Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=CC=1)([O-])=O>CC#N>[CH:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:34][CH:35]=1)([CH3:41])[CH3:40]
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC#N
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C(C)C)cc4)CC3)c2cc1OC
Yield: 71.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (18.8 mg, 68.9 μmol), as prepared in Example 1d, and (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester 21.3 mg, 71.0 μmol), as prepared in the preceding step, was stirred in CH3CN (250 μL) at 80° C. for 4 h. The reaction was then partitioned with DCM (4 mL) and 1 M K2CO3 (4 mL), and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue (EtOAc) provided the title compound (21.5 mg, 72%). 1H-NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.34 (s, 1H), 7.31-7.25 (m, 3H), 7.16 (m, 2H), 6.37 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.60 (tt, 1H), 3.18 (td, 2H), 2.87 (heptet, 1H), 2.24-2.08 (m, 2H), 2.04-1.94 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 434.2, found 435.3 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]#[N:6].OO.C(=O)([O-])[O-:22].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]([NH2:6])=[O:22]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)c(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(F)c1
Yield: 99 %

Procedure:
Hydrolysis of the compound of step 1 using hydrogen peroxide and potassium carbonate in DMSO as described previously afford the above compound in 99% yield.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([CH3:32])[S:14]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:20]3[CH:19]=[CH:18][C:17]([S:14]([N:13]([CH3:32])[CH3:12])(=[O:15])=[O:16])=[CH:22][CH:21]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C)S(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N,N-dimethyl-benzenesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (150.0 mg, 0.7041 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (210.0 mg, 0.6748 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a tan solid (0.074 g, 34%). MP=188-190° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.63 (d, J=6.4 Hz, 1H), 8.38 (d, J=8.2 Hz, 2H), 7.88-7.82 (m, 3H), 7.03 (t, J=6.8 Hz, 1H), 6.21 (br s, 2H), 2.66 (s, 6H). MS=318 (MH)+. 54b) N,N-Dimethyl-4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzenesulfonamide was prepared from 4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N,N-dimethyl-benzenesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (75.0 mg, 0.294 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (48.0 mg, 0.0878 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.034 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (d, J=6.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 2H), 7.91 (d, J=7.8 Hz, 2H), 7.63 (d, J=6.3 Hz, 1H), 7.49 (d, J=7.8 Hz, 2H), 7.00-6.95 (m, 3H), 6.69 (s, 1H), 3.20-3.15 (m, 4H), 2.78 (s, 6H), 2.63-2.58 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1.[CH2:25](B(O)O)[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1)[CH3:26]
Reactant: CCB(O)O
Reactant: COC(=O)c1ccc2c(Br)cnc(-c3c(F)cc(F)cc3F)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cnc(-c2c(F)cc(F)cc2F)c2cc(C(=O)OC)ccc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 54.3 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 4-bromo-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (150 mg), ethylboronic acid (84 mg), tetrakis(triphenylphosphine)palladium (44 mg), tripotassium phosphate (241 mg), toluene (5 mL), and water (0.3 mL) was heated under stirring in an oil bath at 100° C. for one day. The reaction mixture was returned to room temperature, and diluted with water and ethyl acetate, and then the insoluble matter was separated by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-ethyl-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (71 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:33])([F:32])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([N:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.O[N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:33][C:14]([F:13])([F:32])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([N:25]3[CH2:26][CH2:27][CH:28]([O:31][N:35]4[C:43](=[O:44])[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:36]4=[O:45])[CH2:29][CH2:30]3)[CH2:23][CH2:24]2)=[CH:18][CH:17]=1
Reactant: OC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
Diethyl azodicarboxylate (1.23 ml, 2.70 mmol) was added dropwise to a solution of 1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-ol (750 mg, 2.45 mmol), 2-hydroxyisoindoline-1,3-dione (400 mg, 2.45 mmol) and triphenylphosphine (707 mg, 2.70 mmol) in tetrahydrofuran (15 ml) at 0° C. and the whole was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexane: 25/75 to 45/55) to give 2-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yloxy)isoindoline-1,3-dione (1.00 g, 85%) as pale yellow amourphous.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][C:10]3([CH2:17][OH:18])[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][CH2:16][C:10]12[CH2:17][OH:18]
Reactant: OCC12CCCN1CCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OCC12CCCN1CCNC2
Temperature: 25 °C
Yield: 105.1 %

