Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=4)=[CH:22][CH:21]=3)[CH:14]=2)[NH:9][CH:8]=1)#[N:6]>>[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:4][CH2:3][CH2:2][OH:1])[N:27]=4)=[CH:22][CH:21]=3)[CH:14]=2)[NH:9][CH:8]=1)#[N:6]
Reactant: NCCO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCO)n4)cc3)cc12

Procedure:
Using 2-hydroxy-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 2.98 (t, 2H, J=7 Hz); 3.44 (bs, 2H); 3.55 (m, 4H); 4.70 (t, 1H, J=6 Hz); 7.17 (m, 3H); 7.48 (m, 2H); 7.92 (d, 2H, J=9 Hz); 8.18 (m, 3H); 8.38 (d, 1H, J=5 Hz); 8.68 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 427 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH:16][N:17]([CH3:19])[CH3:18])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCCc2ccc(Br)cc21
Product: CN(C)C=C1CCc2ccc(Br)cc2C1=O

Procedure:
The 7-bromo-3,4-dihydro-2-dimethylaminomethylene-1-(2H)naphthalenone starting material was prepared from 7-bromo-3,4-dihydro-1(2H)-naphthalenone (9.0 g, 40.0 mmol) [Griffin, R W et al, J.O.C. (1964), 29, 2109] and N,N-dimethylformamide diethyl acetal (20.6 ml, 120.0 mmol) to give the product as yellow crystals (8.01 g) after recrystallisation from tert.butylmethyl ether. δH (CDCl3) 8.13 (1H, d, 2.2 Hz), 7.72 (1H, s), 7.45 (1H, dd, J 2.2, 8.0 Hz), 7.03 (1H, d, J 8.0 Hz), 3.13 (6H, s) and 2.92-2.74 (4H, m).
Reaction SMILES: [NH:1]=[C:2]1[C:15](NC(NC(OC)=O)=S)=[CH:14][CH:13]=[C:4]([C:5](C2C=CC=CC=2)=O)[CH:3]1CC1C=CC=CC=1.[OH-].[Na+].CI.N=[C:36]1[C:49]([NH:50][C:51](=[N:54][C:55]([O:57][CH3:58])=[O:56])[S:52][CH3:53])=[CH:48][CH:47]=[C:38]([C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:40])[CH:37]1CC1C=CC=CC=1>CN(C)C=O.O>[NH:1]=[C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([CH2:5][C:41]2([C:39](=[O:40])[C:38]3[CH:47]=[CH:48][C:49]([NH:50][C:51](=[N:54][C:55]([O:57][CH3:58])=[O:56])[S:52][CH3:53])=[CH:36][CH:37]=3)[CH:42]=[CH:43][CH:44]=[CH:45][CH2:46]2)[CH2:3]1
Reactant: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N)SC
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)N=C(Nc1ccc(C(=O)C2(CC3=CC=CC(=N)C3)C=CC=CC2)cc1)SC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-iminophenylmethyl-4-(3-carbomethoxythioureido)benzophenone (1.1 g.; 0.0026 mole) in dimethylformamide (10.0 ml.) is added water (3.0 ml.). Additional dimethylformamide (25.0 ml.) is added to dissolve some precipitate and then sodium hydroxide (50% aqueous; 0.21 g.; 0.0026 mole) is added. The resulting solution is stirred at room temperature for 11/2 hours and then methyl iodide (0.38 g.; 0.0026 mole) is added. The solution is stirred for one hour at room temperature and then poured into water (250 ml.). The precipitate is collected by filtration and dried to afford 0.95 g. of 3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone, m.p. 140°-142° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:25][CH2:26][CH2:27][OH:28]>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:25][CH2:26][CH2:27][OH:28]
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCO
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 2-amino-ethanol. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (s, 1 H), 7.85-7.80 (d, J=8.4 Hz, 1 H), 7.80-7.75 (d, J=7.6 Hz, 1 H), 7.75-7.70 (d, J=7.2 Hz, 1 H), 7.61-7.50 (m, 3 H), 6.10 (s, 1 H), 5.48-5.39 (m, 1 H), 5.08-4.95 (m, 1 H), 4.80-4.70 (m, 1 H), 4.52-4.42 (m, 1 H), 3.88-3.80 (t, J=5.6 Hz, 2 H), 3.65-3.60 (t, J=5.6 Hz, 2 H), 3.59-3.40 (m, 2 H), 2.46 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([O:20]C)=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[CH:3]=1.[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([OH:20])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[CH:3]=1
Reactant: COC(=O)Cc1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2c(CC(=O)O)c(C)nc3sc(C)cc23)cc1
Temperature: 60 °C
Yield: 48.3 %

