Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11][CH:12]=1.C(O[B:26](OC(C)C)OC(C)C)(C)C.[OH:35][CH2:36][C:37]([CH3:41])([CH2:39][OH:40])[CH3:38]>C1COCC1>[CH3:38][C:37]1([CH3:41])[CH2:39][O:40][B:26]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11][CH:12]=2)[O:35][CH2:36]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(CO)CO
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COB(c2ccc(CNC(=O)OC(C)(C)C)nc2)OC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 11.3 %

Procedure:
n-BuLi (27 mL, 2.5 M) was slowly added to a stirred solution of tert-butyl (5-bromopyridin-2-yl)methylcarbamate (17.7 g, 61.6 mmol) in THF (280 mL) at −78° C. under an argon atmosphere. After 5 min at −78° C., triisopropylborate (28.5 mL, 123 mmol) was added and the mixture was stirred at −78° C. for 1 h. Neopentyl glycol (6.4 g, 61.4 mmol) was added and the reaction mixture was allowed to reach rt and was stirred for 2.5 d. The reaction was quenched with water (300 mL). The phases were separated and the aqueous phase was extracted with DCM. The organic layer was concentrated and the residue was purified by two successive flash chromatographies (Heptane/EtOAc 9:1→1:4 and DCM/MeOH 24:1 respectively) to give the product (2.23 g) as a white solid. 1H NMR 8.57 (dd, 1 H) 7.94 (dd, 1 H) 7.65 (dd, 1 H) 3.76 (s, 4 H) 3.30 (s, 3 H) 1.47 (s, 9 H) 0.96 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:31])[C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([C@H:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26]C)=[O:25])[C:17]3=[O:22])=[O:10])=[CH:4][CH:3]=1.[OH-].[Li+].C(O)(C)(C)C.O.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:31])[C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([C@H:23]([CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])[C:17]3=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C(C)C)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)[C@H](C(=O)O)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-methyl 2-(5-((S)-2-(4-chlorophenyl)propanamido)-1-oxoisoquinolin-2(1H)-yl)-3-methylbutanoate (0.43 g, 0.00088 mol) was stirred with lithium hydroxide (0.05 g, 0.002 mol) in tert-butyl alcohol (6 mL, 0.06 mol) and water (3 mL, 0.2 mol) at 0° C. for 1 hour. 1 N HCl was added until pH<7 and then reaction mixture was extracted with CH2Cl2 (40 mL×3). The organic layers were dried over MgSO4, filtered, purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) and gave a light yellow solid. 1H NMR δ (CDCl3) δ: 8.17 (br, 1H), 7.86 (br, 1H), 7.52-7.29 (m, 6H), 7.03 (br, 1H), 6.09-6.05 (m, 1H), 5.00-4.87 (m, 1H), 3.87-3.82 (m, 1H), 2.70-2.60 (m, 1H), 1.64 (d, J=7.0 Hz, 3H), 1.14 (d, J=6.5 Hz, 3H), 0.78 (d, J=6.4 Hz, 3H). MS m/z 427.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:43])[CH:4]=[C:5]([C:8]([NH:10][N:11]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][NH:19][S:20]([NH:23][C:24]([N:26]3[CH2:29][C@H:28]([NH:30]C(=O)OCC4C=CC=CC=4)[C:27]3=[O:41])=[O:25])(=[O:22])=[O:21])=[O:17])[C:12]2=[O:42])=[O:9])[NH:6][CH:7]=1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:30][C@H:28]1[CH2:29][N:26]([C:24]([NH:23][S:20]([NH:19][NH:18][C:16]([N:13]2[CH2:14][CH2:15][N:11]([NH:10][C:8]([C:5]3[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:43])[CH:4]=3)=[O:9])[C:12]2=[O:42])=[O:17])(=[O:22])=[O:21])=[O:25])[C:27]1=[O:41]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)N2CCN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)N2CCN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of (S)-[1-[[[[2-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1imidazolidinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added to a mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid. The mixture was stirred overnight at room temperature and evaporated in vacuo. The residue was triturated with ethyl acetate to provide the title compound in quantitative yield.
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:5])[CH3:4]>C(O)C.[Zn]>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: CC(C)Nc1ccccc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a mixture of ethanol (600 mL) and 2 M sodium hydroxide solution (320 mL) cooled in an ice bath was added Zn dust (59.5 g) slowly. While stirring the Zn slurry, N-isopropyl-N-(2-nitrophenyl)amine (41 g, 0.228 mol) dissolved in ethanol (50 mL) was added. The mixture was stirred at 0° C. for 30 min, then heated to 85° C. The mixture was stirred at 85° C. for about 12 h until the refluxing solution of the mixture became a colorless solution. The mixture was then cooled to 0° C. and filtered. The collected solid was rinsed with ethyl acetate (200 mL). The filtrate and rinsed solution were combined, and evaporated in vacuo to remove excess volatile solvents. During the concentration, the mixture became pale brown/yellow. The aqueous concentrate was extracted with ethyl acetate (800 mL). The organic solution was concentrated to dryness, to provide the title intermediate (33 g) as a brown-pink oil which was used in the next step without further treatment. 1H-NMR (CDCl3, 300 MHz): 6 (ppm) 6.73-6.5 (m, 4H), 3.58-3.55 (hept, 1H), 1.2 (d, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]1[O:15][C:14]2[C:9](=[N:10][CH:11]=[C:12](Br)[CH:13]=2)[CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[N:22][CH:23]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]1[O:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:20]3[CH:21]=[N:22][CH:23]=[C:18]([CH3:17])[CH:19]=3)[CH:13]=2)[CH:8]=1
Reactant: CN1CCC[C@@H]1c1cc2ncc(Br)cc2o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cncc(-c2cnc3cc([C@H]4CCCN4C)oc3c2)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(1-methyl-2-(R)-pyrrolidinyl)-6-(bromo)-furo[3,2-b]pyridine from Example 47 in toluene are added (5-methyl3-pyridyl)tributyltin and tetrakis(triphenylphosphine)palladium(O). After being refluxed overnight, the resulting mixture is cooled to room temperature. Solvent is removed, and the residue is chromatographed on a silica gel column.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[S:7][C:8]([C:11]2C=C[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].BrC1[S:33]C(Br)=CC=1>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.C1(C)C=CC=CC=1>[CH2:17]([C:14]1[S:33][C:11]([C:8]2[S:7][C:6]([Sn:5]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCc1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)cc1
Reactant: Brc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)s1