Procedure:
To a solution of [2-(phenylmethyl)hexahydropyrrolo[1,2-a]pyrazin-8a(6H)-yl]methanol (D66, 180 mg) in anhydrous methanol (5 mL) under a Nitrogen atmosphere at rt, ammonium formate (475 mg) and palladium (10% on carbon, 13 mg) were added. The resulting suspension was heated at reflux temperature for 3.5 hours, then allowed to cool to r.t. and filtered over Celite. The organic extract was dried and concentrated in vacuo to give the desired compound (120 mg) as orange waxy solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:43])[CH2:30][CH2:31][C:32]([N:34]([CH3:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33]>>[CH3:43][N:29]([CH3:28])[CH2:30][CH2:31][C:32]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH3:42])=[O:33]
Reactant: CN(C)CCC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C29H30N4O4
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[C:12]([CH2:17][OH:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[C:12]([CH2:17][OH:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccnc1CO)NCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: OCc1ncccc1CCNCc1ccccc1
Temperature: 50 °C
Yield: 23.7 %

Procedure:
To a solution of N-benzyl-2-[2-(hydroxymethyl)-pyridin-3-yl]-acetamide (357 mg, 1.5 mmol) in THF (2 mL) was added borane in THF (5 mL of a 1.0 M solution, 5 mmol) and the mixture heated at 50° C. for 3 h. The reaction was cooled, quenched with MeOH (5 mL) and heated at 50° C. for 1 h. The resultant mixture was cooled, concentrated under reduced pressure, diluted with 3 N HCl (5 mL) and heated at 80° C. for 6 h. After cooling, an aqueous 15% NaOH solution was added until a basic pH (pH=13) was obtained and the mixture was extracted with CH2Cl2 (3×10 mL). The phases were separated and the combined organic fractions were dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:10:1) to afford benzyl-2-[2-(hydroxymethyl)-pyridin-3-yl]-ethylamine (86 mg, 41%) as a yellow oil. 1H NMR (CDCl3) 2.75 (t, 2H, J=6.8 Hz), 2.88 (t, 2H, J=6.8 Hz), 4.75 (s, 2H), 7.18–7.34 (m, 6H), 7.50 (d, 1H, J=7.8 Hz), 8.43 (d, 1H, J=4.9 Hz). ES-MS m/z 243 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][C:4]=1[C:9]([O:11]C)=[O:10].[OH-].[Li+].Cl>C1COCC1.CO.O>[OH:1][CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][C:4]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1scc(C)c1CO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1csc(C(=O)O)c1CO
Temperature: 100 °C

Procedure:
In a 15 mL microwave tube, methyl 3-(hydroxymethyl)-4-methylthiophene-2-carboxylate (440 mg, 2.36 mmol, 1.0 eq) was dissolved in THF/MeOH/water (2:1:1, 2 mL). To above solution was added Lithium hydroxide (68 mg, 2.84 mmol). The mixture was heated at 100° C. for 30 min in microwave reactor, neutralized with 1 N HCl, extracted with dichloromethane, washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. LC-MS (IE, m/z): 195.3 [M+Na]+; 1H NMR (500 MHz, CD3OD, δ in ppm): 7.25 (114, s), 4.86 (2H, m), 2.28 (3H, s);
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH2:8][CH2:9][CH3:10].[N:12]1([C:18]2[N:25]3[C:21](=[N:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=43)[S:20][N:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(#N)C>C1COCC1.CS(C)=O>[CH2:7]([N:15]1[CH2:14][CH2:13][N:12]([C:18]2[N:25]3[C:21](=[N:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=43)[S:20][N:19]=2)[CH2:17][CH2:16]1)[CH2:8][CH2:9][CH3:10]
Reactant: c1ccc2c(c1)nc1snc(N3CCNCC3)n12
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCCN1CCN(c2nsc3nc4ccccc4n23)CC1

Procedure:
A mixture of potassium carbonate (700 mg, 5.06 mmol), butyl bromide (0.43 mL, 0.4 mmol), 3-piperazinyl-1,2,4-thiadiazolo[4,5-a]benzimidazole (798 mg, 3.07 mmol) in THF (15 mL) and DMSO (2 mL) was refluxed for 16 h. The solution was evaporated to dryness, the residue partitioned between dichloromethane and water. The organic layer was washed five times with water, dried over sodium sulfate and evaporated to give an oil. This oil was mixed with acetonitrile, an insoluble solid was formed which was filtered (595 mg). The solid was purified by chromatography to give the title compound which was recrystallized from hexane (5:95) (440 mg, 41%).
Reaction SMILES: C([S-])C.[Na+].[SH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O-:22])=[O:21])[CH:15]=2)[C:9]=1[C:23]([O:25]C)=[O:24]>CN(C=O)C>[SH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=2)[C:9]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1c(CCS)cccc1-c1cccc(C(=O)[O-])c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2cccc(CCS)c2C(=O)O)c1
Temperature: 200 °C
Yield: 56.8 %

