Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])=[C:9]([Cl:11])[Cl:10])[CH:5]=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].Cl[S:18]([OH:21])(=O)=[O:19].[NH2:22]C1C=C(C(C)=C(Cl)Cl)C(S(Cl)(=O)=O)=CC=1S(Cl)(=O)=O>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])=[C:9]([Cl:10])[Cl:11])[C:5]([S:18]([NH2:22])(=[O:21])=[O:19])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=C(Cl)Cl)c1cc(N)c(S(=O)(=O)Cl)cc1S(=O)(=O)Cl
Reactant: CC(=C(Cl)Cl)c1ccc(S(N)(=O)=O)c(N)c1
Product: CC(=C(Cl)Cl)c1cc(N)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reaction time: 1 h

Procedure:
100 Mg. of the 2-amino-4-(1,1-dichloroprop-1-en-2-yl)benzenesulfonamide and 1.0 ml. of chlorosulfonic acid is mixed at 5° to 10° C. and then immersed into an oil bath of 100° to 110° for 1 hour. The reaction mixture is cooled in ice, added onto ice, extracted into CH2Cl2, the solution is washed twice with water, dried and concentrated in vacuo to yield 75 mg. of crude 4-amino-6-(1,1-dichloroprop-1-en-2-yl)-1,3-benzenedisulfonylchloride, identified by nuclear magnetic resonance and mass spectral analyses. 100 Mg. of this disulfonylchloride is then dissolved in 4 ml. of tertbutanol and ammonia gas is bubbled into the solution for about 10 minutes at room temperature. It is kept at room temperature for 15 minutes and then concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with dilute aqueous HCl, water, dried and concentrated in vacuo to 87 mg. of crude product which slowly crystallized. It is recrystallized from a methanol-benzene-methylene-chloride mixture to give 4-amino-6-(1,1-dichloroprop-1-ene-2-yl)-1,3-benzenedisulfonamide with m.p. 199° to 202° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CC(C)=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OCC1CO1
Yield: 12 %

Procedure:
A mixture of 15.2 g (0.10 mole) of methyl 2-hydroxybenzoate, 27.6 g (0.20 mole) of K2CO3 and 31 mL (0.40 mole) of epichlorohydrin in 250 mL of acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was dissolved in 100 mL toluene and washed consecutively with 100 mL water, 2×100 mL 1.0 N NaOH, and 2×100 mL water. The organic phase was then dried over MgSO4 and evaporated under reduced pressure to provide the crude product as an oil. Purification was effected by vacuum distillation to provide an oil in 12% yield: boiling point 148° C. (75 u). The NMR and IR spectra and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][C@@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=O)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([CH:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:19][O:18][C:17]3[CH:28]=[CH:29][C:14]([F:13])=[CH:15][CH:16]=3)[O:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O)c1ccccc1
Reactant: O=CCCCC[C@H](O)COc1ccc(F)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCCC[C@@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
25% HCl was added dropwise to sodium salt of benzenesulfinic acid (5 g, 30.5 mmol) until the solid dissolved. The reaction mixture was extracted with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfinic acid (3.9 g, 90%). To an ice-cold mixture of benzene sulfinic acid (1.8 g, 12.4 mmol) and CaCl2 (1.4 g, 12.5 mmol) in dry methylene chloride (50 ml) was added dropwise a solution of (6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (2 g, 8.3 mmol) in methylene chloride (10 ml). The reaction mixture was stirred for 3 hours and filtered through celite, and washed with methylene chloride. The combined organic layer was washed with saturated aqueous Na2CO3, water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using EtOAC-hexane (1:6) as eluent to give (2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.45 g, 80.8%); 1H-NMR (CDCl3, 200 Hz): δ 1.39-2.20 (m, 7H), 2.5 (m, 1H), 3.57-3.90 (m, 2H), 4.45 (m, 1H), 4.72 (dd, J=6.6, 12.0 Hz, 1H), 6.57-7.00 (m, 4H), 7.36-7.96 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C[Mg]Br>O1CCCC1.CCOC(C)=O>[C:17]([OH:19])(=[O:18])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:4]([CH3:5])([OH:8])[CH3:3])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 16 h

