Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1)/[CH:10]=[CH:11]/[C@H:12]1[C@@H:16]([F:17])[CH2:15][C@H:14]([OH:18])[C@@H:13]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[Cl-].[NH4+]>CO>[Si:1]([O:8][C@@H:9]([CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39]1)/[CH:10]=[CH:11]/[C@H:12]1[C@@H:16]([F:17])[CH2:15][C:14](=[O:18])[C@@H:13]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)C2Cc3ccccc3C2)[C@@H](F)C[C@@H]1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)OC(=O)CCC/C=C\C[C@H]1C(=O)C[C@H](F)[C@@H]1/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture consisting of (Z)-isopropyl 7-((1R,2R,3S,5S)-2-((S,E)-3-(tert-butyldimethylsilyloxy)-3-(2,3-dihydro-1H-inden-2-yl)prop-1-enyl)-3-fluoro-5-hydroxycyclopentyl)hept-5-enoate (prepared in Step K, 0.600 g), methanol (5 mL), and 1 N sodium hydroxide (3 mL) was stirred overnight at 0° C. The reaction mixture was acidified with saturated ammonium chloride, extracted into ethyl acetate, washed with brine, and dried over sodium sulfate, filtered, and the solvents were evaporated under reduced pressure. The crude product was purified on silica gel. Elution with hexanes-ethyl acetate (4:1 with 0.4% acetic acid) afforded the title intermediate (0.58 g, 96%).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:12](=[O:14])[CH3:13].[CH3:15][O:16][CH2:17][C:18]1[O:23][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:20]=2[N:19]=1.Cl>O1CCCC1.CCCCCC>[CH3:15][O:16][CH2:17][C:18]([NH:19][C:20]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](=[O:24])[CH2:13][C:12]([NH:11][C:7]1[S:6][CH:10]=[CH:9][N:8]=1)=[O:14])=[O:23]
Reactant: COCc1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
150 ml of a solution of 1.5 moles of butyllithium per liter of hexane were added over 20 minutes at 0° C. to a solution of 15.73 g of N-(2-thiazolyl)-acetamide in 550 ml of tetrahydrofuran and the mixture was stirred at 0° C. for 10 minutes and was cooled to -70° C. A solution of 14.4 g of the product of Step A in 165 ml of tetrahydrofuran was added at -70° C. over 15 minutes to the mixture which was then stirred at -70° C. for 30 minutes and poured into a mixture of ice and N hydrochloric acid. The mixture was extracted with ether and the combined organic phases were washed successively with hydrochloric acid and water, dried and evaporated to dryness under reduced pressure at 20° to 30° C. The residue was empasted with 250 ml of ether and was vacuum filtered. The product was washed with ether and dried under reduced pressure at 20° C. to obtain 15 g of 2-methoxyacetamido-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene-propanamide melting at 152° C.