Procedure:
To a solution of methyl 2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.080 g; 0.246 mmol) in dioxane (4 mL) and water (1.5 mL) was added a 1N lithium oxide solution (1.5 mL; 1.50 mmol). The reaction mixture was heated at 60° C. for 4 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.037 g (48%) of the title compound as a beige solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:9])[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(COC)OC>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[CH3:8])=[CH:14][CH:13]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)c1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccsc2C(C)=O)cc1
Temperature: 80 °C
Yield: 45.1 %

Procedure:
A flask was charged with 1-(3-bromothiophen-2-yl)ethanone (1.00 g, 4.88 mmol), 4-methoxyphenylboronic acid (0.740 g, 4.88 mmol), tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol), dimethoxyethane (50 mL), and 2 N aqueous Na2CO3 (7.3 mL) and then warmed to 80° C. for 7 h. At that time the reaction mixture was poured into H20 and extracted with EtOAc. The organic phase was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified via flash chromatography, eluting with 5-15% EtOAc/hexanes to afford the product (0.50 g, 2.2 mmol). MS (M+H)+ 233.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)O1.Br[C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1>O.C(O)C.C1(C)C=CC=CC=1.CCOC(C)=O.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>[O:31]=[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:29][O:28][C:27]1[CH:37]=[CH:38][C:24]([C:15]2[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=2)=[CH:25][CH:26]=1
Reactant: O=C(COc1ccc(Br)cc1)N1CCCC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2ccc(OCC(=O)N3CCCC3)cc2)cn1
Temperature: 120 °C

Procedure:
Sodium carbonate (0.318 g, 3.0 mmol) in water (2.0 mL) was added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.221 g, 1.0 mmol), 1-[(4-bromophenoxy)acetyl]pyrrolidine (0.341 g, 1.2 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) in ethanol (1.5 mL) and toluene (1.5 mL). The resulting mixture was heated at 120° C. for 3 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (0.29 g) was directly used in next step without further purification. LCMS: (M+H)=299.1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[CH:32]=[C:33]([C:38]([N+:41]([O-:43])=[O:42])=[CH:39][N:40]=1)[C:34]([O:36][CH3:37])=[O:35].Cl>CN(C)C=O.O>[F:1][C:2]([F:22])([F:23])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:31]2[CH:32]=[C:33]([C:38]([N+:41]([O-:43])=[O:42])=[CH:39][N:40]=2)[C:34]([O:36][CH3:37])=[O:35])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)OC)c([N+](=O)[O-])cn1
Yield: 72.7 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenol (1.68 g, 4.86 mmol) in N,N-dimethylformamide (30 mL), potassium carbonate (1.34 g) and methyl 2-chloro-5-nitroisonicotinate (1.58 g) were added, and the resultant mixture was stirred in an oil bath with the oil temperature at 80° C. After completion of the reaction, the reaction solution was neutralized by adding 2 mol/L of hydrochloric acid, added with water, and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using thin-layer silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.86 g, yield 73%) was obtained as a colorless oil.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=[C:16]2[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1.[I:32][C:33]1[CH:34]=[C:35]([CH:42]=[CH:43][CH:44]=1)[C:36](N(OC)C)=[O:37]>C1COCC1.CCOC(C)=O>[Cl:31][C:27]1[CH:26]=[C:25]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:36]([C:35]4[CH:42]=[CH:43][CH:44]=[C:33]([I:32])[CH:34]=4)=[O:37])[CH:14]=3)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: CON(C)C(=O)c1cccc(I)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3cccc(I)c3)ccc2n1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 120.5 %

