Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.[CH3:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li]CCCC>>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([CH:14]([CH3:13])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C/C=C/c1ccccc1
Agent: [Li]CCCC
Product: CC(Cc1ccccc1)N1CCN(c2ccccc2)CC1

Procedure:
According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and 2.22 mmol (=0.26 g=0.29 ml) of β-trans-methylstyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (3:1) gives the product 1-phenyl-4-(1-methyl-2-phenylethyl)piperazine as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([C@H:9](O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][CH3:24])[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].C(N(CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][CH3:24])[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(-c2cccc(CNC)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@@H](Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
19.6 g of the crude product methyl (2S,3R)-2-ethoxy-3-hydroxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate are dissolved in 200 ml of trifluoroacetic acid and 41.7 ml (297 mmol) of triethylamine are added. The reaction medium is stirred at room temperature for 48 hours and then extracted with ethyl acetate. The organic phase is decanted off, washed with a sodium hydroxide solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and methanol (95/5) mixture. 1.6 g (10%) of the expected product are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30].O>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH:23][C:29]([C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[O:30])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Solvent: O
Product: O=C(Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1)c1cccs1

Procedure:
The title compound is prepared from 6-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) and 2-thiophenecarbonyl chloride, containing 0.3 mol of water; mp 187°-188° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH3:4].I[CH2:22][CH2:23]CC.O>O1CCCC1>[CH2:3]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH2:4][CH2:22][CH3:23]
Reactant: CCCCI
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a suspension of sodium hydride (60-72% in mineral oil, 38 mg, 0.94 mmol) in tetrahydrofuran (2 ml) was added a suspension of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 47, step 2, 100 mg, 0.469 mmol) in tetrahydrofuran (5 ml) at 0° C. After 30 min, 1-iodobutane (0.11 ml, 0.94 mmol) was added. The mixture was stirred at room temperature for 3 h and at 70° C. for 4 h. After cooling to room temperature, water (30 ml) was added and extracted with ethyl acetate (50 ml×2). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The obtained solid was washed with hexane to give 67 mg (53%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])([CH3:3])[CH3:2].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH:1]([CH3:3])[CH3:2])=[O:5])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: CC(C)S(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)C(C)C)n1

Procedure:
A mixture of 6.4 g. 3-isopropylsulphinyl-1,2,4-triazole, 8.0 ml. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate was distilled under reduced pressure to give an oily residue which subsequently solidified. This solid residue was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-diallylcarbamoyl-3-isopropylsulphinyl-1,2,4-triazole, m.p. 32° - 34° C. Elemental analysis satisfactory.
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:16]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: O=C1Nc2ccccc2Oc2sccc21
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Yield: 74.2 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.5 g) was suspended in 1,2-dichloroethane (20 ml) and propionyl chloride (770 mg) was added. To this reaction system was added portionwise aluminum chloride (4.7 g) under ice-cooling. Insoluble matter was filtrated, and the filtrate was poured into ice water and chloroform was added. The aqueous layer was extracted twice with chloroform and the combined organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the precipitated crystals were collected by filtration to give 2-propionylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.4 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([CH2:10][N:11]2[C:17](=[O:18])[CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][S:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[ClH:29]>O1CCOCC1>[ClH:29].[NH2:19][CH:16]1[CH2:15][S:14][CH2:13][CH2:12][N:11]([CH2:10][C:9]2[CH:27]=[CH:28][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)[C:17]1=[O:18]
Reactant: CCCCOc1ccc(CN2CCSCC(NC(=O)OC(C)(C)C)C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOc1ccc(CN2CCSCC(N)C2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
260 mg of 39 (0.64 mmol) are taken up in a 25 ml round-bottomed flask and 4 ml of a solution of hydrogen chloride in dioxane (4M) are added. The mixture is stirred for 4 hours at room temperature under argon. After evaporating off the solvent, 280 mg of amine 40 are obtained in hydrochloride form, which product is used directly in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.CCOCC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CNc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a solution of 4-bromo-3-chloro-aniline (0.64 g, 3.10 mmol) in ethanol (7 ml) were added sodium carbonate (0.49 g, 4.65 mmol) and ethyl bromoacetate (0.38 ml, 3.41 mmol). The resulting suspension was stirred at room temperature for 10 min and was then heated at 100° C. for 30 min under microwave irradiation. The mixture was then cooled to room temperature, diluted with ether, and filtered. The filtrate was washed with 1 M aqueous hydrochloric acid, the phases separated, and the aqueous phase extracted with ether. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=gradient 100:0-70:30) to yield a brown oil (0.56 g, 62%); MS (ISP): 296.1, 294.1, 292.1 ([M+H]+.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][C:21]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)=[CH:20][C:19]=4[N:18]=[C:17]([NH2:32])[C:16]=3[N:15]=[C:14]2[CH2:33][O:34][CH2:35][CH3:36])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:32][C:17]1[C:16]2[N:15]=[C:14]([CH2:33][O:34][CH2:35][CH3:36])[N:13]([CH2:12][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][CH:37]=3)[C:25]=2[C:24]2[CH:23]=[CH:22][C:21]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:20][C:19]=2[N:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CNS(C)(=O)=O)cc1
Reaction time: 16 h
Yield: 38.7 %