Procedure:
To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (3.21 g, 10 mmol) in tetrahydrofuran (THF, 100 ml), was added methylmagnesium bromide (10 ml, 30 mmol, 3M solution in ether) dropwise over 15 minutes at room temperature under N2. The resulting mixture was stirred for 16 hours. The mixture was slowly hydrolyzed with aqueous HN4Cl solution. The THF solution was diluted with EtOAc (300 ml), then was washed with water and brine. The organic solution was separated and dried over MgSO4. After removal of solvent, the crude product was purified by flash chromatography (25 g, SiO2 ; eluted with 1 CH3OH:99 DCM). The material thus purified weighed 2.36 g (77%) as white crystals. This was converted to the fumarate salt by treatment with fumaric acid (895 mg) in ethanol. Recrystallization from ethanol yielded white crystals, 2.47 g, m.p.=156°-158° C.
Reaction SMILES: CC(C1C=[C:6]([O:10]C2N=CC(NC(=O)[C@@H](C)N)=CC=2)C=CC=1)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[O:31][C:32]1[N:37]=[CH:36][C:35]([NH:38][C:39](=[O:43])[C@@H:40]([CH3:42])[NH2:41])=[CH:34][CH:33]=1>>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[O:31][C:32]1[N:37]=[CH:36][C:35]([N:38]2[C:39](=[O:43])[C@@H:40]([CH3:42])[NH:41][C:6]2=[O:10])=[CH:34][CH:33]=1
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Reactant: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Product: Cc1ccc(C)c(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1

Procedure:
The title compound was made in a similar fashion to the preparation of Example 9 replacing N1-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-D-alaninamide with N1-{6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 36, 48 mg) to afford the title compound as a yellow powder (31 mg).
Reaction SMILES: [Cl:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][CH:5]=1.OO.C(O)(=[O:19])C.[OH2:21]>>[Cl:1][CH2:2][S:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][CH:5]=1)(=[O:19])=[O:21]
Reactant: CC(=O)O
Reactant: O
Reactant: ClCSc1ccc(-n2cnnn2)cc1
Agent: OO
Product: O=S(=O)(CCl)c1ccc(-n2cnnn2)cc1

Procedure:
A solution of 226 mg. of 1-[p-(chloromethylthio)phenyl]-1H-tetrazole and 0.35 ml. of 30% hydrogen peroxide in 2 ml. of glacial acetic acid was refluxed 15 minutes, cooled, and diluted with water. Crystals filtered off and recrystallized from ethanol gave m.p. 168°-171.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].ClC(Cl)(O[C:12](=[O:18])OC(Cl)(Cl)Cl)Cl.FC(F)(F)C([O-])=O.[C:27]([C:30]1[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[N:32][N:33]([C:35]2([CH2:41][C:42]#[N:43])[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]2)[CH:34]=1)(=[O:29])[NH2:28]>C1COCC1.C(Cl)Cl>[C:27]([C:30]1[C:31]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=2)=[N:32][N:33]([C:35]2([CH2:41][C:42]#[N:43])[CH2:40][CH2:39][N:38]([C:12]([O:6][C:4]([CH3:7])([CH3:5])[CH2:3][O:2][CH3:1])=[O:18])[CH2:37][CH2:36]2)[CH:34]=1)(=[O:29])[NH2:28]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC[NH2+]CC1
Reactant: COCC(C)(C)O
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-methoxy-2-methyl-2-propanol (91 mg, 0.88 mmol) in THF (1.5 mL) and TEA (0.20 mL, 1.4 mmol) was cooled to 0° C. and allowed to stir. Triphosgene (260 mg, 0.876 mmol) was added and the resulting mixture was allowed to warm to ambient temperature and was stirred for 15 minutes. A solution of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (80 mg, 0.18 mmol) and TEA (0.061 mL, 0.44 mmol) in DCM (1.0 mL) was then added to the reaction mixture dropwise. The resulting mixture was heated to 50° C. and allowed to stir for 16 hours. The solution was cooled to ambient temperature, diluted with DCM, washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #28.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[C:8]([O:20][CH3:21])=[C:7]2[C:3]=1[C:4]1[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][C:5]=1[N:6]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[CH2:34]([S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37])[CH3:35].O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([O:15][C:13]([N:11]([CH3:12])[C:9]1[C:8]([O:20][CH3:21])=[C:7]2[C:3]([C:4]3[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][C:5]=3[N:6]2[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:2]([C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([S:36]([CH2:34][CH3:35])(=[O:37])=[O:38])[CH:40]=2)[CH:10]=1)=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COc1c(N(C)C(=O)OC(C)(C)C)cc(Br)c2c3cc(C)cnc3n(C(=O)OC(C)(C)C)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cc(N(C)C(=O)OC(C)(C)C)c(OC)c3c2c2cc(C)cnc2n3C(=O)OC(C)(C)C)c1
Temperature: 140 °C