Procedure:
BuLi 1.6M in hexane (0.0334 mol) was added dropwise at −70° C. to a solution of 6-bromo-4-(3-chlorophenyl)-2-methoxy-quinoline (0.0304 mol) in THF (100 ml), under N2 flow. The mixture was stirred at −70° C. for 10 minutes. A solution of 3-iodo-N-methoxy-N-methyl-benzamide (0.0274 mol) in THF (40 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour and poured out into ice water. EtOAc was added. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated, yielding 16.5 g (100%) of [4-(3-chlorophenyl)-2-methoxy-6-quinolinyl](3-iodophenyl)-methanone (intermediate 73). This product was used without further purification in the next reaction step.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1([C:27](=[O:38])[CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:18][C:16]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:30][CH2:29][CH:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:27]([N:20]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:38])[CH2:3][CH2:2]1)[CH:15]=[CH:14][CH:13]=2)=[O:17]
Reactant: O=C(C(CCCl)c1ccccc1)N1CCCCCC1
Reactant: COC(=O)c1cc2c(N3CCNCC3)cccc2[nH]1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(N3CCN(CCC(C(=O)N4CCCCCC4)c4ccccc4)CC3)cccc2[nH]1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The product of Example 4 (1.30 g, 0.005 mol), 1-azepan-1-yl-4-chloro-2-phenylbutan-1-one (1.50 g, 0.005 mol), triethylamine (0.79 g, 0.0079 mol), and potassium iodide (0.2 g) were suspended in anhydrous dimethyl formamide (30 ml), stirred under argon for 3 h at 100° C., and poured into dilute potassium carbonate (300 ml). The mixture was extracted into ether (3×100 ml) and treated with excess dilute aqueous hydrogen chloride. The precipitate was filtered, washed with ether (3×100 ml), taken up into dilute sodium hydroxide solution (100 ml), and extracted into ether (3×100 ml). The extracts were dried (MgSO4), and evaporated in vacuo to give a yellow crystalline glass. Purification by chromatography [alumina; ethyl acetate-hexane (2:3)] gave the product free base. The dihydrochloride salt of the product (1.35 g) was precipated as a colourless solid by the addition of ethereal hydrogen chloride to a solution of the free base in ethyl acetate, m.p. 152°-168° C. (Found: C, 57.4; H, 7.45; N, 8.7. C30H38N4O3. 2HCl.3H2O requires C, 57.2; H, 7.4; N, 8.9%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1)[CH3:2].BrN1C(=[O:17])CCC1=O.C([O-])([O-])=O.[K+].[K+].CO>CS(C)=O.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][O:17]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1ccc(CC)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: CCc1ccc(C2CO2)nc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a stirred solution of 400 g (2.974 mol) 5-ethyl-2-vinyl-pyridine dissolved in a mixture of 1000 mL of dimethyl sulfoxide and 106 mL water, was added 741.9 g (4.16 mol) N-bromosuccinimide at 0 to −5° C. Reaction mixture was stirred for 1 hr. The progress of reaction was monitored by TLC and after complete consumption of 5-ethyl-2-vinyl-pyridine, 833 g (6.015 mol) of K2CO3 along with 400 mL methanol was added at 25-30° C. Stirring was continued for 1 hr. and after subsequent work-up 358.49 g (80%) of the desired product was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].Cl>CO.C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)=[O:16])[CH2:12][CH2:13]2)=[CH:27][CH:28]=1)#[N:2]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc(C(=O)O)cc3)CC2)cc1
Reaction time: 8 h
Yield: 83 %

Procedure:
Methyl 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate (900 mg, 2.38 mmol) and lithium hydroxide (600 mg, 14.28 mmol) was added to MeOH/THF/H2O(2/1/1, 20 mL), and the mixture was stirred overnight, then acidified with 2M hydrochloric acid (10 mL) to pH 5. A white solid separated, and was collected by filtration and washed with water. The combined filtrate and washings were acidified by adding further 2M hydrochloric acid to pH 1 and the solution was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulphate and evaporated to give 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoic acid (0.718 g, 83%). LCMS (m/z): 364 (MH+).
Reaction SMILES: [NH:1]([C:3]([C:5]1[C:14]([C:15]([NH:17]N)=[O:16])=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([CH2:21][CH3:22])=[CH:10][C:11]=2[Br:20])[N:6]=1)=[O:4])N>C(O)(=O)C>[Br:20][C:11]1[C:12]2[C:13]([OH:19])=[C:14]3[C:15](=[O:16])[NH:17][NH:1][C:3](=[O:4])[C:5]3=[N:6][C:7]=2[CH:8]=[C:9]([CH2:21][CH3:22])[CH:10]=1
Reactant: CCc1cc(Br)c2c(O)c(C(=O)NN)c(C(=O)NN)nc2c1
Solvent: CC(=O)O
Product: CCc1cc(Br)c2c(O)c3c(=O)[nH][nH]c(=O)c3nc2c1
Temperature: 81 °C
Yield: 68.5 %

