Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:17](=[CH:23]OCC)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]>C(O)C>[NH2:16][C:15]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[CH:23][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 24 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (10 g) and ethyl 2-cyano-3-ethoxyacrylate (7.0 g) in absolute ethanol (200 ml) was heated under reflux with stirring for 24 hours. Evaporation of solvent and recrystallisation from diisopropyl ether gave ethyl 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate, m.p. 131°-134°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12.[CH3:20]I.O>CN(C=O)C>[CH3:20][NH:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12
Reactant: CI
Reactant: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CN(C)C=O
Solvent: O
Product: CNc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 80 °C

Procedure:
0.084 g of 1-amino-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of DMF, and 0.5 mL of methyl iodide were added. The reaction mixture was heated to 80° C., allowed to react at that temperature for 6 h, cooled, and 100 mL of water were added. The reaction solution was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with 30 mL of and 30 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to yield a solid (0.033 g). MS (m/z): 292 (M−1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:20])=[C:5]([CH3:19])[C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].S(=O)(=O)(O)O>C(O)(=O)C>[Cl:21][CH2:22][C:23]1[N:1]=[C:2]2[S:3][C:4]([CH3:20])=[C:5]([CH3:19])[C:6]2=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(C(=O)c2c(N)sc(C)c2C)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A mixture of 2-amino-3-(3,4-dimethoxybenzoyl)-4,5-dimethylthiophene (3.6 g), ethyl 4-chloroacetoacetate (2.1 g), concentrated sulfuric acid (0.5 ml) and acetic acid (50 ml) was stirred for two hours at temperature ranging from 90° to 100° C. The reaction mixture was concentrated under reduced pressure. The concentrate was poured into water, which was neutralized with potassium carbonate, followed by extraction with chloroform. The chloroform layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fractions eluted with chloroform-hexane (4:1, v/v), ethyl 6-chloromethyl-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (3.5 g, 67%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.162°-163° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH:22]([NH:25][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N
Reactant: c1ccc(-c2cc(OCC3CO3)c3ccccc3n2)cc1
Product: CC(C)NCC(O)COc1cc(-c2ccccc2)nc2ccccc12

Procedure:
The title compound, m. p. 109-111° C., MS: m/e=337.2 (M+H+), was prepared from (RS)-4-oxiranylmethoxy-2-phenyl-quinoline and isopropylamine.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[OH:16][CH2:17][C:18]1([C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH2:20][CH2:19]1>>[OH:16][CH2:17][C:18]1([C:21]2[CH:26]=[CH:25][C:24]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][C:3]=3[C:8]3[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=3)=[CH:23][CH:22]=2)[CH2:20][CH2:19]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OCC1(c2ccc(B(O)O)cc2)CC1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C2(CO)CC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(1-(hydroxymethyl)cyclopropyl)phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H18N4O, 331. Found, 331.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1.CS(O[CH2:27][CH2:28][C:29]([CH3:33])=[C:30]([F:32])[F:31])(=O)=O.C(=O)([O-])O.[Na+]>O>[CH3:6][C:7]1[C:12]([C:13]([O:15][CH2:27][CH2:28][C:29]([CH3:33])=[C:30]([F:32])[F:31])=[O:14])=[CH:11][N:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1
Reactant: Cc1nc(-c2ccccc2)ncc1C(=O)O
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCOC(=O)c1cnc(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.34 g (1.6 mmol) of 4-methyl-2-phenylpyrimidine-5-carboxylic acid, synthesized in accordance with a method described in “J. Chem. Soc.”, page 2183 (1923), and 0.30 g (1.5 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate, followed by the addition of 0.27 g (3.2 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethtyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:4) to obtain 0.35 g (yield: 73%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-phenylpyrimidine-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)Cl)ccc1Cl
Temperature: 25 °C