Reaction SMILES: ClC1C=CC=C(Cl)C=1N[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([C:24]3[O:28][C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH:31]([CH3:35])[CH2:30]4)=[N:26][C:25]=3[C:36]([F:39])([F:38])[F:37])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)=O.N1C2C(=CC(NC(C3OC(N4CCCC(C)C4)=NC=3C(F)(F)F)=O)=CC=2)C=C1.BrC[C:70]([O:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:71]>>[CH3:35][CH:31]1[CH2:32][CH2:33][CH2:34][N:29]([C:27]2[O:28][C:24]([C:22]([NH:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([CH2:10][C:70]([O:72][C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)=[O:71])[CH:13]=[CH:14]4)=[O:23])=[C:25]([C:36]([F:38])([F:37])[F:39])[N:26]=2)[CH2:30]1
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4C(=O)Nc4c(Cl)cccc4Cl)c3)o2)C1
Reactant: O=C(CBr)Oc1ccccc1
Agent: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ccc4c3)o2)C1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4CC(=O)Oc4ccccc4)c3)o2)C1

Procedure:
Compound 48 was prepared by the general procedure for compound 45, by using compound 44 and phenyl 2-bromoacetate as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.22 (br s, 1H), 8.29 (m, 1H), 8.08 (m, 1H), 7.96 (dd, 1H, J=3.5, 13.3 Hz), 7.58 (m, 1H), 7.45 (m, 1H), 7.34 (m, 2H), 7.07 (d, 1H, J=8.5 Hz), 6.99 (t, 1H, J=7.4 Hz), 6.85 (m, 1H), 4.84 (s, 2H), 4.15 (d, 1H, J=13.2 Hz), 4.10 (d, 1H, J=13.6 Hz), 3.06 (t, 1H, J=12.0 Hz), 2.76 (dd, 1H, J=11.0, 12.3 Hz), 1.71 (m, 3H), 1.54 (m, 1H), 1.15 (m, 1H); 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 527.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Na].[CH2:6]([O:8][C:9](=[O:15])[CH2:10][C:11]([CH2:13]Cl)=[O:12])[CH3:7].C(O)(=O)C>C(O)C.O1CCCC1>[CH2:6]([O:8][C:9](=[O:15])[CH2:10][C:11]([CH2:13][O:3][CH2:2][CH3:1])=[O:12])[CH3:7]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOCC(=O)CC(=O)OCC
Temperature: 25 °C
Yield: 71 %

Procedure:
2.2 moles of sodium ethylate in ethanol--prepared from 55.2 g (2.2 moles) of sodium in 500 ml of ethanol--were diluted with 500 ml of tetrahydrofuran. 164.5 g (1 mol) of γ-chloroacetoacetic acid ethyl ester were added to the solution, at room temperature, sufficiently rapidly that the reaction temperature rose to 50° C., the mixture was then cooled to room temperature, 72 g (1.2 mol) of glacial acetic acid were added, the solvent was evaporated off on a rotary evaporator, the residue was shaken with 250 ml of water and extracted twice with 250 ml of methylene chloride at a time, and the combined organic phases were dried over magnesium sulphate. The solvent was stripped off under reduced pressure and the residue was distilled. 123.6 g (71% of theory) of γ-ethoxyacetoacetic acid ethyl ester of boiling point 75° C./3 mm Hg were thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].S(=O)(=O)(O)O.[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH3:25]>CN(C)C=O>[CH3:25][C:24]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8]([C:7](=[O:17])[C:6]=3[CH:5]=[CH:4][C:3]=2[NH:18]1)=[CH:9][CH:10]=[CH:11][CH:12]=4
Reactant: CC(=O)c1ccccc1
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)Nc2ccc3c(c2N1)C(=O)c1ccccc1C3=O
Reaction time: 72 h

Procedure:
1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto after acetophenone (0.5 ml, 6 mmol) is added thereinto. After mixing and reacting in room temperature for 72 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and recrystallized by hot alcohol, so as to obtain the black compound 21, and the production rate is 28%.