Procedure:
5′,2″:5″,2′″:5′″,2″″-pentathiophene (6TTTTT6) is now discussed. The compound 5′-hexyl-5-tributylstannylbithiophene is prepared from 2′-hexylbithiophene using the procedure described for 2-(tri-n-butylstannyl)-5-(4-n-hexylphenyl)thiophene. A measured 6.25 mmol of this compound, 2.5 mmol of 2,5-dibromothiophene, 145 mg of tetrakis(triphenylphosphine)palladium, and 35 mL of toluene are heated just below reflux for three days under nitrogen. The precipitate is successively washed with dilute hydrochloric acid, water, and acetone, and recrystallized from mesitylene with hot filtration.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH3:2][N:3]([CH2:27][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1)[CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16]
Reactant: CNCCN1C(=O)c2ccccc2C1=O
Reactant: O=Cc1ccc2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCN1C(=O)c2ccccc2C1=O)Cc1ccc2ccccc2n1
Reaction time: 16 h

Procedure:
To the HCl salt of 2-(2-methylamino-ethyl)-isoindole-1,3-dione (1 eq) in dichloromethane was added quinoline-2-carbaldehyde (1.2 eq), sodium triacetoxyborohydride (2 eq), and acetic acid (1.2 eq) at room temperature. The solution was allowed to stir for 16 hours. After concentration, the solution was diluted with ethyl acetate, washed with NaHCO3 (sat.), NaCl (sat.). dried over MgSO4 filtered, concentrated, and pumped on. The yellow oil was then purified using flash chromatography (2% methanol/dichloromethane with 0.1% triethylamine) to yield 2-[2-(methyl-quinolin-2-ylmethyl-amino)-ethyl]-isoindole-1,3-dione as a green solid. MH+(346)
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.N1C=CC=CC=1.C(N)CN>CN(C=O)C>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[C:5]([C:1]#[N:2])[CH:13]=[CH:12][C:8]1=2
Reactant: N#C[Cu]
Reactant: Brc1ccc2sccc2c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: NCCN
Product: N#Cc1ccc2sccc2c1
Temperature: 80 °C
Yield: 92.1 %