Procedure:
4-chloro-3-methoxybenzoic acid, 3.7 g, was wet down with chloroform, 3 mL, and thionyl chloride, 6 mL, was added under an argon atmosphere. The resulting paste was subjected to reflux. After several minutes, the light yellow solution was cooled to room temperature and another 4.0 g of the substituted benzoic acid was added. The mixture was again brought to reflux for one hour. A still head was added to the flask in order to distill off chloroform and excess thionyl chloride at the minimum temperature possible. The still pot residue, containing the product, then solidified. Petroleum ether, 5 mL, was added to dissolve the solid with slight heating. Upon cooling to room temperature, the mother liquor was pipetted off gently, and the remaining solid was pumped in vacuo to obtain 7.3 grams of 4-chloro-3-methoxybenzoyl chloride as a light tan solid. Another 1.03 grams of less pure material could be obtained from the mother liquor.
Reaction SMILES: C(C(C1C=CC(F)=CC=1)C([O:7][C:8](=O)[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:10]([CH3:12])[CH3:11])=O)(C)C.[C:28]1([CH2:34][CH:35]=[C:36]([CH3:41])[CH:37]([OH:40])[C:38]#[CH:39])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH:10]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:8]([O:40][CH:37]([C:36]([CH3:41])=[CH:35][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:38]#[CH:39])=[O:7])([CH3:12])[CH3:11]
Reactant: CC(C)C(C(=O)OC(=O)C(c1ccc(F)cc1)C(C)C)c1ccc(F)cc1
Reactant: C#CC(O)C(C)=CCc1ccccc1
Solvent: c1ccncc1
Product: C#CC(OC(=O)C(c1ccc(F)cc1)C(C)C)C(C)=CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.11 Grams (20 millimoles) of α-isopropyl-4-fluorophenylacetic anhydride and 1.86 g (10 millimoles) of 6-phenyl-4-methylhexa-4-ene-1-yne-3-ol are dissolved in 30 ml of a dry pyridine. The resulting solution is stirred overnight at room temperature. Next day, the reaction solution is poured into 100 g of ice water and extracted with three 30-ml portions of ether. The ether layers obtained are combined and extracted twice with an aqueous saturated sodium hydrogen carbonate. Thereafter, the ether layer is further washed once with a 10% aqueous hydrochloric acid and three times with water, followed by drying over anhydrous sodium sulfate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=O)=[CH:3][CH:2]=1.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:22][NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: CCCCC(=O)c1ccncc1
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: CCCCC(=NNC(=O)c1ccccc1)c1ccncc1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A mixture of 5.97 gm (0.0366 mole) of n-butyl 4-pyridinyl ketone, 5.45 gm (0.04 mole) of benzoic acid hydrazide and 100 ml of absolute ethanol is refluxed 4.5 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point, cooled to room temperature and chilled. The solids which deposit are collected, washed with water and dried to yield 7.89 gm (77%) of the title compound having a melting point of 142.1° C.
Reaction SMILES: [C:1]([Mg]Br)([CH3:4])([CH3:3])[CH3:2].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH:36]=[O:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH:36]([OH:37])[C:1]([CH3:4])([CH3:3])[CH3:2])[N:29]=[C:28]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Mg]Br
Reactant: CCCCc1nc(C=O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
2.77 ml of a 2M solution of t-butylmagnesium bromide in tetrabydrofuran were added at -55° C. and under an atmosphere of nitrogen to a solution of 1.32 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-formylimidazole-5-carboxylate [prepared as described in step (a))above] in 26 ml of tetrahydrofuran, and the resulting mixture was stirred at a temperature of -55° C. to -50° C. for 30 minutes. At the end of this time, the reaction mixture was diluted with 50 ml of ethyl acetate and with a saturated aqueous solution of ammonium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.87 g of the title compound as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:18])=O>O1CCOCC1>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of compound of Example 1a (1.0 eq) in dioxane (approx 4.5 vol) was treated with thionyl chloride (1.5 eq) and heated to 80° C. A clear solution formed at approximately 75° C. The mixture was stirred for 3 hours at 80° C. Unreacted thionyl chloride was distilled off and after distillation the residue was cooled to 10° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O>C(O)C>[NH2:2][C:1]1[C:3]([C:4]([NH2:6])=[O:5])=[CH:14][C:13]2[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=1
Reactant: Nc1ccccc1C=O
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc2ccccc2nc1N
Temperature: 50 °C
Yield: 80.1 %