Reaction SMILES: [CH2:1]1[CH2:8][CH:7]([NH2:9])[C:5](=[O:6])[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([C:27](Cl)=[O:28])=[CH:24][C:23]=2[CH:30]=1>ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([C:27]([NH:9][CH:7]3[CH2:8][CH2:1][CH2:2][CH2:3][NH:4][C:5]3=[O:6])=[O:28])=[CH:24][C:23]=2[CH:30]=1
Reactant: NC1CCCCNC1=O
Reactant: COc1ccc2oc(C(=O)Cl)cc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2oc(C(=O)NC3CCCCNC3=O)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a being cooled solution of DL-α-amino-ε-caprolactam (0.83 g) and triethylamine (1.1 ml) in dichloromethane (12 ml), a solution of (5-methoxybenzofuran-2-yl)carbonyl chloride (1.37 g) in dichloromethane (5 ml) was added dropwise below 10° C. After being stirred for 3 hours at ambient temperature, the appeared precipitates was collected by filtration to give DL-α-(5-methoxybenzofuran-2-yl)carbonylamino-ε-caprolactam (1.20 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[H][H]>O1CCCC1.[Pt]=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (44.6 g, 153 mmol) in 1.95 L tetrahydrofuran was added 9.0 gm platinum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 60 p.s.i. at ambient temperature for 24 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 32.6 gm (73.7%) of the title compound as a white solid. MS(m/e): 293(M+). EA calculated for C14H17N2Br: C, 57.32; H, 5.96; N, 9.69.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]Cl)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:22]=2[C:23]#[N:24])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[NH:19][C:20]([C:25]([F:28])([F:26])[F:27])=[C:21]([S:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:22]=2[C:23]#[N:24])=[CH:16][CH:17]=1
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: ClSc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Sc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3,4-Dichlorophenylsulfenyl chloride (1.6 g, 7.49 mmol) is added to a solution of 2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile (2.02 g, 7.48 mmol) and triethylamine (1.67 g, 16.5 mmol) in methylene chloride. The reaction mixture is stirred at room temperature for 24 hours and concentrated in vacuo to obtain a residue. The residue is slurried in ethyl acetate and the resultant mixture is filtered to remove solids. The filtrate is diluted with hexanes to precipitate a solid which is collected and dried to give the title product as a cream colored solid (mp 94°-97° C.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.C(O)(=O)C.S(=O)(=O)(O)O.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[C:7]([Br:24])[CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
A vigorously stirred solution of 1,3-bis(trifluoromethyl)benzene (107 g) in a mixture of glacial acetic acid (22 mL) and concentrated sulfuric acid (142 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (77.25 g) at 25° C. The exothermic reaction raised the temperature to approximately 40° C. After aging at 45° C. for 4.5 h, the mixture was cooled to approximately 0° C. and poured into cold water (250 mL). After washing with 5N NaOH (75 mL) the organic layer contained 137 g of the desired 3,5-bis(trifluoromethyl)-1-bromobenzene by assay (94% yield). This product was used in the next step without further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@H:8]([NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]1[O:32][CH2:31][CH2:30][O:29]1>C(#N)C.O>[O:29]1[CH2:30][CH2:31][O:32][CH:28]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C@H:7]1[C@@H:8]([NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:10])[NH:6]1
Reactant: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Solvent: O
Solvent: CC#N
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1c1ccccc1C1OCCO1

Procedure:
The product of Example 4 (1.56 g, 3 mmol) was dissolved in a mixture of acetonitrile (120 ml) and distilled water (30 ml), degassed with argon for 30 minutes, and brought to reflux. A degassed solution of K2S2O8 (5.67 g, 21 mmol) and Na2HPO4.7H2O (2.81 g, 10.5 mmol) in distilled water (120 ml) was added in 8 equal portions at 4 minute intervals to the refluxing solution, the reaction being kept at pH >6 by the addition of solid Na2HPO4.7H2O. The acetonitrile was evaporated and the residue was extracted with ethyl acetate. The extracts were washed with brine, dried, and evaporated to an oil, 2.07 g. The oil was extracted with petroleum ether to remove the dimethoxybenzaldehyde and then was triturated with ethyl acetate-ether. It was cooled in ice and the resulting solid product was collected; 0.54 g (49%), mp 137-138° dec.
