Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].Cl[O-].[Na+].NC(N)=[O:16].S(=O)(=O)(O)O.[OH2:23]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:16])=[O:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: O
Reactant: NC(N)=O
Reactant: N#Cc1ccc(CN)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]Cl
Product: N#Cc1ccc(C(=O)O)cc1
Reaction time: 2 h
Yield: 123.5 %

Procedure:
A mixture containing p-cyanobenzylamine (13.2 g), water (50 g), and ferric chloride (0.2 g) was stirred, and a 14 wt. % aqueous solution (200 g) of sodium hypochlorite was added dropwise thereto at room temperature over two hours. The reaction mixture was further stirred for one hour. Subsequently, water (100 g) and urea (4 g) were added to the mixture, and the resultant mixture was further stirred for minutes. The pH of the mixture was adjusted to four through addition of 98 wt. % sulfuric acid. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 12.1 g of p-cyanobenzoic acid (yield 82%, based on p-cyanobenzylamine). High performance liquid chromatographic analysis revealed that the obtained p-cyanobenzoic acid had a purity of 95%.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7](S(C)(=O)=O)[CH:8]=[C:9]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH:10]=1)=[O:5])C.CO.CC1C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:11]([C:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[NH:7][CH:8]=2)[CH:39]=[N:38][CH:37]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cc(N=Cc2cccc(F)c2F)cn1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: O=C(O)c1cc(-n2cncc2-c2cccc(F)c2F)c[nH]1
Yield: 12.3 %

Procedure:
To a solution of 4-[(2,3-difluoro-benzylidene)-amino]-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid ethyl ester (500 mg, 1.40 mmol) in co-solvents of MeOH (10 mL) and DME (5 mL) was added TosMIC (410 mg, 2.10 mmol) and K2CO3 (390 mg, 2,82 mmol). The reaction mixture was heated under reflux for 2 hours and the solvents were removed by evaporation. The residue was treated with LiOH in THF/H2O at room temperature for 14 hours. After removal of the solvents by evaporation, the residue was acidified by 2N HCl solution. The crude product was then purified by HPLC to afford 50 mg desired product (12%). MS (ES−): m/e=288.0 (M−H); LC/Method A/2.45 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2].C(N)(=[S:17])C>Cl.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]([NH2:8])=[S:17])[CH3:2]
Reactant: CCOc1ccc(C#N)cc1OCC
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(N)=S)cc1OCC
Reaction time: 5 h
Yield: 63.5 %