Procedure:
Cyanoacetamide (19.4 g., 0.23 mole) is added to a solution of sodium ethoxide (6.65 g., 0.29 mole) in absolute ethanol (460 ml.) maintained at 50° C. The mixture is stirred and o-aminobenzaldehyde (28.0 g., 0.23 mole) in absolute ethanol (100 ml.) added. After fifteen minutes stirring at 50° C., the reaction mixture is cooled in an ice bath, filtered and dried to give 34.5 g (84% yield) of product; m.p. 240°-242° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[CH3:30][NH2:31]>CS(C)=O>[OH:29][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][NH:31][CH3:30])[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]4[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: CN
Solvent: CS(C)=O
Product: CNCCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Yield: 61.2 %

Procedure:
Bromide (204) (40 mg, 0.09 mmol) prepared as described in example 173 was reacted with aqueous methylamine solution (10 mol equiv.) according to the procedure described in example 179 except that the reaction was performed in dimethylsulfoxide at room temperature for 3 h, to give amine (214) (22 mg, 61%) as an orange/yellow powder, mp 265–268° C. 1H NMR δ [(CD3)2SO] 9.33 (br s, 1H), 8.41 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.64 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.47 (m, 3H), 7.14 (dd, J=8.8, 2.5 Hz, 1H), 4.51 (t, J=6.8 Hz, 2H), 2.40 (t, J=6.5 Hz, 2H), 2.20 (s, 3H), 1.88 (m, 2H). FABMS found [M+H]+:400.1659. C24H22N3O3 requires 400.1661.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8]>C(#N)C>[N:1]1([CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=CC(=O)OC
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: COC(=O)CCn1ccnc1
Yield: 98.1 %

Procedure:
5.0 g(73.4 mmol) of imidazole and 12.6 g(148.6 mmol) of methyl acrylate were dissolved in 100 ml of acetonitrile, and then refluxed for 8 hours. Acetonitrile and the excess methyl acrylate was removed under reduced pressure. Then, 200 ml of ethyl acetate was added to the residue and the solution thus obtained was washed with saturated sodium chloride solution. Removal of ethyl acetate under reduced pressure provided 11.1 g(Yield: 90%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[CH:14]2)=[CH:9][C:8]=1[OH:17].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:14]=[N:13][CH:12]=[CH:11]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccncc2cc1-c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccncc4cc3-c3ccccn3)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 21.7 %

Procedure:
7-Pyridin-2-yl-isoquinolin-6-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (50 mg), and 4-dimethylaminopyridine (33 mg) were suspended in o-dichlorobenzene (3 ml), and the mixture was stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (8 mg, yield 22%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])[CH2:14][CH2:13]1)(=[O:11])=[O:10])#[N:2].C1C=C([O:42]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@@H:27]([CH2:29][NH+:30]([O-:42])[C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])[CH2:16][CH2:17]1)(=[O:11])=[O:10])#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(S(=O)(=O)c4ccccc4C#N)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(S(=O)(=O)c4ccccc4C#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-N-[[3-[4-[4-[(2-cyanophenyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (VIII-G, R1=COCH3, R9=2-cyanophenyl, X1=F, X2=H) (0.5 g) is suspended in 10 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.616 g) is added and the reaction mixture is stirred at room temperature for 2 hours. The reaction is concentrated and the resulting oil is chromatographed on silica gel using 7% methanol (saturated with ammonia) in chloroform as eluent to afford 0.33 g of the N-oxide.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH:4]([CH3:18])[CH2:3]1.[Br:20]Br>C(O)(=O)C>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH2:13][Br:20])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH:4]([CH3:18])[CH2:3]1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)C(C)CC2(C)C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C(=O)CBr)C(C)(C)CC(C)C2(C)C