Reaction SMILES: C[Al](C)C.[CH3:5][CH:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([O:23]C)=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[CH3:7].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH2:42])[NH:40][N:41]=2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1(C)C=CC=CC=1>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH:42][C:21]([C:18]3[CH:19]=[N:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][N:8]([CH:6]([CH3:5])[CH3:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)=[O:23])[NH:40][N:41]=2)[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCCN(C(C)C)CC2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C(C)C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
Trimethylaluminium (1.19 ml, 2.38 mmol) was added dropwise to a stirred suspension of methyl 2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (265 mg, 0.95 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (235 mg, 0.95 mmol) in toluene (4.76 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (81 mg, 17%) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[Cl:32][C:33]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[C:38]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[CH:12]=[C:13]([O:15][S:16]([C:19]([F:22])([F:20])[F:21])(=[O:17])=[O:18])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 1, step (d)) under the conditions described in Example 1, step (e-g)) using 4-chloro-5-trifluoromethylphenylboronic acid in step (e). RT=4.31 min
Reaction SMILES: CO[C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)=[O:14]>CC(O)=O.O>[OH:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[O:14][C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[CH:12][C:11]2=[O:23]
Reactant: COc1ccc(C(=O)CC(=O)c2cccc(OC)c2OC)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(O)cc2)oc2c(O)cccc12
Temperature: 110 °C
Yield: 51.9 %

Procedure:
1-(2,3-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (3.1 g, 9.86 mmol) was dissolved in mixture of Hi (10 mL) and AcOH (10 mL) and heated at 110° C. for 4 days. The reaction mixture was cooled to rt, diluted with water and solids were filtered. The solid product was washed with water, dried and purified by column chromatography, using 30% EtOAc in dichloromethane to give 1.3 g (52%) of 8-hydroxy-2-(4-hydroxy-phenyl)-4H-chromen-4-one. MS (ES) m/z: 255.08 (M+1), and 154.15.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[O:7][C:8]=1[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)(=[O:3])[NH2:2].Cl.O1CCOCC1.C([O-])=O>C(Cl)Cl>[NH2:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[O:7][C:6]([C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])=[N:5][C:4]=2[C:1]([NH2:2])=[O:3])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Agent: Cl
Agent: O=C[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of tert-butyl 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)benzylcarbamate (0.110 g, 0.26 mmol) in DCM (10 mL) was added 4M HCl in dioxane (1.5 mL, 6.0 mmol) and the resulting mixture stirred at room temperature overnight. The solvent was then removed in vacuo. The residue was purified by preparative HPLC to afford 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.0366 g, 0.11 mmol, 43%) as a white solid as the formate salt. 1H NMR (DMSO) 3.95 (2H, s), 7.40 (2H, t), 7.55 (2H, d), 7.74 (3H, m), 8.21 (2H, d), 8.33 (1H, s). LCMS (2) Rt: 2.30 min; m/z (ES+) 330.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])(=[O:9])=[O:8])[C:3]=1[C:19]([O:21][CH3:22])=[O:20].[C:23](OCC)(OCC)([O:25][CH2:26]C)[CH3:24]>C(O)(=O)C.C(#N)C>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[NH:10][S:7]([C:4]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[C:2]([N:1]=[C:23]([O:25][CH3:26])[CH3:24])[NH:6][N:5]=1)(=[O:8])=[O:9]
Reactant: CCOC(C)(OCC)OCC
Reactant: COC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)n[nH]c1N
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)n[nH]c1N=C(C)OC

Procedure:
5.0 g (15mmol) 5-amino-N-(2,6-difluorophenyl)-4-methoxycarbonylpyrazole-3-sulphonamide was heated under reflux with 50 ml acetonitrile, 2.1 ml (17.5 mmol) triethyl orthoacetate and 3 drops acetic acid for 8 hours. The undissolved residue was filtered and the filtrate concentrated. The residue was chromatographed with hexane/ethyl acetate over silica gel and recrystallised from ether.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])#[N:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[C:10]([C:8]#[N:9])=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC#N