Procedure:
A solution of 29 g of 3,4-diethoxybenzonitrile and 23 g of thioacetamide in 120 ml of 10% hydrochloric acid-DMF was stirred at 90° C. for 3 hours and then 130° C. for 5 hours. After evaporation of the solvent, the residue was washed with diethyl ether (2×100 ml) and water (2×100 ml). The resulting crystals were collected by filtration and dried to obtain 21.7 g of 3,4-diethoxythiobenzamide.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=O.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O.C([O-])([O-])=O.[K+].[K+].C[N:27](C=O)C>>[C:3]([C:4]1[NH:27][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:10][N:6]=1)([CH3:8])([CH3:7])[CH3:2]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cnc(C(C)(C)C)[nH]2)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
A red suspension of 2,2-dimethylpropionamide hydrochloride (Atlantic, 1.00 g, 7.32 mmol), 2-bromo-4′-methylacetophenone (Aldrich, 1.56 g, 7.32 mmol) and K2CO3 (1.52 g, 11.0 mmol) in DMF (20 mL) was stirred at 75° C. for 3 h. The mixture was cooled to RT, concentrated in vacuo, suspended in water (25 mL) and extracted with DCM (2×25 mL). The combined organics were passed through a hydrophobic frit, concentrated in vacuo, redissolved in MeOH (5 mL), applied to an SCX-2 cartridge (20 g) and washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (60 mL); concentration in vacuo left a yellow foam (1.26 g). FCC, using 1-5% MeOH in DCM, gave the title compound as a pale yellow solid (770 mg, 49%). LCMS (Method 3): Rt 2.26 min, m/z 215 [MH+].
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (400 mg) in dry N,N-dimethylformamide (6 ml) at room temperature and under nitrogen was added potassium carbonate (630 mg) in one go. The reaction was stirred at 60° C. for 1.5 hours and then cooled to 50° C. 2-(Bromomethyl)tetrahydro-2H-pyran (175 μl) was added in one go and the reaction heated to 50° C. overnight and then at 90° C. for 2 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic layer was separated and concentrated in vacuo. The product was semi-purified by MDAP to afford a mixture of the title compound and an isomer. This mixture was taken on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.Cl[C:12](=[O:18])[C:13](OCC)=[O:14].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH:23][C:12](=[O:18])[C:13]([NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COC(CN)OC
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)C(=O)NCC(OC)OC)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
To a mixture of (4-methoxyphenyl)methanamine (9.90 g, 72.2 mmol) in THF (40 mL) was slowly added ethyl 2-chloro-2-oxoacetate (10.84 g, 79 mmol). After stirring the reaction at RT for 15 min, a solution of 2,2-dimethoxyethanamine (9.10 g, 87 mmol) and N,N-diisopropylethylamine (37.8 mL, 217 mmol) in EtOAc (40.0 mL) was added. The reaction was heated at reflux for 18 hours; whereupon, after cooling to RT, saturated NaHCO3 (50 ml) was added and the mixture extracted with EtOAc (50 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (CH2Cl2 to 5% MeOH/CH2Cl2) to elute N1-(2,2-dimethoxyethyl)-N2-(4-methoxybenzyl)oxalamide (7.50 g, 25.3 mmol, 35.1% yield) as white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 9.07 (1H, s), 7.69 (1H, t, J=5.65 Hz), 7.59 (1 H, d, J=8.78 Hz), 6.74 (1H, d, J=8.78 Hz), 4.46 (1H, t, J=5.40 Hz), 3.79 (2H, s), 3.53 (2H, t), 3.44 (6H, s), 2.23 (6H, d, J=5.27 Hz), 1.37 (6H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.O(Cl)[Cl:7].[P+5].[F:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][C:25](=O)[NH:24][C:23]=3[CH:29]=2)[CH:14]=[CH:15][CH:16]=1>C(Cl)(Cl)Cl>[Cl:7][C:25]1[C:26](=[CH:3][N:2]([CH3:5])[CH3:1])[O:27][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=3)=[CH:29][C:23]=2[N:24]=1
Reactant: CN(C)C=O
Reactant: ClOCl
Reactant: O=C1COc2ccc(CCc3cccc(F)c3)cc2N1
Agent: [P+5]
Solvent: ClC(Cl)Cl
Product: CN(C)C=C1Oc2ccc(CCc3cccc(F)c3)cc2N=C1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of dimethylformamide (0.82 mL, 10.6 mmol, 2.5 equiv) in chloroform (10 mL) at 0° C. was added phosphorus(V) oxychloride (0.78 mL, 8.49 mmol, 2 equiv). After stirring 10 min at 0° C., the reaction vessel was warmed to 23° C. for 10 min then re-cooled to 0° C. A solution of 6-[2-(3-fluoro-phenyl)-ethyl]-4H-benzo[1,4]oxazin-3-one in chloroform (7 mL) was added. After stirring a further 5 min at 0° C. the reaction was warmed to reflux (oil bath) for 4 h then cooled to 23° C. and partitioned between dichloromethane and water (100 mL each). The aqueous layer was adjusted to pH 12 with 5 N aqueous sodium hydroxide, and then the organic layer was separated. The organic layer was washed with brine (100 mL) and set aside. The original aqueous layer was re-extracted with dichloromethane (100 mL). The two organic extracts were combined, dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 80 g silica gel column as a solution in dichloromethane (5 mL) then eluted with ethyl acetate in heptane (0-40% ethyl acetate linear gradient over 16 column volumes at a flow rate of 60 mL/min) to give 985 mg (2.86 mmol, 67%) of the title compound as an orange/brown oil.
Reaction SMILES: [H][H].[CH2:3]([O:5][CH:6]([O:21][CH2:22]C)[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[C:11]=1[O:19][CH3:20])C.[CH3:24]OC(OC)CN.C=O>[Pt]=O.CO>[CH3:22][O:21][CH:6]([O:5][CH3:3])[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[C:11]=1[O:19][CH3:20])[CH3:24]
Reactant: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Reactant: COC(CN)OC
Reactant: [H][H]
Agent: O=[Pt]
Agent: C=O
Solvent: CO
Product: COc1c(CN(C)CC(OC)OC)ccc2c1OCO2
Yield: 99.1 %