Procedure:
A stirred mixture of 2,3-bishydrazinocarbonyl-5-bromo-7-ethyl-4-hydroxyquinoline (0.40 g, 1.1 mM) in glacial acetic acid (12 mL) was heated at 81° C. for 1.5 hr. After cooling to room temperature, the reaction mixture was filtered and the collected solids washed with acetic acid and air dried to provide the title compound (0.25 g, 70%) as a light brown solid, mp>400° C.; MS(CI): 336 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[C:41]([O:44][CH2:45][CH2:46][CH2:47][C:48](=[O:50])Cl)(=[O:43])[CH3:42].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[C:41]([O:44][CH2:45][CH2:46][CH2:47][C:48]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:50])(=[O:43])[CH3:42]
Reactant: CC(=O)OCCCC(=O)Cl
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Reaction time: 0.25 h
Yield: 49.4 %

Procedure:
4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (1.10 g, 2.03 mmol) obtained from Reference example 1 was dissolved in N,N-dimethylformamide (5 ml), and then sodium hydride (ca. 50 mg, 2.1 mmol) was added thereto at room temperature. The mixture was stirred for 15 minutes, then 4-chloro-oxobutyl acetate (330 mg, 2.0 mmol) obtained from Example 12-(1) was added thereto, and the resulting mixture was stirred for another 1 hour. The mixture was diluted with ethyl acetate, and a saturated aqueous solution of ammonium chloride was poured thereinto. The organic layer was separated, then washed successively with an aqueous solution of sodium hydrogen carbonate and with an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude compound was purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d. ×600 mm) and JAIGEL-2H (20 mm i.d. ×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (662 mg, 49% yield) as a colorless amorphous solid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH2:11]([C:16]1[CH:17]=C(O)[CH:19]=[C:20]([CH:22]=1)[OH:21])[CH2:12][CH2:13][CH2:14][CH3:15]>>[OH:21][C:20]1[C:19]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:17]=[C:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:22]=1
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: COC(=O)C1SCCC1=O
Product: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(1-pentyl)resorcinol to give 1,2-dihydro-9-hydroxy-4-oxo-7-(1-pentyl)-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CS)cc1
Reactant: C#Cc1ccc(F)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccc(F)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 78% yield following oxidation. 1HNMR (CDC13) δ 4.60 (2H, s), 6.65 (1H, d, JH,H=11.83), 7.20-7.65 (8H aromatic+1H ethylenic).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].Cl[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41].[F-].[K+]>CN(C=O)C>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COC(=O)CCCCl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1c(C(C)(C)C)cc(SC(C)(C)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 16.4 %

Procedure:
Probucol (5, 9.69 mmol) and methyl 4-chlorobutyrate (3.1 g. 1.4 eq) were stirred in DMF (15 mL) and potassium fluoride on alumina (7 g, 5 eq) was added. The mixture was stirred at room temperature under nitrogen for 20.5 hours. It was filtered, diluted with ethyl acetate (100 mL), washed with water and brine, dried over sodium sulfate, and evaporated. Chromatography (MPLC, 10% to 80% of dichloromethane in hexanes) gave 0.98 g of methyl 4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyrate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[BH4-].[Na+].O>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12]
Reactant: O=Cc1ccc2ccccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc2ccccc2n1
Yield: 84.1 %

Procedure:
2-Quinolinecarbaldehyde (2.00 g, 12.7 mmol) was dissolved in 25 mL of methanol. To this solution was added sodium borohydride (0.24 g, 6.4 mmol) in small portions over a period of 20 minutes. Then 2 mL of water were added and the mixture was evaporated. The residue was dissolved in ethyl acetate (75 mL) and washed with water (3×75 mL) and evaporated. The residue was chromatographed in CH2Cl2-methanol gradient, eluting the product at 97:3 CH2Cl2-methanol, and providing 1.7 g of quinolin-2-yl-methanol in 85% yield; 1H NMR (CDCl3) δ 4.92 (s, 2H), 7.26 (d, J=2.1 Hz, 1H), 7.30-7.57 (m, 1H), 7.68-7.75 (m, 1H), 7.82 (dd, J=8.0 Hz, J=0.9 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H).