Procedure:
Methanesulfonyl chloride (0.13 mL, 1.7 mmol) was added dropwise to a mixture of 1-(4-aminomethylbenzyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.520 g, 1.2 mmol) in dichloromethane (10 mL). The reaction was stirred for 16 hours and then saturated aqueous sodium carbonate was added. The layers were separated and the aqueous fraction was extracted with 95:5 chloroform/methanol. The organic fractions were combined and washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography with a gradient of CMA (2%–10%) in chloroform as the eluent. A final recrystallization from 2-propanol provided 0.240 g of N-{4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}methanesulfonamide as white granular crystals, mp 228.0–229.0° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Br:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]1[CH:17]=[CH:18][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:26]1[CH:25]([CH2:24][C:22]([OH:23])=[O:21])[CH2:30][CH2:29][CH2:28][C:27]2=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(Br)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-bromophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C(#N)C>[Br:35][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: COc1ccc2[nH]cc(CCO)c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc2[nH]cc(CCBr)c2c1
Reaction time: 2 h

Procedure:
A mixture of 10 g of the product obtained in Stage 1 (0.0523 mol), 16.5 g of triphenylphosphine (0.0628 mol), 17.3 g of carbon tetrabromide (0.0628 mol) and 200 ml of acetonitrile is left stirring for 2 hours. The solvent is then evaporated under vacuum and the product purified by chromatography on a silica column, Merck 70-230 mesh, using dichloromethane as eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(O)Cc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of 20 g (82.64 mmol) of O-benzylvanillin in 200 mL of dry tetrahydrofuran was slowly added to a stirred solution of benzyl magnesium chloride (103.30 mmol) in 150 mL of diethylether at 10° C. over 20 min, and the reaction mixture was then boiled for 10 min, cooled, quenched with a mixture of ice and dilute hydrochloric acid and evaporated at reduced pressure. The residue was dissolved in dichloromethane, the solution washed with brine, dried with sodium sulphate and the solvent was evaporated under reduced pressure leaving a crystalline residue that was recrystallised from diethylether and petroleum ether. 1-(4-Benzyloxy-3-methoxyphenyl)-2-phenyl-1-ethanol was obtained as white crystals, m.p. 97 to 98° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH2:27]([NH2:31])[CH2:28][CH2:29][NH2:30].[BH4-].[Na+]>C1COCC1.CO>[NH2:30][CH2:29][CH2:28][CH2:27][NH:31][CH2:16][C:13]1[C:14]([F:15])=[C:2]([F:1])[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: NCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NCCCNCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 was reacted with propane-1,3-diamine in THF. The thus-obtained imine was reduced with sodium borohydride in methanol to give the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41]C(C#N)=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.Cl.[OH-].[Na+].[C:48]([OH:51])(=[O:50])[CH3:49]>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][C:49]([C:48]([OH:51])=[O:50])=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)O
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (128 mg) obtained in Example 191-(1) was dissolved in acetic acid (2 ml) and added thereto was a concentrated hydrochloric acid aqueous solution (2 ml). The mixture was refluxed for 6.5 hours. To the mixture was added a 10% aqueous sodium hydroxide solution at 0° C., and the mixture was washed with ethyl acetate. The aqueous layer was acidified by adding concentrated hydrochloric acid, and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by washing with a mixture of ethyl acetate and diethyl ether to give the desired 1-(β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene (49 mg) as pale brown powder. ESI-Mass m/Z 489/491 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH:15]C(=O)C(C)(C)C)[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(COCc2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(COCc2ccc(F)cc2)n1