Procedure:
0.2 g of platinum oxide catalyst was added to 20 ml of methanol, through which hydrogen was passed to activate the catalyst. 10.81 g (60 mmol) of 2-methoxy-3,4-methylenedioxybenzaldehyde (1) and 6.37 g (60 mmol) of aminoacetaldehyde dimethylacetal (99% purity) in 20 ml of methanol were added to carry out hydrogenation for 3.5 hours. Then, 5.24 ml (66 mmol) of 35% formalin was added to carry out hydrogenation for 9 hours. The catalyst was filtered out and the filtrate was concentrated under vacuum to obtain 16.85 g of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal (3) as an oil (yield 99%). IR and NMR spectra of the resultant product are listed below. ##STR24##
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([SiH2][O:24][C:25](C)(C)[C:26]1([OH:37])[CH:33]2[CH:29]([O:30][C:31]([CH3:35])([CH3:34])[O:32]2)[C:28]([Cl:36])=[CH:27]1)(C)(C)C.CCCCCC>O1CCCC1.C(OCC)(=O)C>[Cl:36][C:28]1[CH:29]2[O:30][C:31]([CH3:35])([CH3:34])[O:32][CH:33]2[C:26]([CH2:25][OH:24])([OH:37])[CH:27]=1
Reactant: CC1(C)OC2C(Cl)=CC(O)(C(C)(C)O[SiH2]C(C)(C)C)C2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OC2C(Cl)=CC(O)(CO)C2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran (27 mL, 1.3 equiv) was added to a stirred solution of silyl ether 52 (6.7 g, 20 mmol, 1.0 equiv) in tetrahydrofuran (80 mL) at 25° C. The resulting brown solution was stirred at 25° C. for 3 h. The reaction mixture was concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (25% hexane in ethyl acetate) to afford S5 (4.4 g, 99% yield) as a brown oil. Rf=0.44 (25% hexane in ethyl acetate); 1H NMR (500 MHz, C6D6) δ 5.37 (t, 1H, J=1 Hz, CHCCl), 4.79 (dd, 1H, J=0.5, 5.5 Hz, CH(OR)), 4.23 (dd, 1H, J=1, 5.5 Hz, CH(OR)), 3.64 (d, 1H, J=11 Hz, CH2(OH)), 3.37 (d, 1H, J=11 Hz, CH2(OH)), 1.23 (s, 3H, CH3), 1.07 (d, 3H, J=0.6 Hz, CH3); 13C NMR (125 MHz, C6D6) δ 139.51, 130.65, 113.46, 85.82, 85.33, 83.12, 65.29, 27.29, 26.08; IR (neat film) 3401 (m), 2989 (w), 2937 (w), 1624 (w) cm−1; HRMS (ESI) m/z: Calcd for C9H13ClNaO4 (MNa+) 243.0400, observed 243.0412.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[CH3:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17]CC=C)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C[N+]1([O-])CC[O:37]CC1.[CH3:41][C:42]([OH:45])(C)[CH3:43]>C1COCC1.O>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[CH3:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:41][CH:42]([OH:45])[CH2:43][OH:37])[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(C)(C)O
Reactant: C=CCCCn1cnc2c(F)c(Nc3ccc(Br)cc3C)c(C(=O)NOCC3CC3)cc21
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCC(O)CO)c1F
Reaction time: 5 h
Yield: 74 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11f (0.307 g, 0.612 mmol) is dissolved in 4:1 THF/water (8 mL) and 1.134 mL (0.061 mmol) of an 0.054 M 0504 solution in t-BuOH iias added followed by NMO (0.093 g, 0.796 mmol). After 5 hours, the reaction mixture is quenched by the addition of 10% NaHS2O3 solution. After 10 minutes, the reaction mixture is filtered through Celite rinsing with ethyl acetate and methylene chloride. The filtrate is diluted with ethyl acetate and washed with 0.01 N HCl, and brine. The organic layer is dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by FCC eluted with 9:1 ethyl acetate/MeOH to give 0.244 g (74%) pure desired product.
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[H-].[Na+].[C:9]([C:11]1[CH:12]=[C:13]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][N:27]=[C:28]4[CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:19]=2)[CH:14]=[CH:15][C:16]=1F)#[N:10]>CN(C=O)C>[C:9]([C:11]1[CH:12]=[C:13]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][N:27]=[C:28]4[CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:19]=2)[CH:14]=[CH:15][C:16]=1[N:4]1[CH2:5][CH2:6][CH:2]([F:1])[CH2:3]1)#[N:10]
Reactant: FC1CCNC1
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(F)c(C#N)c4)n3)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(N5CCC(F)C5)c(C#N)c4)n3)cccc12
Reaction time: 0.17 h
Yield: 21 %

