Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(O)(=O)C=[O:4].[CH2:7]1[CH2:12][CH2:11][CH:10]([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][CH2:8]1>CN(C=O)C>[C:14]([NH:13][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1)([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:4]
Reactant: O=CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
To a stirred solution of glyoxylic acid monohydrate (431 mg, 4.56 mmol) in anhydrous DMF (5 mL) were added NHS (563 mg, 4.89 mmol) and DCC (1.00 g, 4.85 mmol). A white solid (dicyclohexylurea) formed immediately. As the reaction was exothermic, the flask was cooled in an ice-bath for a while (approximately 5 minutes). The reaction mixture was then stirred under nitrogen at room temperature for approximately 1 hour. The solid was filtered off and washed with DMF. The filtrate (containing glyoxylic acid NHS ester) was then added to the reaction mixture obtained above. After stirring the mixture for approximately 5 minutes, a clear solution was obtained. TLC revealed completion of the reaction. The solvent was removed under reduced pressure. Flash chromatography (20:1 and 15:1 CH2Cl2—CH3OH followed by 20:1, 15:1 and 12:1 CH2Cl2—CH3OH containing 1% acetic acid) provided the desired Pro4-de novo-CHO (132 mg, 55%). The mass spectrum was in agreement with the assigned structure.
Reaction SMILES: C(O)C(N)(CO)CO.[NH2:9][C@@H:10]([CH2:14][CH2:15][C:16](N[C@H](C(NCC(O)=O)=O)CS)=O)[C:11]([OH:13])=[O:12].C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-].[CH2:41](S)[C@@H:42](O)[C@H:43]([OH:46])[CH2:44]S.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.CC1C=CC(NC(C2C=CC(CN3CCN(C)CC3)=CC=2)=O)=CC=1NC1N=CC=C(C2C=CC=NC=2)N=1>O>[NH2:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:14][C:15]1[CH:16]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 1 h

Procedure:
Bead-Based Kinase Assays. SwellGel Discs (Pierce) were suspended in cold 50 mM Tris, pH 7.5 so that 1 μl of bead suspension bound 1 μg of GST fusion protein. One nmol of GST-Crkl substrate was incubated with the glutathione bead suspension for 1 h at 4° C. with constant rotation. The substrate-bound beads were washed twice with ice-cold 50 mM Tris-HCl, pH 7.5 containing 10 mM MgCl2. Substrate-bound beads were then incubated with either recombinant v-Abl or K562 cell lysate. The v-Abl reaction mixtures contained: 20 μl 4×buffer (200 mM Tris-HCl, 40 mM MgCl2, 4 mM DTT, pH 7.5); 20 μl 40 μM ATP; 0.5 μl v-Abl (EMD Biosciences, Inc., San Diego, Calif.); 0 or 20 μl 400 μM imatinib; and water to a total volume of 80 μl. The K562 cell lysate reaction mixtures contained: 20 μl 4×buffer; 20 μl 40 μM ATP; 50 μg K562 cell lysate; 0 or 20 μl 400 μM imatinib; and water to a total volume of 80 μl. The reactions allowed to proceed for 1 h at 30° C. Following the reaction, the beads were washed twice with ice-cold 50 mM Tris, pH7.5. GST-Crkl substrates were eluted with 10 mM reduced glutathione in 50 mM Tris-HCl, pH 8.0. Kinase assay samples were loaded in a 12% SDS-PAGE gel and transferred to nitrocellulose membranes according to standard procedures. Consistent sample loading was verified using the Memcode Reversible Protein Stain Kit (Pierce). Membranes were probed with anti-phosphotyrosine antibodies.