Reactant: O=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of cyclohexanone (84.1 g, 1 mol) in dry benzene (100 mL) was added methyl cyanoacetate (99.1 g, 1 mol), ammonium acetate (10 g) and glacial acetic acid (20 mL). The reaction mixture was heated to reflux using Dean-Stark apparatus for 12 hours and allowed to cool to room temperature. Excess of solvents was removed in vacuo and the residue was dissolved in EtOAc (400 mL). The organic layer was washed with water, dried over sodium sulfate and evaporated to give cyano-cyclohexylidene-acetic acid methyl ester as pale yellow oil. Further purification of the pale yellow oil by distillation (10 mm Hg, 150–155° C.) gave product the title compound (110 g, 61%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.70–1.85 (m, 6H), 2.70 (t, 2H), 3.00 (t, 2H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 25.9, 28.6, 28.9, 31.9, 37.2, 52.8, 101.9, 115.8, 162.7, 180.8.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:27])[CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:8](=[O:27])[CH2:9][C:10]2[N:14]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Sc2ccccn2)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2ccc(Cl)cc2)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-thioacetic acid S-pyridin-2-yl ester 1c and 4-chlorophenylmagnesium bromide using a similar procedure described above. 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.38 (s, 3H), 4.61 (s, 2H), 7.02 (d, J=9.8 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.51 (t, J=9.1 Hz, 3H), 7.65 (s, 1H), 7.84 (d, J=8.4 Hz, 2H). Mass spectrum m/e 375 (M+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:21]3[C:20]4[CH:19]=[CH:18][C:17]([C:22]5[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=5)=[CH:16][C:15]=4[NH:14][C:13]=3[C:12]([C:28]#[N:29])=[CH:11][N:10]=2)[C@H:4]([CH3:30])[CH2:3]1.OO.C(=O)([O-])[O-:34].[K+].[K+]>CS(C)=O>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:21]3[C:20]4[CH:19]=[CH:18][C:17]([C:22]5[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=5)=[CH:16][C:15]=4[NH:14][C:13]=3[C:12]([C:28]([NH2:29])=[O:34])=[CH:11][N:10]=2)[C@H:4]([CH3:30])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3cc(-c4cnn(C)c4)ccc3c12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C(N)=O)c2[nH]c3cc(-c4cnn(C)c4)ccc3c12
Temperature: 70 °C

Procedure:
To a stirred solution of 1-{[(1R,2R,4R)-4-hydroxy-2-methylcyclohexyl]amino}-7-(1-methyl-1H-pyrazol-4-yl)-5H-pyrido[4,3-b]indole-4-carbonitrile (15 mg, 0.037 mmol) in DMSO (2 mL) were added hydrogen peroxide (30%, 0.038 mL, 0.38 mmol) and potassium carbonate (28 mg, 0.20 mmol). The reaction mixture was heated to 70° C. overnight, cooled to room temperature, filtered, and purified by prep-HPLC to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.42 (s, 1H); 8.07 (d, 1H); 7.99 (s, 1H); 7.88 (s, 1H); 7.77 (s, 1H); 7.48 (dd, 1H); 3.97 (m, 1H); 3.93 (s, 3H); 3.69 (m, 1H); 1.22-2.17 (series of m, 7H); 1.03 (d, 3H). LRMS (APCI) calc'd for (C23H26N6O2) [M+H]+, 419.2. found 419.1.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10][CH2:9]1.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH:30]=O)[CH3:25].C([BH3-])#N.[Na+]>C(O)(C)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:30][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10][CH2:9]1)[CH3:25]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: O=C1c2ccccc2CN1C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CN2CCC(N3Cc4ccccc4C3=O)CC2)ccc1C
Yield: 29.5 %

Procedure:
To a solution of 2-piperidin-4-yl-2,3-dihydro-isoindol-1-one trifluoroacetate (164.0 mg, 0.27 mmol, 1.0 equiv; 36% purity according to mass balance in preceeding step) in isopropanol (3.4 mL) was added 3-ethoxy-4-methyl-benzaldehyde (44.8 mg, 0.27 mmol, 1.0 equiv; intermediate B19), titanium tetra-isopropoxide (232.8 mg, 0.82 mmol, 3.0 equiv) and sodium cyanoborohydride (34.3 mg, 0.55 mmol, 2.0 equiv). The reaction mixture was allowed to react overnight and then poured directly onto a silica column. Eluting with ethyl acetate/triethylamine (98:2) yielded 29.0 mg (29%) of the title compound as white crystals. MS (ISP): 365.1 [M+H]+.