Procedure:
A mixture of CuCN (86 g, 960 mmol), 5-bromobenzo[b]thiophene (157 g, 723 mmol), pyridine (80 mL) and DMF (1400 mL) was heated at reflux for 14 h. After cooled to 80° C., the reaction mixture was poured into a cold aqueous solution of ethylenediamine (400 mL in 2 L water) cooled by an icebath. The product was extracted with ether (2×1.5 L). The ether layer was washed with brine (1 L), dried (Na2SO4), and concentrated. The residue was recrystallized from CHCl3/Hexanes (50 mL/2000 mL) to give benzo[b]thiophene-5-carbonitrile (106 g, 90%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.61 (d, J=5.4 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.41 (d, J=5.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:15]=[C:16]([F:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33].[OH-].[Na+].Cl>CO.C1COCC1.O>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:15]=[C:16]([F:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]
Reactant: COC(=O)CCc1cc(F)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(F)cc(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
To a solution of methyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-fluorophenyl)propanoate (380 mg) in methanol (4.0 mL) and THF (3.0 mL) was added a solution of sodium hydroxide (183 mg) in water (4.0 mL), and the mixture was stirred at room temperature for 15 hr. 2N Hydrochloric acid was added to the reaction to mixture to adjust to pH<2, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (290 mg) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:10](=O)[CH2:11][CH2:12][CH3:13].S1C=CC=C1>CO.[Pd]>[CH2:10]([N:4]1[CH2:5][CH2:6][C@@H:7]([CH2:8][OH:9])[C@H:2]([OH:1])[CH2:3]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: OC[C@@H]1CCNC[C@H]1O
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCCCN1CC[C@@H](CO)[C@H](O)C1
Yield: 99.5 %

Procedure:
A mixture of intermediate (1-a) (0.022 mol) and butanal (0.025 mol) in methanol (150 ml) was hydrogenated with palladium on activated carbon (10%) (1 g) as a catalyst in the presence of a solution of thiophene (4% in THF) (1 ml). After uptake of H2 (1 equiv.), the catalyst was filtered off and the filtrate was evaporated, yielding 4.1 g of (±)-trans-1-butyl-3-hydroxy-4-piperidinemethanol (interm. 1-b) (99.5%, used in next reaction step without further purification).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12]CC3C=CC(OC)=CC=3)=[N:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.FC(F)(F)C(O)=O>ClCCl.CC(C)=O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([OH:12])=[N:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: COc1ccc(COc2ccc(-n3ccnn3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: ClCCl
Product: Oc1ccc(-n2ccnn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(1H-1,2,3-triazol-1-yl)-2-(4′-methoxybenzyloxy)pyridine from step 3 of this example (890 mg, 3.15 mmol) was dissolved in dichloromethane (11 ml). Trifluoroacetic acid (3.64 ml, 47.3 mmol) was added and the mixture stirred at RT. Within 10 minutes the reaction had turned light purple. The reaction mixture was evaporated 40 minutes after TFA addition, then reconstituted in CH2Cl2/heptane and evaporated again. The residue was purified by column chromatography on a Biotage 40 g SiO2 column, eluting with 0-15% methanol in CH2Cl2 to give a white solid. The white solid was suspended in acetone and filtered over celite to remove silica from the crude. The filtrate was then evaporated and pumped on high vacuum overnight to give the title compound as a complex with acetone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].CN([CH:15]=[O:16])C.[C:17]([O-])([O-])=O.[K+].[K+]>>[N+:8]([C:7]1[C:2]2[NH:1][C:15](=[O:16])[CH2:17][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CN(C)C=O
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2cccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.8 %

Procedure:
To a solution of 2-amino-3-nitrophenol (4.62 g, 30 mmol) in DMF (20 ml) ethylbromoacetate (3.3 ml, 30 mmol) and K2CO3 (4.56 g, 33 mmol) were added and the reaction was stirred at room temperature for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ether/hexane gave 4.65 g of a yellow solid. Yield: 80%. 1HNMR (DMSO, 200 MHz) δ 4.74 (2H, s), 7.15 (1H, t, J=8.4 Hz), 7.41 (1H, dd, J=8.2 Hz, J′=1.6 Hz), 7.77 (1H, dd, J=8.4 Hz, J′=1.2 Hz), 10.38 (1H, bs)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCC1CCN(Cc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 9 h
Yield: 59.3 %

Procedure:
To a solution of ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate (21 g) in ethanol (20 ml) was added sodium borohydride (9.1 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 10.55 g of 1-benzyl-3-hydroxy-4-hydroxymethylpiperidine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:28]O>O>[CH3:28][O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[CH2:13][C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Temperature: 25 °C

