Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.Br[CH:21]([CH3:31])[C:22]([O:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:6][C:5]1[CH:18]=[CH:19][C:2]([O:1][CH:21]([CH3:31])[C:22]([O:24][CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:23])=[CH:3][CH:4]=1)[CH:16]=[N:15]2
Reactant: CC(Br)C(=O)OCc1cccs1
Reactant: Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)OCc1cccs1

Procedure:
To a 250 milliliter roundbottom flask equipped with stir bar, reflux condenser, connecting tube, and nitrogen atmosphere were added 4.3781 grams (0.0161 moles) of 2-(4-hydroxyphenoxy)-6-chloroquinoxaline, 4.000 grams (0.0161 moles) of 2-thiophenylmethyl 2-bromopropanoate, 4.4377 grams (0.0321 moles) of anhydrous potassium carbonate, and 100 milliters of acetonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[F:7][C:8]([F:31])([F:30])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[Cl:28])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:30][C:8]([F:7])([F:31])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([NH:1][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])=[CH:20][C:19]=2[Cl:28])=[CH:12][CH:11]=1
Reactant: CC(C)(O)CN
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1cc(Cl)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 1-amino-2-methyl-propan-2-ol (184 mg, 2.06 mmol), N-(4-trifluoromethoxy-phenyl)-2-chloro-4-fluoro-5-nitro-benzoic acid amide (650 mg, 1.7 mmol), Cs2CO3 (839 mg, 2.6 mmol) and 10 mL DMF is stirred for 1 h at 50° C., poured into ice water, concentrated and the resulting precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH2:39][N:40]5[CH:44]=[N:43][CH:42]=[N:41]5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][CH2:39][N:40]5[CH:44]=[N:43][CH:42]=[N:41]5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4cncn4)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4cncn4)cc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[2-(1,2,4-triazol-1-yl)ethyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.86 g) was dissolved in methylene chloride (25.8 ml), and to the mixture was added dropwise a solution of m-chloroperbenzoic acid (0.36 g) in methylene chloride (17.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[2-(1,2,4-triazol-1-yl)ethyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 284) (0.57 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([C:12]([F:15])([CH3:14])[CH3:13])[CH2:10]I)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:1]([O:5][C:6]([NH:8][CH:9]([C:12]([F:15])([CH3:13])[CH3:14])[CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NC(CI)C(C)(C)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCOC(=O)NC(C)C(C)(C)F
Reaction time: 20 h
Yield: 89.5 %

Procedure:
A Parr bottle was charged with palladium (II) hydroxide (800 mg), a solution of N-butoxycarbonyl-1-iodo-2-amino-3-fluoro-3-methyl-n-butane (3.26 g, 9.8 mmol) in ethanol (80 mL) and triethylamine (0.99 g, 9.8 mmol). The reaction mixture was placed under hydrogen gas (50 psig) and shaken for 20 hours. The mixture was filtered through Celite® and evaporated. The residue was dissolved in diethyl ether (100 mL) and washed with 1N aqueous HCl (2×50 mL), water (2×50 mL), and then dried (MgSO4). Filtration and evaporation gave a residue that was chromatographed (silica gel, diethyl ether/hexane (3/1)) to afford 1.80 g of N-butoxycarbonyl-2-amino-3-fluoro-3-methyl-n-butane: 1H NMR (CDCl3) δ4.65 (br, 1H), 3.70 (br m, 1H), 1.45 (s, 9H), 1.39 (d, 3H), 1.32 (d, 3H), 1.18 (d, 3H) ppm.
Reaction SMILES: C(O[C:6]([N:8]([N:10]1[C:19]2[C:14](=[C:15]([F:23])[C:16]([F:22])=[C:17]([F:21])[C:18]=2[F:20])[C:13](=[O:24])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11]1)C)=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[CH3:6][NH:8][N:10]1[C:19]2[C:14](=[C:15]([F:23])[C:16]([F:22])=[C:17]([F:21])[C:18]=2[F:20])[C:13](=[O:24])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11]1
Reactant: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)c(F)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
4.2 g of the compound (193) obtained above was dissolved in 30 ml of ethyl acetate, and while cooling with ice, 40 ml of 4N hydrochloric acid solution in dioxane was added to the solution. The solution was stirred overnight at room temperature, and the solvent was removed by distillation. The residue was dissolved in 100 ml of chloroform, and 50 ml of aqueous 10% sodium carbonate solution was added to the solution. The solution was stirred for 30 minutes at room temperature. The organic layer was separated and after drying over magnesium sulfate, the solvent was removed by distillation. Crystals were dispersed in ether and filtered to obtain 2.9 g of the subject compound (194) in a 91% yield.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[N:21]#[C:22]Br>C1COCC1.CCOC(C)=O>[CH2:13]([N:6]([CH2:5][C@@H:2]1[CH2:3][O:4][C:22]([NH2:21])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: N#CBr
Reactant: CCN(C[C@@H](N)CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(C[C@@H]1COC(N)=N1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
To a stirred solution of (R)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (235 mg) at r.t. in THF (10 ml) under an argon atmosphere were added potassium carbonate (334 mg) and a solution of cyanogen bromide (256 mg) in THF (5 ml). Stirring at r.t. was continued for 18 h. The mixture (off-white suspension) was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient:CH2Cl2->CH2Cl2/MeOH 9:1) to provide (R)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (142 mg, 54%) as off-white solid. MS (ISP): 220.1 ([M+H]+)
Reaction SMILES: CS(O[CH:6]([CH2:21][CH3:22])[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33]>C1(C)C=CC=CC=1>[Cl:32][C:26]1[C:25]([CH3:33])=[C:24]([N:23]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[CH2:21][CH3:22])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: CCC(CCC(OS(C)(=O)=O)c1ccccc1)OS(C)(=O)=O
Reactant: Cc1c(N)ccc(C#N)c1Cl
Solvent: Cc1ccccc1
Product: CCC1CCC(c2ccccc2)N1c1ccc(C#N)c(Cl)c1C
Yield: 2 %