Reaction SMILES: N[C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[C:3]=1[Br:12].CC(O)=O.[PH2](O)=O.N([O-])=O.[Na+]>O>[Br:12][C:3]1[C:4]([F:11])=[C:5]([CH:8]=[C:9]([F:10])[CH:2]=1)[CH:6]=[O:7]
Reactant: Nc1c(F)cc(C=O)c(F)c1Br
Agent: O=N[O-]
Agent: O=[PH2]O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cc(F)cc(Br)c1F
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A mixture of 16 g of 4-amino-3-bromo-2,5-difluorobenzaldehyde and 375 mL of AcOH is stirred until homogenous and 188 mL of 50-52% aqueous hypophosphorous acid is added. Next a solution of 6.8 g of NaNO2 in 38 mL of H2O is added dropwise over 15 minutes with ice cooling to maintain a temperature of 15°-20° C. The ice bath is removed and stirring continued for 1 hour. the reaction mixture is poured into 1 L of ice/H2O and extracted with 3×300 mL of CH2Cl2. The CH2Cl2 extracts are washed with H2O, 2×10% NaOH, and 2×H2O (250 mL each), dried with Na2SO4 and concentrated in vacuo to give 13.32 g (80% yield) of 3-bromo-2,5-difluorobenzaldehyde, m.p. 36°-38° C. Recrystallization from Et2O/hexane furnishes the title compound melting at 37°-40° C. with M+1 ions at 221 and 223 in the mass spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][OH:37])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][OH:37])[CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OCC1CCCNC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCC(CO)C3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 3-piperidine methanol (0.022 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[3-(hydroxymethyl)piperidinomethyl]indol-2-yl)isoindolinone.
Reaction SMILES: N[C:2]1[C:3]2[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[NH:28][C:4]=2[N:5]=[C:6]([C:8]2[N:9]=[C:10]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=3[F:27])[N:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=23)[N:7]=1.[I-:34].[Cs+].II.N(OCCC(C)C)=O>COCCOC.[Cu]I>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([C:10]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=3[F:27])=[N:9][C:8]=2[C:6]2[N:7]=[C:2]([I:34])[C:3]3[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[NH:28][C:4]=3[N:5]=2)[CH:16]=1
Reactant: [I-]
Reactant: CC1(C)C(=O)Nc2nc(-c3nc(Cc4c(F)ccc(F)c4F)n4cc(Cl)ccc34)nc(N)c21
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: CC1(C)C(=O)Nc2nc(-c3nc(Cc4c(F)ccc(F)c4F)n4cc(Cl)ccc34)nc(I)c21
Yield: 34.4 %

Procedure:
556 mg (1.176 mmol) of 4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (described in WO 2010/065275) was put in 1,2-dimethoxyethane (14 ml), and 305 mg (1.176 mmol) of caesium iodide, 149 mg (0.588 mmol) of iodine and 67 mg (0.353 mmol) of copper(I) iodide were added at room temperature. Then isopentyl nitrite (0.933 ml) was added and it was heated overnight to 60° C. Next day, 305 mg (1.176 mmol) of caesium iodide, 149 mg (0.588 mmol) of iodine and 67 mg (0.353 mmol) of copper(I) iodide, and isopentyl nitrite (0.933 ml) were added again and it was heated for 3 days to 60° C. After cooling, it was combined with a smaller batch (starting from 50 mg 4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one). It was extracted with ethyl acetate and saturated aqueous sodium thiosulphate and the phases were separated. The organic phase was extracted twice more with saturated aqueous sodium thiosulphate. Then the organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered, concentrated by evaporation and the residue was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 236 mg of the title compound was obtained (31% of theor.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH3:17])[N:5]([C:13](=[O:16])[CH2:14][OH:15])[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12].[H-].[Na+].[CH3:21][N:22]([CH3:27])[S:23](Cl)(=[O:25])=[O:24]>C(COC)OC>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH3:17])[N:5]([C:13](=[O:16])[CH2:14][O:15][S:23]([N:22]([CH3:27])[CH3:21])(=[O:25])=[O:24])[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12]
Reactant: COC(=O)[C@H](C)N(C(=O)CO)c1c(C)csc1C
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](C)N(C(=O)COS(=O)(=O)N(C)C)c1c(C)csc1C
Temperature: 25 °C

Procedure:
8.13 g (0.03 mol) N-(hydroxyacetyl)-N-(2,4-dimethylthien-3-yl)-alanine-methylester is added in portions to a slurry of 1.05 g (0.035 mol) sodium hydride (80% in mineral oil) in 50 ml dry dimethoxyethane with stirring at 10°-15° under a blanket of nitrogen. The mixture is stirred at room temperature for half an hour, and then are added 4.3 g (0.03 mol) dimethylsulphamic acid chloride. The mixture is stirred for 18 hours at 50°, then cooled to room temperature, filtered, concentrated in vacuo, the residue taken up in CHCl3, washed thoroughly with water, dried over MgSO4 and evaporated in vacuo to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6]/[C:7](/[C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH2:32])=[O:31])=[C:8](/[NH:10][C:11](=[O:26])[C:12]([CH3:25])([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[CH3:13])\[CH3:9])=[CH:4][CH:3]=1.CC(OO)=O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH2:32])=[O:31])[C@@H:8]([NH:10][C:11](=[O:26])[C:12]([CH3:13])([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[CH3:25])[CH3:9])=[CH:36][CH:37]=1
Reactant: C/C(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)=C(\Cc1ccc(Cl)cc1)c1cccc(C(N)=O)c1
Agent: *CC*
Agent: CC(=O)OO
Solvent: CC(C)O
Product: C[C@H](NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C(N)=O)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
3-{(1Z)-1-(4-chlorobenzyl)-2-[(2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoyl)amino]-prop-1-en-1-yl}benzamide (486 g, Example 15) was charged to a 5 L bottle, and isopropanol (3.3 L) was added to the bottle to create a slurry. The resulting slurry was transferred by vacuum through a polyethylene line into a 2 gallon stainless steel autoclave. The 5-L bottle was rinsed with 1 L of isopropanol and the rinse was also transferred into the 2 gallon autoclave. The autoclave was degassed with N2 (5×), and then placed under partial vacuum. The catalyst bomb was connected to the autoclave via flexible polyethylene tubing (flushed with N2) and the catalyst solution was drawn into the autoclave followed by the isopropanol wash from the rinse chamber. The autoclave was sealed, degassed with N2 purges three times, degassed with H2 purges three times and pressurized up to 150 psi. The stirrer was initiated, and the temperature was raised to 40° C. The reaction was aged at 150 psi, 40° C. for 18 hours. The temperature was dropped to room temperature, and the resulting solution was transferred to a polyethylene jug and assayed for ee and purity (475.7 g assay of the title compound, 98% assay yield, 99.6 LCAP, 92.1% ee).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH2:29][CH2:30][CH2:31][CH3:32])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])=[O:27])=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH3:4].Cl>C(O)(C)C.C(O)C>[CH2:29]([C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])=[O:27])=[CH:16][CH:15]=2)[C:10]([C:11]#[N:12])=[C:6]([CH:3]([OH:5])[CH3:4])[N:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: CCCCc1nc(C(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
68 mg of sodium borohydride were added to a solution of 718 mg of 4-acetyl-2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-cyanoimidazole [prepared as described in step (b) above] in a mixture of 20 ml of isopropanol and 10 ml of ethanol, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the pH of the reaction mixture was adjusted to a value of 3 by the addition of 1N aqueous hydrochloric acid, after which the solvent was distilled off under reduced pressure. The resulting residue was mixed with methylene chloride and water, and the methylene chloride layer was separated. The aqueous layer was extracted three times with methylene chloride, and the combined extracts were dried and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature. The solid which then deposited was collected by filtration and dried, to give 398 mg of the title compound as a colorless powder, melting at 200°-201° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[N:24]=[N:25][C:26](Cl)=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[N:24]=[N:25][C:26]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)nnc2CC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccccc3)nnc2CC1
Temperature: 90 °C
Yield: 149.9 %

Procedure:
5 g phenylboronic acid in 30 mL dioxane was added to 3.2 g 3-chloro-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester and 388 mg (1,1′-bis(diphenyl-phosphinoferrocene)palladium(II)dichloride in 50 mL dioxane under argon. The reaction was stirred at 90° C. over night. The mixture was cooled to RT diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydroxide and brine. The solvent was removed and the precipitate was purified by column chromatographie to yielded 5.5 g of the desired product. (M+H)+=325
