Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)[OH:10])[CH:2]=1.[O:26]=[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41](O)=[O:42])[C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][C:29]([CH3:33])([CH2:30][CH3:31])[C:28](=[O:34])[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=1)[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:42])=[O:26]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)COc1cccc([C@H](O)CCc2cccnc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1cccnc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of alcohol 21 (530 mg, 1.54 mmol) in CH2Cl2 (5 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 393 mg, 1.54 mmol, followed by 1,3-dicyclohexylcarbodiimide (381 mg, 1.85 mmol), and 4-(dimethylamino)-pyridine (132 mg, 1.08 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20-60% EtOAc/hexanes) to give (1R)-3-(3-Pyridyl)-1-[3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (860 mg, 96%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 8.46 (m, 2H), 7.50-6.80 (m, 6H), 5.80 (t, J=6.1 Hz, 1H) , 5.32 (d, J=5.0 Hz, 1H), 4.54 (s, 2H), 3.38 (d, J=12.8 Hz, 1H), 3.14 (td, J=12.6, 3.0 Hz, 1H) 2.60 (m, 2H), 2.36 (d, J=13.7 Hz, 1H), 2.25 (m, 1H), 2.10 (m, 1H), 1.75 (m, 4H), 1.49 (s, 9H), 1.45 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 0.90 (t, J=7.4 Hz, 3H); 13C NMR (CDCL3, 75 MHz) (single diastereomer, mixture of rotamers) 208.2, 175.1, 170.0, 168.2, 167.7, 158.6, 150.2, 148.1, 141.3, 136.6, 130.2, 123.8, 120.1, 115.0, 113.6, 107.9, 82.8, 66.1, 51.7, 47.1, 44.6, 39.2, 37.8, 34.4, 33.0, 29.2, 28.4, 26.7, 25.3, 23.9, 23.5, 21.6, 21.4, 9.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 59.1 %

Procedure:
5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.233 g, 0.571) and ethyl formate (0.140 mL, 1.71 mmol) were dissolved in anhydrous ethanol (1.10 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.10 mL, 2.85 mmol). This reaction mixture was heated at 78° C. for 1 h, turning the reaction mixture to a brownish red color. The reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale brown precipitate. The suspension was filtered yielding a tan solid as pure 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.147 g, 0.337 mmol, 59%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][CH:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:5][N:4]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>>[CH3:24][O:16][C:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:8][C:6]2[O:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:7]=2)[N:15]=1
Reactant: O=C1CCCCC(Cc2cc(C(F)(F)F)no2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2cc(C(F)(F)F)no2)CCCC1

Procedure:
The title product of Example 119 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.[N:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CC#N>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(O)C.COCCOC>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[C:10]3[C:2]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[N:3][NH:4][C:5]3=[CH:6][N:7]=2)[CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: Ic1n[nH]c2cnc(-c3cccnc3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: CC#N
Product: c1cncc(-c2cc3c(-c4ccncc4)n[nH]c3cn2)c1
Temperature: 160 °C
Yield: 21.2 %

Procedure:
To a microwave tube was added 3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4 (100 mg, 0.31 mmol), pyridin-4-ylboronic acid (190 mg, 1.55 mmol), Pd(dppf)Cl2 (50 mg, 0.06 mmol), sodium carbonate (131 mg, 1.24 mmol), 1,2-dimethoxyethane (2 mL), ethanol (0.3 mL) and water (0.3 mL). The tube was flushed with nitrogen for 2 minutes and heated in a Biotage microwave at 160° C. for 1 hour. The solvent was distilled off and the crude product was purified via reverse phase HPLC eluting with 15% CH3CN aqueous 10 mmol NH4HCO3 solution to afford 194 as a white solid (18 mg, 21%). 1H NMR (400 MHz, DMSO) 1H NMR (500 MHz, DMSO) δ 9.44 (s, 1H), 9.28 (s, 1H), 8.76-8.73 (m, 3H), 8.62-8.59 (m, 2H), 8.19 (d, J=6.0 Hz, 2H), 7.55-7.53 (m, 1H). ESI MS m/z=274 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([OH:16])=O)=[N:6]1.S(Cl)(Cl)=O.[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[CH:30][N:29]=[CH:28][N:27]=1>N1C=CC=CC=1>[C:32]([C:31]1[C:26]([NH:25][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)=[O:16])=[N:27][CH:28]=[N:29][CH:30]=1)#[N:33]
Reactant: O=C(O)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: N#Cc1cncnc1N
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cncnc1NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
At RT, 39.4 g (145 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (preparation described in US2010/004235, page 27) were initially charged, and then thionyl chloride (370 ml) was added. The suspension was heated to reflux for 2 h and the now clear solution was concentrated under reduced pressure. 100 mg (0.345 mmol) of the acid chloride thus prepared were initially charged in pyridine (1.0 ml) and then 41.5 mg (0.345 mmol) of 4-amino-5-cyanopyrimidine were added in portions. The mixture was stirred at RT for 7 h and then left to stand overnight. Subsequently, volatile constituents were removed under high vacuum, the residue was separated by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 30 mg (23% of theory) of the title compound in solid form.
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=O.[CH2:24]([CH2:26][NH2:27])[OH:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:25][CH2:24][CH2:26][NH:27][CH2:1][C:3]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: NCCO
Reactant: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNCCO)c1
Reaction time: 2 h
Yield: 109.8 %