Procedure:
Dissolve methanesulfonic acid 4-methanesulfonyloxy-1-phenyl-hexyl ester (381 mg, 1.09 mmol) in toluene (10 mL) in a reaction tube. Add 4-amino-2-chloro-3-methylbenzonitrile (363 mg, 2.18 mmol), purge with nitrogen and cap. Heat the reaction in a 120° C. oil bath for 17 h. Cool, concentrate, and purify by silica gel chromatography using 5-30% EtOAc/hexanes to obtain 7 mg (1%) of the title compound (a mixture of 4 isomers) as a clear oil. MS (ESI+): 325 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:16]=[CH:15]3)=[O:10])=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[N:16]=[CH:15]4)=[O:10])=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(NC(=O)Nc2ccc3c(cnn3CCN3CCCC3)c2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Yield: 45.4 %

Procedure:
A mixture of 1-(4-amino-phenyl)-3-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-yl]-urea (364 mg, 1 mmol), phenylboronic acid (244 mg, 2 mmol), copper(II) acetate (364 mg, 2 mmol), triethylamine (0.2 mL, 2 mmol), in 20 mL of dichloromethane was refluxed overnight. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (acetonitrile/ethyl acetate/triethylamine, 10/4/1) to provide the title compound as a pale white solid (200 mg, 45%). 1H NMR (300 MHz, DMSO-d6) ppm 1.63 (m, 4H), 2.45 (m, 4H), 2.86 (d, J=6.44, 2H), 4.46 (d, J=6.44, 2H), 6.74 (m, 1H), 6.98 (m, 2H), 7.03 (m, 2H), 7.18 (m, 1H), 7.33–7.36 (m, 3H), 7.58 (m, 1H), 7.88 (m, 1H), 7.90 (s, 1H), 7.95 (s, 1H), 8.44 (s, 1H), 8.55 (s, 1H); MS (DCI/NH3) m/z 441 [M+H]+.
Reaction SMILES: [C:1]([NH:24][C@@H:25]([CH3:45])[C:26]([O:28][C@H:29]([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1)[C:31]([O:33][CH3:34])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\CC.C(O)(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC>>[C:1]([NH:24][C@@H:25]([CH3:45])[C:26]([O:28][C@H:29]([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1)[C:31]([O:33][CH3:34])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)O[C@H](C)[C@H](NC(=O)c1cccnc1)C(=O)OC
Agent: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](C)C(=O)O[C@H](C)[C@H](NC(=O)c1cccnc1)C(=O)OC