Procedure:
To a deoxygenated suspension of sodium ethanethiolate (0.135 g, 1.60 mmol) in DMF (0.5 mL) was added a solution of 3-(2-mercaptoethyl)-[1,1′-biphenyl]-2,3′-dicarboxylic acid, 2-methyl ester (0.10 g, 0.32 mmol) in DMF (0.5 mL). Argon was bubbled through the mixture for 10 minutes. The reaction was heated at 100° C. for 1 hour and 200° C. for another hour. After the mixture cooled to room temperature, the reaction was quenched with 1 N HCl (20 mL) and was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to afford 3-(2-mercaptoethyl)-[1,1′-biphenyl]-2,3′-dicarboxylic acid (0.055 g, 57%) as a white solid: 1H NMR (CDCl3) δ1.51 (t, J=8.0 Hz, 1H), 2.87-2.93 (m, 2H), 3.12-3.08 (m, 2H), 7.37 (m, 2H), 7.57-7.47 (m, 2H), 7.70 (dm, J=7.9 Hz, 1H), 7.98 (dm, J=7.8 Hz, 1H), 8.30 (m, 1H); 13C NMR (CDCl3) δ26.2, 38.8, 128.1, 129.3, 129.7, 129.8, 129.9 (2C), 130.5, 133.3, 134.4, 137.7, 139.1, 141.2, 172.3, 176.9. Elemental analysis calculated for C16H14O4S: C, 63.56; H, 4.67; S, 10.61. Found: C, 63.65; H, 4.88; S, 10.33.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[CH3:35]>CN(C=O)C.[Cu]I>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1/[C:34](/[CH3:35])=[CH:33]\[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: CC(=CBr)c1ccccc1Cl
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-chlorobenzene (277 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. Yield: 0.37 mg as the TFA salt. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.25 (m, 2H), 7.10 (t, 1H), 7.05 (s, 1H), 7.0 (m, 2H), 6.90 (d, 1H), 6.75 (s, 1H), 4.40 (d, 1H), 4.0 (d, 1H), 3.40 (m, 1H), 3.20 (m, 1H), 2.90 (m, 1H), 2.80 (s, 3H), 2.65 (m, 1H), 2.40 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.Cl.C(OCC)C>CC(O)C>[NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]=1
Reactant: NCC1(O)CCCc2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: NCC1=CCCc2ccccc21
Yield: 59 %

Procedure:
1-Aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene, the product of Example 7, was refluxed in a 2N solution of hydrogen chloride in 2-propanol (250 mL) for 5 hours. A portion of the 2-propanol was removed under reduced pressure to give a slurry. Diethyl ether was added to precipitate the hydrochloride salt. The resulting suspension was then filtered. The filter cake was then recrystallized from methanol/diethyl ether to give 16.18 g (59% yield based on 1,2,3,4-tetrahydronaphthalene-1-one) of the desired product as a light tan solid; 1H NMR (CD3OD) δ 2.31-2.40 (m, 2H), 2.80 (t, 2H, J=8 Hz), 4.0 (s, 2H), 6.26 (t, 1H, J=4.5 Hz), 7.19-7.29 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](Cl)=[O:26])[CH3:23].N1C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:22]([N:24]([CH2:28][CH3:29])[C:25]([O:12][C:11]1[CH:10]=[C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([N+:19]([O-:21])=[O:20])[C:2]=1[OH:1])=[O:26])[CH3:23]
Reactant: COC(=O)c1c(-c2noc(C)n2)cc(O)c(O)c1[N+](=O)[O-]
Reactant: CCN(CC)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)Oc1cc(-c2noc(C)n2)c(C(=O)OC)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrobenzoate (compound 1-5) (50 mg), diethylcarbamoyl chloride (0.024 mL), 4-dimethylaminopyridine (4 mg) and pyridine (2 mL) was stirred at room temperature for 3 hours. After addition of ethyl acetate, the mixture was acidified with 2 mol/L hydrochloric acid. The separated organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20%-100% ethyl acetate/hexane, gradient elution) to give the title compound (31 mg). The structural formula was illustrated in table 13.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[C:12]([O:13][Si](C)(C)C)=[C:11]([C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH:10]=[CH:9][C:8]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](I)[CH:28]=1.[H-].[Na+].[O:36]=[C:37]1[O:41][N:40]=[C:39]([C:42]2[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=2)[CH:45]=[O:46])[NH:38]1>O1CCCC1>[C:18]([C:11]1[CH:10]=[CH:9][C:8]([O:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:45]([OH:46])[C:44]3[CH:43]=[C:42]([C:39]4[NH:38][C:37](=[O:36])[O:41][N:40]=4)[CH:49]=[CH:48][CH:47]=3)[CH:30]=[CH:31][CH:32]=2)=[C:7]([Cl:6])[C:12]=1[OH:13])(=[O:20])[CH3:19]
Reactant: C=C(O[Si](C)(C)C)c1ccc(OCc2cccc(I)c2)c(Cl)c1O[Si](C)(C)C
Reactant: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccc(C(O)c3cccc(-c4noc(=O)[nH]4)c3)c2)c(Cl)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 1.01 mL, 2.02 mmol) to a solution of 2-chloro-1-(3-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene (1.00 g, 1.83 mmol) in tetrahydrofuran (0.1M) chilled to 0° C. After 15 minutes, warm to room temperature. After 1 hour, cool to −78° C. Add sodium hydride (60% dispersion, 80 mg, 2.01 mmol) to a solution of 3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde (348 mg, 1.83 mmol) in tetrahydrofuran (0.1 M). Sonicate the solution for 5 minutes then add it via syringe to the gringard reagent. After 30 minutes, warm the reaction to room temperature. Quench with 10% aq hydrochloric acid. Pour the reaction into brine and extract with 25% isopropyl alcohol:75% dichloromethane. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes:acetic acid (50%:50%:0.1%) to yield the title product as a white solid (120 mg, 14%): 1H NMR (DMSO-d6) δ 2.61 (s, 3H), 5.32 (s, 2H), 5.79 (d, 1H), 6.15 (d, 1H), 6.87 (d, 1H), 7.32-7.41 (m, 3H), 7.49 (m, 2H), 7.59 (dt, 1H), 7.64 (dt, 1H), 7.89-7.92 (m, 2H), 12.96 (bs, 1H), 13.13 (s, 1H); MS (esi negative) m/z (rel intensity) 465 (100).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH:12]=2)[CH:24]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(Cn2ccc3ccccc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1

