]([CH3:22])=[O:24])=[CH:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: CS(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: CS(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Methylsulfinyl benzene boronic acid. MS (M+H) 415.1
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21].C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[F:28][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1F
Temperature: 0 °C
Yield: 65.2 %

Procedure:
A well stirred suspension of 3.0 g (0.01 mole) of 3-hydroxy-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 150 ml of methylene chloride was cooled to -70°, and 7.5 ml (0.06 mol) of diethylaminosulfur trifluoride was added dropwise over a period of 10 min. The reaction mixture was then allowed to warm slowly over a period of 26 min. to -10° and then poured into 200 ml of ice water. The organic layer was separated, dried over MgSO4, and evaporated to dryness under reduced pressure to give 2.95 g (98%) of crude product. Recrystallization from benzene-heptane gave 2.00 g (67%) of 3-fluoro-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one as off-white crystals: mp 206°-207° (dec); 1H nmr (DMSO-d6) δ 5.95 ppm (d, J = 56 Hz, 1H), 7.47 ppm (m, 7H), 11.25 ppm (s, 1H); 19F nmr (DMSO-d6) δ -162.0 ppm (d, J = 56 Hz, 1F) and δ -113.0 ppm (m, 1F).