Procedure:
A 5 mL microwave vial was charged with Compound 250 (520 mg, 1.0 mmol), 3-(ethylsulfonyl)phenylboronic acid (321 mg, 1.5 mmol) and Pd(PPh3)4 (116 mg, 0.10 mmol). To the mixture was added dioxane (2 mL) and a saturated aqueous solution of K2CO3 (1 mL). The reaction mixture was heated at 140° C. for 20 min. in microwave. The reaction was diluted with EtOAc and washed with water and brine. The organic extracts were dried (Na2SO4) and concentrated and the crude Compound 251 was taken forward for Boc deprotection.
Reaction SMILES: Cl.O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]1[CH2:44][O:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>CO>[N:48]1[CH:49]=[CH:50][CH:51]=[C:46]([O:45][CH2:44][CH:32]2[CH2:33][NH:34][CH2:35][CH2:36][N:31]2[C:23]2[S:22][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)[CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: c1cncc(OCC2CNCCN2c2nc3ccccc3s2)c1
Reaction time: 12 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (116.4 mg, 0.215 mmol) in MeOH (1 mL). After 12 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 41.7 mg (59%) of the desired product as an off-white, sticky solid. LC-MS: RT=4.38 min, [M+H]+=327.1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([CH2:24][CH:25]=O)=[CH:16]1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1.[OH-].[Na+]>ClCCl.C(O)(=O)C>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([CH2:24][CH2:25][N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]2)=[CH:16]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCc1coc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(CCc2coc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
13 ml of acetic acid and 61 g of sodium triacetoxyborohydride are added in succession to a solution of 33 g of 2-(benzofuran-3-yl)acetaldehyde and 41.3 g of tert-butyl 4-piperidylcarbamate in 1.4 litres of dichloromethane. After 24 hours' stirring at room temperature, a 20% sodium hydroxide solution is added. After 10 minutes, the reaction mixture is decanted and the organic phase is washed, dried and concentrated. Chromatography over silica gel (cyclohexane/ethyl acetate 30/70) enables the expected product to be isolated.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][P:26]([O:32][CH2:33][CH:34]=[CH2:35])([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[CH:20][C:7]=1[C:8]([O:10]CC1C=CC(OC)=CC=1)=[O:9])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][P:26]([O:32][CH2:33][CH:34]=[CH2:35])([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[CH:20][C:7]=1[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)OCc2ccc(OC)cc2)c1
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.2 %