Procedure:
This material was prepared in analogy to example 86 step B] from N-[6-(4-Fluoro-benzyloxymethyl)-pyridin-2-yl]-2,2-dimethyl-propionamide (0.825 g) and 3M aqueous NaOH (4.35 mL) as a yellow oil (0.596 g). MS (ESI): 233.1 (MH+).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[S:14][C:15]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:16][N:17]=1.CN(C)[CH:30]=[O:31]>C(OCC)C>[F:20][C:19]([F:22])([F:21])[C:18]([C:15]1[S:14][C:13]([CH:30]=[O:31])=[N:17][CH:16]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CN(C)C=O
Reactant: OC(c1cnc(Br)s1)(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a nitrogen purged three-necked flask was added n-butyl lithium in hexane (2.5M, 9.09 mmol, 3.64 mL) and diethyl ether (8 mL). The solution was cooled to −78° C. and 2-(2-bromothiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.03 mmol, 1 g) in diethyl ether (7 mL) added drop wise over a period of 15 minutes. The mixture was stirred at −78° C. for 20 minutes before the drop wise addition of N,N-dimethylformamide (4.54 mmol, 0.332 g) in diethyl ether (4 mL). The mixture was stirred at −78° C. for 1 hour then was allowed to warm to −60° C. and stir for 1 hour. The mixture was slowly quenched with 4M hydrochloric acid at −60° C. and allowed to warm to room temperature. The mixture was extracted with diethyl ether (100 mL), washed with 4M hydrochloric acid (50 mL), followed by water (50 mL) and then brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with a gradient of heptane to 50% ethyl acetate/50% heptane) to afford the title compound (500 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:15]([OH:18])(=[O:17])[CH3:16]>[Pd]>[C:15]([OH:18])(=[O:17])[CH3:16].[Cl:1][C:2]1[C:3]([CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: N#CCc1ncc(C(F)(F)F)cc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: NCCc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
113 g of [3-chloro-5-(trifluoromethyl)-2-pyridinyl]acetonitrile (0.51 mol, 1 eq.) are diluted in 2.5 L of acetic acid. 30 g of palladium (5% on charcoal) are added. The reaction medium is stirred at ambient temperature under a hydrogen pressure of 5 bar. The progress of the reaction is followed by TLC; when the [3-chloro-5-(trifluoromethyl)-2-pyridinyl]acetonitrile has been completely used up, the medium is filtered over a bed of celite, and then concentrated to dryness so as to produce the 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethanamine acetate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=1)=[O:10])[CH3:7]>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[CH:12]=1)=[O:10])[CH3:7]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccco1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1CCCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.4 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-furan-2-yl-ethyl)-amide (370 mg, 0.66 mmol) was dissolved in methanol (6 ml) and ethyl acetate (2 ml). The flask was flushed with argon then 20% palladium hydroxide on carbon (50% water, 100 mg, 0.71 mmol) was added. The reaction mixture was stirred under hydrogen atmosphere (balloon) at room temperature for 48 h then filtered over Celite and rinsed with dichloromethane/ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2.5% MeOH) to afford 300 mg (86%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(tetrahydro-furan-2-yl)-ethyl]-amide as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[O:20][C:21]([C:24]3[CH:29]=[C:28]([CH:30]=[CH2:31])[CH:27]=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[H][H]>CCO.CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[O:20][C:21]([C:24]3[CH:25]=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:27]=[C:28]([CH2:30][CH3:31])[CH:29]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: C=Cc1cc(-c2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)o2)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(-c2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)o2)cc(C(F)(F)F)c1
Yield: 24 %

Procedure:
A mixture of example 114 compound (20 mg, 0.04 mmol) and 10% Pd—C (10 mg) in EtOH was hydrogenated using hydrogen balloon for 2 hours. The mixture was diluted with EtOAc, filtered through silica gel pad and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (5 mg, 24%) after recrystallization with EtOAc/Hex.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].N1C=CC=CC=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[O:12]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:27])=[O:26])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)CCO2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CCOc2ccc(NS(=O)(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 6-amino-2,3-dihydro-4H-chromen-4-one (330 mg, 2.02 mmol) in CH2Cl2 is treated with pyridine (1 mL) and benzenesulfonyl chloride (0.28 mL, 2.2 mmol), stirred at ambient temperature for 1 hour, poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is washed sequentially with dilute hydrochloric acid until the pH of the wash is <2 and a saturated solution of sodium bicarbonate, dried over MgSO4 and concentrated in vacuo to afford the title compound as a beige solid, 460 mg (74% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].CN(C)[CH:9]=[CH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH:2]([N:5]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6]1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=O)C=CN(C)C
Reactant: CC(C)NN
Agent: Cl
Product: CCOC(=O)c1ccn(C(C)C)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using isopropylhydrazine hydrochloride and ethyl 4-(Dimethylamino)-2-oxobut-3-enoate at 120° C. for hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-40%). tR: 3.73 min (HPLC 1); tR: 0.80 min (LC-MS 2); ESI-MS: 183 [M+H]+ (LC-MS 2); Rf=0.69 (hexane/EtOAc 1:1).