Procedure:
1.077 g 3-Indol-1-ylmethyl-phenylamine (obtained in Step 2, 4.84 mmol) and 0.722 g 4,6-dichloropyrimidine (4.84 mmol) was dissolved in 50 cm3 of isopropyl-alcohol, 1.27 cm3 N,N-diisopropyl-ethylamine (0.939 g, 7.27 mmol) were added and the mixture was refluxed for three days. Then the mixture was evaporated under reduced pressure, 100 cm3 of water was added and it was extracted with 3×70 cm3 ethyl-acetate. Combined organic layer was washed with brine, dried over MgSO4 and evaporated to a yellowish oil. The residue was crystallized from minimal amount of acetonitrile and washed with diethyl-ether to give the desired product as an off-white solid. Overall yield for Step 2 and Step 3: 1.015 g (63%). For analitical results and compound identification see Table 1. The compound was used as a starting material in the preparation of Example 91.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.S1C(C[CH:16]2[C:21](=[O:22])[O:20][C:19]([CH3:24])([CH3:23])[O:18][C:17]2=[O:25])=CC2C=CC=CC1=2.S1C(CC(C(O)=O)C(O)=O)=CC2C=CC=CC1=2>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH:16]2[C:21](=[O:22])[O:20][C:19]([CH3:24])([CH3:23])[O:18][C:17]2=[O:25])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C(O)C(Cc1cc2ccccc2s1)C(=O)O
Product: CC1(C)OC(=O)C(Cc2ccc(F)cc2)C(=O)O1

Procedure:
The title compound was prepared using 4-fluorobenzaldehyde in place of benzo[b]thiophene-2-carbaldehyde using the procedure described for the preparation of 5-(benzo[b]thiophen-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 39: step a).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].Cl.[OH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16](O)=[O:17].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[OH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([NH:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:17]
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H](O)CC(C)C)c1ccccc1

Procedure:
To a cooled (0° C.) solution of methyl (2S)-amino(phenyl)acetate (3.06 g), (2S)-2-hydroxy-4-methylpentanoic acid hydrochloride, NMM (1.85 ml), and HOBt (6.15 g) in dichloromethane (50 ml) was added EDAC-HCl (5.81 g). Additional NMM (2.31 ml) was then added. The mixture was stirred for 2h at 0° C., then overnight at RT. The reaction was concentrated and the residue was taken up in Ethyl acetate washed with 0.1N hydrochloric acid, saturated sodium bicarbonate, brine, dried, filtered and evaporated to afford the title compound (4.20 g). 1H NMR (300 MHz, CDCl3) δ 0.92-0.95 (m, 6H), 1.47-1.67 (m, 2H), 1.76-2.04 (m, 1H), 2.63 (bs, 1H), 3.74 (s, 3H), 4.21 (d, 1H, J=9 Hz), 5.58 (d, 1H, J=8 Hz), 7.26-7.42 (m, 5H). MS APCI, m/z=280 (M+1). LC/MS: 1.95 min.