Procedure:
The same synthetic sequence outlined above for the preparation of (2S,3R)-methyl 3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoyloxy)-2-(nicotinamido)butanoate was used, except that (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA) was used instead of DHA. MS calculated for C34H47N3O6: 593.35. Found: [M+H]+ 594.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](N)=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][OH:16]>>[CH3:15][O:16][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: NC(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CO
Product: COC(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32 mmol) in methanol (40 mL) was treated with Amberlyst® 15 ion exchange resin (15.00 g). The resulting reaction mixture was heated under reflux for 64 h. The reaction mixture was allowed to cool to 25° C. and then filtered to remove the Amberlyst® 15 ion exchange resin. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 4-chloro-3-nitrophenylacetic acid methyl ester (1.91 g, 89%) as a yellow oil: EI-HRMS m/e calcd for C9H8ClNO4 (M+) 229.0142, found 229.0146.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.CCOCC.C(=O)(O)[O-].[K+]>O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:15]2[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCCN(c2nc(Cl)ncc2[N+](=O)[O-])C1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 3.16 g (0.02 mole) of piperidine-3-carboxylic acid ethyl ester, 3.71 g (0.019 mole) of 2,4-dichloro-5-nitro-pyrimidine and 60 mL of ether at 5 degrees, was added a solution of 4 g (0.04 mole) of potassium bicarbonate in 40 mL of water was added over 25 minutes. The mixture was stirred for an additional 1 hour, then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-88:12) to give 3.99 g of (rac)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester (IV-67).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18].C(N(CCCC)CCCC)CCC>[OH-].[Na+].O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:22]([OH:23])=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH3:7])[N:6]=2)[C:17]=1[OH:18]
Reactant: Cc1nc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Cc1nc2nc(O)c(-c3ccc(F)cc3F)c(O)n2n1

Procedure:
4 g (40.95 mmol) 3-Amino-5-methyl-1,2,4-triazole, 10 g diethyl (2,4-difluorophenyl)malonate and 9 g tributylamine are stirred at 180° C. over night. The solution is diluted with 2N NaOH solution and water and the resulting mixture is extracted three times with methyl-tert. butylether. These organic extracts are discarded. The aqueous phase is acidified at 0° C. with concentrated HCl. The precipitate is collected by filtration, washed with water and dried. This product (4.47 g=33.4%) is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:16](Cl)[O:17][CH3:18].CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:16][O:17][CH3:18])[CH:5]=[O:6]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(Br)c1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
A solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.0 g, 4.1 mmol) in DMF (10 mL) was cooled at 0° C., NaH (180 mg, 4.5 mmol) was added, and the mixture was stirred for 15 minutes. MOM-Cl (360 mg, 4.5 mmol) was added, and the mixture was warmed to room temperature in two hours. TLC (PE:EtOAc=5:1) indicated that the starting material was consumed. Ice water was added to quench the reaction, and aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatograph to give 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (0.7 g, yield: 59.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:23]([CH3:25])[CH3:24])[CH2:13][CH2:12][C:11](CCC3C=CC=CC=3)([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OCC)C.Cl.[OH-].[Na+]>C(OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:23]([CH3:25])[CH3:24])[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN(C)C1(c2ccc(Br)cc2)CCC(O)(CCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: CN(C)C1(c2ccc(Br)cc2)CCC(=O)CC1
Yield: 91.2 %

Procedure:
7.48 g 4-(4-bromophenyl)-4-dimethylamino-1-phenethylcyclohexanol were dissolved in 30 ml diisopropylether and 10 ml diethylether and were stirred for 4 days with 13 ml 4-molar hydrochloric acid. To work up the reaction mixture, it was alkalized by addition of sodium hydroxide solution (32% by weight), extracted three times with 30 ml dichloromethane in each case, the combined extracts were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. The 5.02 g 4-(4-bromophenyl)-4-dimethylaminocyclohexanone obtained, dissolved in 22 ml tetrahydrofuran, were added dropwise to 18 ml 1.0 molar phenethyl magnesium chloride solution in THF in a nitrogen atmosphere at ambient temperature and were stirred overnight. To work up the mixture with ice cooling, 28 ml ammonium chloride solution (20% by weight) were added, the phases were separated, the mixture was extracted three times with 25 ml diethylether in each case, the combined organic phases were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. The crude product obtained (5.83 g) was taken up in 50 ml diethylether, extracted three times with 40 ml hydrochloric acid (5% by weight) in each case and the combined extracts were washed twice with 40 ml dichloromethane in each case. The dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. 3.66 g of a light brown resin were obtained and were chromatographed with diethylether/hexane (V:V=2:1) over silica gel. The 1.38 g 4-(4-bromophenyl)-4-dimethylaminocyclohexanone obtained were dissolved in 20 ml 2-butanone and converted by reaction with 474 μl chlorotrimethylsilane and 34 μl water, stirring overnight with subsequent filtration, diethylether washing and vacuum drying, into 1.47 mg of the corresponding hydrochloride.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.[CH:27]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)=O.C(N(CC)CC)C.C([BH3-])#N.[Na+]>O1CCOCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12
Reactant: O=Cc1ccc2ccccc2n1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1nccn2c(C3CCN(Cc4ccc5ccccc5n4)CC3)nc(-c3cc4ccccc4[nH]3)c12