Procedure:
[3-(2-Formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid (0.12 g, 0.37 mmol), ethanolamine (0.02 mL, 0.37 mmol), and sodium triacetoxyborohydride (0.12 g, 0.56 mmol) were combined in CH2Cl2 (10 mL) and stilled for 2 hours. After work-up, 0.15 g of the desired product was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(N(C(C)C)CC)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:4]1[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)c1n[nH]c2c(Cl)nc(Cl)nc12
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1n[nH]c2c(Nc3cccc(Cl)c3)nc(Cl)nc12
Yield: 16 %

Procedure:
5,7-Dichloro-3-isopropylpyrazolo[4,3-d]pyrimidine (90 mg), 1.2 mL of 3-chloroaniline and 250 μL of diisopropyl ethylamine were stirred at 60° C. for 24 hours. The reaction mixture was evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with the following solvent system: CHCl3/heptane (100/17), to give 7-(3-chloroanilino)-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine, yield 16%, mp=257-259° C. MS (ES+): 322.3 (100%, M+H+), 324.3 (64%, M+H+). 1H NMR (CDCl3; 300 MHz): 1.54 d (6H, J=7.1 Hz); 3.60 sept (1H, J=7.1 Hz), 7.16 d (1H), 7.34 t (1H), 7.88 d (1H), 8.10 s (1H).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[O:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:31][O:30][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:20]=1[NH:19][CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(CC(C)C)c1cc(-c2ccccc2)oc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.3 g), methyl 4-amino-3-methoxybenzoate (1.1 g), sodium carbonate (1.1 g) and sodium iodide (3.0 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (6 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (1.0 g, 50%) as an amorphous compound.
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22](/[N:25]=[CH:26]/[C:27]4[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:10][C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]4[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:10][C:9]1=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)nn1Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1oc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3)CC2)nn1Cc1ccccc1
Yield: 84.8 %

Procedure:
3-Benzyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9d, 0.47 g, 1 mmol) on reduction with sodiumcyano borohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-benzyl-5-[1-(4-[(5-nitro-2-furyl) methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10d, 403 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1COCC1>[O:11]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[CH:3][CH:4]=2)[NH:8]1
Reactant: Nc1ccc2c(c1)NC(=O)C2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Yield: 65.1 %

Procedure:
To 6-aminoindolin-2-one (30 mg, 0.202 mmol) in THF (1 mL) was added acetic anhydride (19 uL, 0.202 mmol). After 2 hrs the product was precipitated with ether, filtered and dried to give 25 mg, 66% of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.41 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.49 (s, 2H), 2.12 (s, 3H); MS ESI 191.0 [M+H]+, calcd for [C10H10N2O2+H]+ 191.08.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C)C1C=CN=CC=1.C(C(C)=O)C(C)C>[N:10]([CH2:2][CH:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CC(O)CCl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)CC(O)CN=[N+]=[N-]
Reaction time: 11 h
Yield: 104.7 %

Procedure:
To a mixture of methyl 4-chloro-3-hydroxybutyrate (5 g, 33 mmol), and methyl isobutyl ketone (40 ml) are added sodium azide (2.3 g, 36 mmol) and 4-dimethylaminopyridine (403 mg, 3.3 mmol) and the mixture was refluxed under stirring for 11 hours. After cooling the salt was filtered off and the solvent was distilled off under vacuo and there was obtained methyl 4-azido-3-hydroxybutyrate (5.5 g) as a crude product. And followed by the same procedure as in example 1, there was obtained 4-hydroxy-2-pyrrolidone (2.3 g, 23 mmol, yield:70%). When the above reaction was carried out in the absence of 4-dimethylaminopyridine, it took more than 120 hours to detect the disappearance of the starting materials on gas chromatography.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.[N+:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])#[C-:20].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:9][CH:20]=[N:19][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=[N:3][CH:2]=1
Reactant: O=C(O)c1ccncn1
Reactant: [C-]#[N+]CC(=O)OC
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of pyrimidine-4-carboxylic acid (261 mg, 2.00 mmol) and DIPEA (0.52 mL, 2.96 mmol) in DMF (8 mL) was added methyl isocyanoacetate (0.28 mL, 2.93 mmol) at rt. The resulting yellow solution was stirred at rt for 5 min and cooled to 0° C. DPPA (0.54 mL, 2.43 mmol) was then added and the resulting solution was stirred at 0° C. for 1 h and at rt for 30 min. Aq. sat. NaHCO3-solution was added and the mixture extracted with EtOAc (4×). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by FC (hept/EtOAc 9:1 to 100% EtOAc) yielded methyl 5-(pyrimidin-4-yl)oxazole-4-carboxylate. LC-MS conditions A: tR=0.68 min, [M+H]+=206.43.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C1COCC1.CO>[Cl:20][C:17]1[N:16]=[N:15][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(c2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 121.9 %