Procedure:
A solution of 3-fluoropyrrolidine (Anichem Product List; 16.39 mg, 0.130 mmol) in DMF (2.5 ml) was cooled in an ice bath and sodium hydride (6.89 mg, 0.172 mmol) was added. The mixture was stirred for 10 mins then 1,1-dimethylethyl 3-{5-[5-(3-cyano-4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-1-isoquinolinyl}propanoate (D50; 58 mg, 0.130 mmol) was added. The ice bath was removed and the solution was stirred at room temperature for 3 hrs. Further sodium hydride (3.13 mg, 0.078 mmol) was added and the resulting solution was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried with magnesium sulphate and concentrated under vacuum. The residue was purified by Mass-Directed Auto-Preparative HPLC (formic acid modifier) to provide the title compound as a cream solid (14 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5](O)[C:6]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:19].CN(C)C1C=CC=CC=1>[NH4+].[OH-]>[Cl:19][C:5]1[C:6]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:7]=2[N:8]=[C:3]([NH2:2])[N:4]=1
Reactant: Nc1nc(O)c2sc3ccccc3c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)c2sc3ccccc3c2n1
Temperature: 110 °C
Yield: 52 %

Procedure:
A suspension of 2-amino-benzo[4,5]thieno[3,2-d]pyrimidin-4-ol hydrochloride (179 mg, 0.7 mmol), POCl3 (1.5 mL), and N,N-dimethylaniline (0.15 mL) was heated at 110° C. for 3 h. The mixture was cooled to rt and the resulting suspension was added dropwise to a 0° C. solution of aq. NH4OH (19 g/L; 30 mL). The suspension was filtered and the collected solid dried to yield 87 mg (52%) of a crude solid, which was immediately used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH:7]([CH2:13][C:14](=O)[CH3:15])[CH2:6]2.O.[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1[N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[C:14]([CH3:15])=[CH:13][C:7]=1[CH2:6]2
Reactant: COc1ccc2c(c1)CC(CC(C)=O)C2=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)Cc1cc(C)n(CC(C)O)c1-2
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A solution of 1.2 g of (RS)-5-methoxy-2-(2-oxopropyl)-1-indanone and 60 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 1.65 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 90 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.17 g (82%) of (RS)-1-(6-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow solid which was used without further crystallization in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24]([O:26]CC)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[NH3:29]>CO>[NH2:29][C:24](=[O:26])[CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: N
Reactant: CCOC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC(N)=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(R)-tert-Butyl 3-((R)-(3-chlorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (1.50 g, 3.65 mmol) was dissolved in 7 M NH3 in MeOH, and stirred at rt for 6 h. The mixture was evaporated under reduced pressure to afford the (R)-tert-butyl 3-((R)-(2-amino-2-oxoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate in quantitative yield. MS: 383 (M+−1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2B1OC(C)(C)C(C)(C)O1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[ClH:22].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1cccc2c(B3OC(C)(C)C(C)(C)O3)cccc12
Product: COc1cccc2c(-c3cnnc(Cn4ccnc4C)c3)cccc12
Product: Cl