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:20])([CH3:19])[C:5](=[O:18])[C:6]([C:13](OCC)=[O:14])=[C:7]2[OH:12].C(N(C(C)C)C(C)C)C.Cl.[NH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:19])([CH3:20])[C:5](=[O:18])[C:6]([C:13]([NH:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:14])=[C:7]2[OH:12]
Reactant: CCOC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To a solution of ethyl 5-fluoro-1-hydroxy-4,4-dimethyl-3-oxo-3,4-dihydronaphthalene-2-carboxylate (2.0 g, 7.2 mmol) in 1,4-dioxane (15 mL), was added N-ethyl-N-isopropylpropan-2-amine (2.3 mL, 13 mmol) and tert-butyl 2-aminoacetate hydrochloride (1.6 g, 9.3 mmol). After heating at 80° C. for 12 hours, the solvent was removed in vacuo, and the residue was purified using flash chromatography (15% EtOAc/hexane) to afford the product as a white solid (1.6 g). MS (m/z)=362 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[N:7][CH:8]=1.[O:17]=[C:18]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C.[Cl-].[Li+]>CCCCCC.C(OCC)(=O)C.O.O1CCCC1>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:6]1[N:7]=[CH:8][C:3]([CH2:2][CH:19]([C:18](=[O:17])[CH2:24][CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:5]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cn1
Reactant: CCCCC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Yield: 51 %

Procedure:
Process 1: Under argon atmosphere, a tetrahydrofuran (900 mL) solution of 2-[5-(bromomethyl)pyridin-2-yl]benzonitrile (31.9 g, 117 mmol), methyl 3-oxoheptanoate (27.8 g, 176 mmol), diisopropylethylamine (31.0 g, 240 mmol), and lithium chloride (8.2 g, 193 mmol) was refluxed for 23 hours under heating. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydeous sodium sulfate, and concentrated in vacuo. The residues obtained were subjected to silica gel column chromatography (hexane/ethyl acetate=2:1), to obtain methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxoheptanoate (20.9 g, 51%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=O)[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.Cl.[NH2:25]O>C(O)C.CCOCC.CCCCCCC.[Zn]>[NH2:25][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[NH:8][C:9](=[O:10])[C:4]3[CH:3]=[C:2]([CH3:1])[S:23][C:5]=3[N:6]=2)[CH:16]=1
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Reactant: NO
Agent: Cl
Agent: [Zn]
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CN)c(C(F)(F)F)n3)nc2s1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
A solution of 1-((6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (2.92 mmol, 1 g) and hydroxylamine hydrochloride (3.21 mmol, 0.223 g) in ethanol (7 mL) was heated to 80° C. and this temperature was maintained for 3 h. The reaction mixture was allowed to cool to room temperature & diluted with ether and heptane before the resulting precipitate was collected by filtration. The resulting solid was taken up in acetic acid (5 mL) and zinc (7.79 mmol, 0.510 g) and the whole was stirred at room temperature for 3 days with occassional agitation by sonication. The reaction mixture was filtered through celite and the pad washed with MeOH before the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and applied to an SCX cartridge that had been equilibrated with the same solvent before being eluted with 2N NH3/MeOH to give a light yellow solid (271 mg, 0.79 mmol, 50.6%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1.CC(C)(O)[C:16]#[N:17].C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]1[C:16]#[N:17]
Reactant: O=C1CCC=C1CCCCCCO
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1CCC(=O)C1CCCCCCO
Yield: 72.5 %

Procedure:
A mixture of 2-(6-hydroxyhexyl)-2-cyclopenten-1-one (10.5 g., 0.058 mole), acetone cyanohydrin (5.6 g., 0.065 mole), 6% aqueous sodium carbonate (5.2 ml.) and methanol (35 ml.) was stirred and heated under reflux for 4 hours. Methanol was removed in vacuo, water (70 ml.) was added and the mixture was extracted with diethyl ether and dried over magnesium sulphate. The solvent was removed by evaporation and the residue was distilled under reduced pressure to give 2-(6-hydroxyhexyl)-3-oxocyclopentanecarbonitrile (8.8 g., 73%), b.p. 135°-178°C./0.15 mm.Hg, nD25 1.4812.