Procedure:
A mixture of 4-methoxybenzyl 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoate (590.3 mg, 1.17 mmol) obtained from Example 1-(10) and anisole (600 mg, 5.55 mmol) was cooled to 0° C., and then trifluoroacetic acid (2 ml) was added thereto with stirring. The mixture was warmed to room temperature and allowed to stand for 20 minutes. The mixture was diluted with toluene and was concentrated under reduced pressure to eliminate the volatile components (repeated three times), and an aqueous solution of sodium hydrogen carbonate was added thereto, then the aqueous layer was washed with ethyl acetate. To the aqueous layer was added carefully a 2N aqueous solution of hydrochloric acid (10 ml), and the liberated carboxylic acid was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to afford the title compound (477.5 mg, quantitative yield) as a colorless oil.
Reaction SMILES: [C:1]([N:3]=[CH:4]OCC)#[N:2].[NH2:8][CH:9]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.C(OCC)(=O)C>C(O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:9]([NH:8][CH:4]=[N:3][C:1]#[N:2])[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1
Reactant: Cn1c(=O)cc(-c2ccccc2)c2cc(C(N)c3ccc(Cl)cc3)ccc21
Reactant: CCOC=NC#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(=O)cc(-c2ccccc2)c2cc(C(NC=NC#N)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
Ethyl N-cyano-methanimidate (3.6 g) was added dropwise at room temperature to a solution of intermediate (5-b) (10.6 g) in ethanol (90 ml) and the mixture was stirred at room temperature for 48 hours. Water and ethyl acetate were added, the organic layer was decanted, washed with water, dried (MgSO4), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated, yielding 10.5 g (88%) of (±)-N-[[[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)methyl]amino]methylene]cyanamide (interm. 5-c).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 55 °C
Reaction time: 0.05 h
Yield: 54.8 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (418 mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred 13 minutes. In one portion benzyl alcohol (534 μL, 5.16 mmol) was added. The solution was stirred for 17.5 hours at room temperature and 2.75 minutes at 55° C. The solution was allowed to cool to room temperature and water (10 mL) was added. The insoluble material was filtered and dried to give the title compound (360 mg, 55% yield, m.p. 254° C.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]2[C@@H:19]([CH2:20][CH2:21][OH:22])[O:18][CH2:17][CH2:16][N:15]2[C:23]([CH:25]2[CH2:28][CH2:27][CH2:26]2)=[O:24])[CH:10]=[CH:11][C:12]=1[Cl:13].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][S:2]([O:22][CH2:21][CH2:20][C@H:19]1[O:18][CH2:17][CH2:16][N:15]([C:23]([CH:25]2[CH2:26][CH2:27][CH2:28]2)=[O:24])[CH:14]1[C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C1CCC1)N1CCO[C@H](CCO)C1c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC[C@H]1OCCN(C(=O)C2CCC2)C1c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Methanesulfonyl chloride (0.071 ml, 0.92 mmol) and 4-dimethylaminopyridine (catalytic amount) were added to a solution of 2-[(2R)-(3,4-dichlorophenyl)-4-(cyclobutanecarbonyl)morpholin-2-yl]ethanol (219 mg, 0.61 mmol), which was prepared in Example 1(a), in pyridine (2 ml) with ice-cooling under a nitrogen atmosphere. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was acidified with ice-cooled hydrochloric acid (10%) and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography using n-hexane/ethyl acetate=¼ as a developing solvent to afford the desired compound (255 mg, 96%) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]#[N:18]
Reactant: N#CCCl
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOc1cccc(F)c1
Temperature: 50 °C
Yield: 94.2 %

Procedure:
To a solution of 3-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) is added potassium carbonate (828 mg, 6.0 mmol) followed by chloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture is stirred and heated at 50° C. for 14 h. The reaction mixture is cooled to RT, diluted with EtOAc, and washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane gives 712 mg of the product 386.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14](Cl)([CH3:16])[CH3:15])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CCCCCC.Cl>[Br:1][C:2]1[C:3]([CH3:8])=[CH:4][C:5]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][C:10]([CH3:18])([CH3:11])[C:6]=2[CH:7]=1
Reactant: Cc1ccccc1Br
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 20 g (117 mmol) of 2-bromotoluene and 14.4 g (97.4 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 mL of dichloromethane was added 1.56 g (16.9 mmol) of aluminum chloride and the mixture heated at reflux. After 16 hours, the mixture was cooled to room temperature, diluted with 150 mL of hexane and 100 mL of 1 N HCl was added. The organic layer was separated and the aqueous layer was extracted with hexane. The combined organic layers were washed with saturated NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by filtration through a pad of silica gel with elution with hexane and afforded 23.9 g (87%) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a solid. (m.p.: 81.1-85° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=[O:6]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc(Cl)c1

Procedure:
Compounds of Formula Ib, where R=SOCH(R2)A can be prepared from the appropriate compounds of Formula Ia wherein R=SCH(R2)A by oxidation with m-chloroperoxybenzoic acid as shown in Equation 12. The reaction can be carried out by stirring equivalent amounts of Ia with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as chloroform at 0° to reflux for 12-24 hours. The insoluble m-chlorobenzoic acid produced is removed by filtration and the chloroform solution is concentrated to yield the crude product. Purification by standard techniques will give the desired product. Oxidation of Ia with one equivalent of hydrogen peroxide in acetic acid at room temperature will also give the sulfoxides Ib. ##STR35##
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][CH2:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=CCNc1ccccc1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCNc1ccccc1C(N)=O
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 2-(3-ethoxycarbonyl-2-propenylamino)benzamide (2.35 g) in methanol (50 ml) was added 10% palladium on carbon (230 mg). The mixture was stirred vigorously under 3 atmospheric pressure of hydrogen. After 2 hours, the catalyst was filtered off, and the solvent was evaporated. The residue was chromatographed on silica gel (40 g). Elution with a mixed solvent of ethyl acetate-hexane (1:1 V/V) gave 2-(3-ethoxycarbonylpropylamino)benzamide (1.95 g).