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared from 2-(5-methoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][CH:21]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+].C(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[N:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:29]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)nc1
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
(4Z)-6-Iodo-4-{[(6-piperazin-1-ylpyridin-3-yl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (150 mg, 0.315 mmol) is dissolved in N-methylpyrrolidinone (3 mL) and methylene chloride (0.9 mL), followed by addition of sodium triacetoxyborohydride (0.77 mg, 3.63 mmol), acetaldehyde (0.46 mL, 8.14 mmol) and acetic acid (0.47 mL, 8.2 mmol). After stirring at room temperature for 1 h, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 110 mg (69%) of the title compound as a brown solid. MS (ESI) m/z 504.2 (M+H)+1
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1([CH:10]([C:18]([CH3:20])=[CH2:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1([CH:10]([C:18]([CH3:20])=[CH2:19])[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]1=[O:9]
Reactant: BrCc1ccccc1
Reactant: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.3 %

Procedure:
A cold (0° C.) solution of tert-butyl 3-(2-methylpropyl)-2-oxo-α-(propen-2-yl)-3-pyrrolidineacetate (1.11 g, 3.76 mmol) in dry THF (25 mL) is treated with NaH (60% dispersion in mineral oil, 226 mg, 5.64 mmol) in one portion. After 30 minutes, benzyl bromide (537 μL, 4.51 mmol) is added. The solution is allowed to slowly warm to room temperature, stirring under N2 overnight. The mixture is quenched with H2O (25 mL) and extracted with EtOAc (3×25 mL). The organic extracts are combined, washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield 1.70 g of yellow oil. The oil is purified by silica gel chromatography (30 g SG, 10% EtOAc/hexane) to give 1.37 g (94%) of the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](C2C=C(S([O-])(=O)=O)C=CC=2C)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[OH-:20].[K+].[N+]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])=[O:32])=[CH:27][CH:26]=1)([O-])=O.[OH-].[Na+]>CS(C)=O.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:20][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])=[O:32])=[CH:27][CH:26]=1)#[CH:2]
Reactant: [OH-]
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: C#Cc1cccc(-c2cc(S(=O)(=O)[O-])ccc2C)c1
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: C#Cc1cccc(Oc2ccc(C(=O)C(=O)c3ccccc3)cc2)c1
Temperature: 90 °C
Yield: 64.6 %

Procedure:
To 100 ml of anhydrous methanol was added 20 g (0.073 mole) of 3-ethynylphenyl(p-toluenesulfonate) and 8.19 g (0.146 mole) of potassium hydroxide. The mixture was heated to reflux under a nitrogen atmosphere and maintained at reflux for 4 hours. A distillation apparatus was attached to the flask, and methanol was distilled from the flask until the residue approached dryness. Then, 400 ml of anhydrous benzene was added, and distillation was continued until 200 ml of benzene was removed. The reaction mixture was freeze dried under reduced pressure, leaving a dry, white powder. The white powder was dissolved in 150 ml of dimethylsulfoxide and transferred to an addition funnel under nitrogen. The solution was added over a 60 minute period to a solution of 4-nitrobenzil (18.6 g, 0.073 mole) in dimethylsulfoxide (300 ml) and stirred at 90° C under nitrogen. When addition was completed, the reaction mixture was stirred overnight at 23° C and poured into a solution of sodium hydroxide (50 g) in ice water (1 liter). Extraction with toluene (3×50 ml) followed by chromatography on silica gel with benzene as eluent gave 15.4 g (65% yield) of 4-(3-ethynylphenoxy)benzil as a yellow oil which solidified upon standing overnight at 23° C into a pale yellow solid (m.p. 79°-81° C).