Procedure:
A solution of 1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30 mg, 0.09 mmol), 2-formylquinoline (17 mg, 0.11 mmol) and triethylamine (0.019 mL, 0.14 mmol) in 1,4-dioxane (1 mL) was treated with sodium cyanoborohydride (5.7 mg, 0.090 mmol) and microwaved at 300 watts, 120° C. for 20 min. The mixture was concentrated in vacuo, the residue was dissolved in methanol loaded onto an SCX ion exchange cartridge, and then eluted with 1M NH4OH in methanol. The semi-pure material thus obtained was then subjected to semi-preparative HPLC to afford desired product. 1H NMR (400 MHz, MeOD) δ ppm 2.13-2.33 (m, 4 H), 2.90 (t, J=10.86, 9.60 Hz, 2 H), 3.47 (d, J=10.11 Hz, 2 H), 4.29 (s, 2 H), 6.74 (s, 1 H), 7.02-7.11 (m, 2 H), 7.19 (t, J=8.08, 7.07 Hz, 1 H), 7.47 (d, J=9.09 Hz, 1 H), 7.58-7.65 (m, 3 H), 7.69 (d, J=8.59 Hz, 1 H), 7.80 (t, J=8.34, 6.82 Hz, 1 H), 7.96 (d, J=7.33 Hz, 1 H), 8.08 (d, J=8.34 Hz, 1H) and 8.39 (d, J=8.59 Hz, 1 H). MS (ES+): m/z 474.23 [MH+].
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27]>C1COCC1>[C:11]1([C:8]2[O:7][C:6]([C:4]([C:22]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=3)=[O:5])=[CH:10][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)o1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(-c3ccccc3)o2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of 38d (0.231 g, 1 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 4.0 mL, 2 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with water, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1d as white crystals (35.5%). 1H NMR (CDCl3) δ 7.85-7.82 (m, 1H), 7.48-7.36 (m, 4H), 7.35 (s, 2H), 7.25 (d, 1H, J=4.0 Hz), 6.86 (d, 1H, J=4.2 Hz), 3.96 (s, 3H), 3.95 (s, 6H); MS (ESI) m/z 339.1 (M+H)+.
Reaction SMILES: C(OC(=O)C[CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])(C)(C)C.[CH3:17]O>C1COCC1>[CH:13]([CH:12]1[CH2:17][O:11][C:9](=[O:10])[CH2:8]1)([CH3:14])[CH3:15]
Reactant: CO
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CC(C)C1COC(=O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A solution of 2-isobutyl-succinic acid-4-t-butyl ester (8.0 g, 34.7 mmol) in 100 mL of THF is cooled to 0° C. under Ar and borane dimethyl sulphide complex (2.6 g, 34.7 mmol) is added. The reaction mixture is stirred at 0° C. for 10 minutes, and at room temperature overnight. The solution is cooled to 0° C. and 100 mL of MeOH is added. The solvents are evaporated, and the remaining oil is dried under hi-vacuum for 2 hours. The oil remaining is taken up in 100 mL of THF, and a catalytic amount of p-toluene sulfonic acid is added. The solution is warmed to reflux overnight. After being cooled to room temperature, the solvent is evaporated, and the oil is taken up in Et2O (100 mL). The Et2O solution is extracted with 2.0N Na2CO3 (2×50 mL) followed by 100 mL of brine and dried over MgSO4. Evaporation of Et2O followed by medium pressure chromatography (MPLC) of the remaining oil in 20% EtOAc/Hexanes gives 4.4 g (89% yield) of 4-isopropyl-dihydro-furan-2-one as an oil. NMR (H1, 400 MHz, CDCl3) δ 0.9 (6H, m); δ 1.3 (2H, dd); δ 1.5 (1H, m); δ 2.1 (1H, m); δ 2.6 (2H, m); δ 3.6 (1H, m); δ 4.4 (1 H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])[C:22]([Cl:34])=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].O.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])[C:22]([Cl:34])=[CH:21][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)OCc3ccccc3)cc2Cl)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)O)cc2Cl)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of benzyl 2-(benzyloxy)-5-chloro-4-(4-methylpiperazine-1-carbonyl)benzoate (may be prepared as described in D75) (400 mg, 0.837 mmol) in tetrahydrofuran (THF) (5.00 mL) were added lithium hydroxide (63.4 mg, 2.65 mmol) and water (1.5 mL). The mixture was stirred at 40° C. for 2 hours. After cooling, 2M hydrochloric acid (1.386 mL, 2.77 mmol) was added. The solvent was removed in vacuo to give the title product as a crude solid (324 mg, assuming 100% yield).