Procedure:
[1-(6-Chloro-pyridazin-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.59 g 1.89 mmol) was dissolved in THF:MeOH 2:1 (45 ml) and HCl in 1,4-dioxan (4M, 3.8 ml, 7.56 mmol) was added. The reaction was stirred at rt for 3 h and then at 60° C. for 2 h. The solvent was evaporated to yield the title compound (0.49 g, 100%) as the hydrochloric salt. 1H-NMR (CD3OD, 500 MHz): δ 8.10 (d, 1H), 7.92 (d, 1H), 4.41-4.35 (m 2H), 3.67-3.57 (m, 1H), 3.55-3.46 (m, 2H), 2.32-2.24 (m, 2H), 1.96-1.83 (m, 2H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OCCNCCO
Product: N#Cc1ccc(CN(CCO)CCO)cc1

Procedure:
4-{[Bis-(2-hydroxyethyl)-amino]-methyl}benzonitrile was prepared according to the general method as outlined in Example 1 (Step 4) starting from diethanolamine (10.2 g, 97 mmol) and α-bromo-p-tolunitrile (15.8 g, 81 mmol). Yield, (68%); white solid; mp 163° C. MS: 221.2 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:14].[H][H]>CO.O.[Pd]>[ClH:14].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CNS(=O)(=O)c1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)c1cccc(CN)c1
Reaction time: 48 h

Procedure:
To a solution of 3-cyano-N-methyl-benzenesulfonamide (4.88 g, 2.49 mmol) in MeOH (160 mL) is added concentrated HCl in water (16 mL) followed by the addition of Palladium on Carbon (10 wt %, 50 wt % water, 1.6 g). With magnetic stirring, the reaction is alternately placed under vacuum and 1 atmosphere of hydrogen (balloon) for three cycles. The reaction is then left under 1 atmosphere of hydrogen with stirring for 2 days. The reaction is filtered through celite and fresh Palladium on Carbon (10 wt %, 50 wt % water, 1.6 g) is added. The reaction is stirred for 24 hours under 1 atmosphere of hydrogen. The reaction is filtered through celite and the filtrate is concentrated in vacuo to provide 3-aminomethyl-N-methyl-benzenesulfonamide hydrochloride, as a solid (99%). MS: 201 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.12 (d, 2H), 7.23-7.57 (m, 2H), 7.70 (d, 1H), 7.81 (d, 1H), 8.49 (broad-s, 3H).
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[CH3:14][O:15][CH:16]([O:27][CH3:28])[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>CO>[I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]=[CH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:16]([O:27][CH3:28])[O:15][CH3:14])=[CH:26][CH:25]=1
Reactant: COC(COc1ccc(C=O)cc1)OC
Reactant: Cc1ccc2ccccc2[n+]1C
Agent: [I-]
Solvent: C1CCNCC1
Solvent: CO
Product: COC(COc1ccc(C=Cc2ccc3ccccc3[n+]2C)cc1)OC
Yield: 70.2 %

Procedure:
In 20 ml of methanol, 4.28 g of 1,2-dimethylquinolinium iodide and 3.47 g of p-(2,2-dimethoxyethoxy)benzaldehyde were dissolved. The resultant solution, with 0.3 ml of piperidine added thereto, was refluxed for seven hours. The solution was left to cool. The crystals which consequently deposited were collected through filtration and then washed thoroughly with acetone. Consequently, there was obtained 5.03 g of 1-methyl-2-[p-(2,2-dimethoxyethoxy)-styryl]quinolinium iodide which boiled at 209°~212° C. This product in water showed absorption bands (λmax) at 224, 255, 307 and 399 nm. The infrared absorption spectrum (KBr) showed peaks at 1610, 1590, 1572, 1516, 1240, 1180, 1130, 1068, 985, 830, 780 and 760 cm-1.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.O>CN(C)C=O>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[C:15]4[C:10]([CH2:11][CH2:12][NH:13][C:14]4=[O:17])=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[CH:27][CH:26]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C1NCCc2ccc(N3CCNCC3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCc2ccc(N3CCN(Cc4ccc(Cl)cc4)CC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
7-Piperazin-1-yl-3,4-dihydro-2H-isoquinolin 1-one (100 mg) synthesized according to the method described in J. Med. Chem., 39, 4583 (1996) was dissolved in N, N-dimethylformamide (5 ml). Potassium carbonate (71 mg) and 4-chloro benzyl bromide (106 mg) were added to the solution. The mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution. The mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=9:1) to give 7-[4-(4-chlorobenzyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one (75 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:57][CH3:58])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]([CH2:54][CH3:55])([O:49][Si](C)(C)C)[CH2:47][CH3:48])=[C:40]([CH3:56])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:59])=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]([CH2:54][CH3:55])([OH:49])[CH2:47][CH3:48])=[C:40]([CH3:56])[CH:39]=3)[CH2:57][CH3:58])=[CH:31][C:30]=2[CH3:59])=[CH:27][CH:28]=1
Reactant: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.166 mL, 0.166 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 125-(4); 19.3 mg, 0.033 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was diluted with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (11.6 mg, 69%).