Procedure:
A solution of 1,1,3,4,4,6-Hexamethyl-7-acetyl-1,2,3,4-tetrahydronaphthalene(33 g.) in 40 ml. glacial acetic acid was treated slowly with 20 g. bromine. Warming was necessary to initiate the reaction, evidenced by disappearance of the red colouration. When all the bromine had been added,the mixture was cooled and poured onto ice to give a pale green gum. The whole was extracted with ether, the ethereal extracts washed with dilute Na2CO3, water and finally dried over MgSO4. Evaporation ofthe ether gave a pale green solid which was recrystallised from EtOH to give the title compound 27.6 g. (64%), m.p. 68° C. Analysis : Calculated for C18H25OBr, C, 64.09%; H, 7.47%. Found : C, 64.40%; H, 7.65%.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2].[Cl:17][S:18](O)(=[O:20])=[O:19].ClCCl>O>[C:10]([CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:15]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:16][C:6]=1[O:5][CH2:4][C:1]([NH2:2])=[O:3])(=[O:11])[NH2:12]
Reactant: O=S(=O)(O)Cl
Reactant: NC(=O)COc1ccccc1OCC(N)=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Temperature: 0 °C
Yield: 77.5 %

Procedure:
2-Carbamoylmethoxyphenoxyacetamide (Intermediate A84, 112 g, 0.50 mol) was added portion-wise over 15 min to rapidly stirred chlorosulfonic acid (582.5 g, 5.0 mol) cooled to 0° C. Dichloromethane (120 mL) was then added, and the mixture was heated in a 60°-70° C. bath for 3 hr. The mixture was slowly poured into 1.5 Kg of crushed ice, and then water (500 mL) was added. The resulting solid was collected, washed with water (3×500 mL) and acetone (3×500 mL), resuspended in acetone (1 L), again collected, washed with acetone (500 mL), and air dried to yield 125 g (77%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([N:30]1[CH2:34][CH2:33][C:32]([F:36])([F:35])[CH2:31]1)=[O:29])[C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])=[CH:18][CH:17]=1)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([N:30]1[CH2:34][CH2:33][C:32]([F:36])([F:35])[CH2:31]1)=[O:29])[C@H:10]([CH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH2:18][CH2:17]1)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@@H](c1ccc(N2CCCC2=O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CN(C)C(=O)[C@@H](C1CCC(N2CCCC2=O)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1

Procedure:
To a solution of the material prepared in Step A (0.46 g, 0.91 mmol) in 100 mL of acetic acid was placed solid platinum (IV) oxide (200 mg). The mixture was placed under 3 atm hydrogen for 24 h at ambient temperature. The mixture was then filtered through Celite, and concentrated in vacuo. Purification by reverse phase liquid chromatography (25%-65% acetonitrile in water gradient) afforded the title compound as a mixture of cis and trans 1,4-disubstituted cyclohexyl diastereomers. These diastereomers were separated by chiral HPLC (Chiracel OD column, 5% ethanol in hexanes) affording each pure diastereomer: The faster eluting diastereomer: LC/MS 514.4 (M+1); the slower eluting diastereomer: LC/MS 414.4 (M+1-Boc).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c(NC(CCN3CCCC3)c3cccc(N)c3)ncnc12
Reactant: Clc1ccccn1
Product: NC(=O)c1cccc2c(NC(CCN3CCCC3)c3cccc(Nc4ccccn4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 549 starting with 4-[1-(3-Amino-phenyl)-3-pyrrolidin-1-yl-propylamino]-quinazoline-8-carboxylic acid amide and 2-chloro-pyridine: LCMS [468.1 (M+1)].