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[CH3:19][Li]>C1COCC1>[F:12][S:11]([F:16])([F:15])([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:17])[CH3:19])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methyl-4-(pentafluoro-λ6-sulfanyl)benzamide (Preparation 42, 3.0 g, 10.3 mmol) in THF (100 mL) at 0° C. was added drop-wise methyl lithium (1.5M solution, 10.3 mL, 15.5 mmol). The reaction was stirred at 0° C. for 2 hours, then quenched with a saturated aqueous solution of ammonium acetate. The reaction was extracted with ethyl acetate and dried over MgSO4 before concentrating in vacuo to afford the title compound that was used without further purification.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[N:5]12[CH2:15][CH2:14][CH2:13][N:12]=[C:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2>>[S-:1][C:2]#[N:3].[NH+:5]12[CH2:15][CH2:14][CH2:13][N:12]=[C:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: C1CCC2=NCCCN2CC1
Agent: N#C[S-]
Agent: [NH4+]
Product: C1CCC2=NCCC[NH+]2CC1

Procedure:
38.1 g (0.5 mol) of ammonium thiocyanate were introduced into a 500 ml stirred reactor fitted with nitrogen inlet and separate feed device and suspended in 200 ml of methanol. Over the course of 30 minutes 76.1 g (0.5 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added, where upon the reaction mixture was solubilized. The mixture was stirred for a further three hours and then the solvent was evaporated and the remaining solid dried in vacuo.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[Cl:13][C:14]1[C:23]([NH2:24])=[C:22]([NH:25][CH2:26][C:27]2[O:31][N:30]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:28]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:13][C:14]1[C:23]2[N:24]=[C:1]([CH2:2][CH3:3])[N:25]([CH2:26][C:27]3[O:31][N:30]=[C:29]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[CH:28]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 110 °C
Yield: 67.9 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (0.020 g, 0.19 mmol), triethyl orthopropionate (2.5 g, 14 mmol), 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined and heated at 110° C. for 18 hours. Most of the volatiles were removed under reduced pressure to provide a suspension. The solid was isolated by filtration, washed with diethyl ether, and dried to provide 2.624 g of 4-chloro-2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[C:6]([O:14][CH2:15][O:16][CH3:17])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH3:13][O:12][CH2:11][O:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([O:14][CH2:15][O:16][CH3:17])[CH:7]=1
Reactant: COCOc1cc(OCOC)cc(C(=O)OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COCOc1cc(CO)cc(OCOC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
The above-obtained 3,5-bis(methoxymethoxy)benzoic acid methyl ester (9.1 g, 36 mmol) was dissolved in diethylether (50 mL) and cooled to 0° C. To the obtained solution, lithium aluminum hydride (2.0 g, 54 mmol) was slowly added followed by stirring at 0° C. for 2 hours. The reaction mixture was further added with sodium sulfate decahydrate (40 g), and was stirred for another 1 hour. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 3,5-bis(methoxymethoxy)phenylmethanol (7.6 g, 94%).