Procedure:
A solution of 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid in MeOH with a catalytic amount of conc. sulfuric acid was heated to reflux for 5 hours, cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4 and conc. in vacuo to give 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester as white solid. MS: 309[M-H].
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23](=[O:48])[CH2:24][CH2:25][C:26]1[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]/[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:30][CH:29]=[C:28](I)[N:27]=1>>[CH3:21][O:22][C:23](=[O:48])[CH2:24][CH2:25][C:26]1[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]/[C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)=[CH:30][CH:29]=[C:28]([C:19]#[C:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[O:20])=[CH:17][CH:16]=2)[N:27]=1
Reactant: C#Cc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Product: COC(=O)CCc1nc(C#Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 30 %

Procedure:
Under the conditions of example 5 A, 1.31 g of the crude N-benzenesulfonyl-4-ethinylbenzoic acid amide is reacted with 1.9 g of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with dichloromethane/0-5% methanol. 750 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-[2-(4-benzenesulfonamidocarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[OH-].[Li+].[I-].[CH:17]1[C:27]2[CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[NH:22][C:21]=2[CH:20]=[CH:19][C:18]=1[CH2:32][N+]1(C)CCCCC1.O>CN(C=O)C>[CH2:1]([C:3]1[N:13]([CH2:32][C:18]2[CH:19]=[CH:20][C:21]3[NH:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[CH2:25][CH2:26][C:27]=3[CH:17]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: C[N+]1(Cc2ccc3c(c2)CCc2ccccc2N3)CCCCC1
Agent: [I-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
[step 1] 2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 36.55 g, 209 mmol) was dissolved in DMF (365.5 mL), and the solution was added with lithium hydroxide (5.62 g, 235 mmol), followed by stirring at room temperature for 15 min. 1-(10,11-Dihydro-5H-dibenzo[b,f]azepin-2-ylmethyl)-1-methylpiperidinium iodide (JP-A-7-61983; 95.0 g, 219 mmol) and DMF (73.1 mL) were added thereto, and the mixture was stirred at 40° C. for 8 hr. After cooling to room temperature, water (175.4 mL) was added dropwise, and the mixture was stirred under ice-cooling for 2 hr. The precipitate was collected by filtration, and dissolved in chloroform (520 mL) with heating. Activated carbon (5.2 g) was added, and the mixture was stirred for 30 min with heating, and the hot solution was filtered. Ethyl acetate (1041 mL) was added to the filtrate, and the precipitate was collected by filtration to give 2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (36.7 g, 46%).
Reaction SMILES: [C:1](#[N:5])[C:2]([CH3:4])=[CH2:3].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:13]>C(#N)C>[Cl:13][C:2]([CH3:4])([CH2:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]#[N:5]
Reactant: Nc1ccccc1
Reactant: Cl
Reactant: C=C(C)C#N
Solvent: CC#N
Product: CC(Cl)(C#N)Cc1ccccc1
Yield: 87.9 %

Procedure:
Following the general procedure of Example I, 364 mmols of methacrylonitrile were reacted with 25 mmols of distilled aniline in 30 mL of acetonitrile and in the presence of 38 mmols of concentrated HCl and 2.5 mmols of cuprous oxide. The process resulted in an 87.9% yield of 2-chloro-2-methyl-3-phenylpropionitrile.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.[NH2:23][NH2:24].O>N1C=CC=CC=1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:5][N:4]=[N:3][C:2]=2[NH:23][NH2:24])=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2cnnc(Cl)c2-c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Yield: 96 %

Procedure:
3-Chloro-4,5-bis(4-chlorophenyl)pyridazine (10.0 g, 30.0 mmol) was dissolved in pyridine (30 mL) and hydrazine mono-hydrate was added (4.5 g, 90.0 mmol). The reaction mixture was refluxed for 3 h and was then added to water (100 mL). The pale colored solid was collected by filtration and rinsed thoroughly with water. The product was dried in a vacuum oven to give the title compound, 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (9.5 g, 96%). MS: M+H=331. 1H NMR (DMSO-d6, 500 MHz): δ 8.59 (1H, s), 8.56 (1H, br), 7.40 (2H, d, J=10 Hz), 7.35 (2H, d, J=10.0 Hz), 7.14-7.16 (4H, m).