Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]([F:48])([F:47])[F:46])=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([F:46])([F:47])[F:48])=[CH:37][CH:38]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CBr)cc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl ]-butanamide (Example 51, Step A) and 4'-bromomethyl-2-trifluoromethyl-1,1'-biphenyl by the procedure described in Example 1, Step K. 1H NMR (300 MHz,CDCl3): 1.37 (s,3H), 1.39 (s,3H), 1.73 (m,1H), 2.2-2.6 (m,5H), 4.50 (m,1H), 4.82 (d,15Hz,1H), 5.06 (s,2H), 5.29 (d,15Hz,1H), 5.65 (s,1H), 6.70 (d,7Hz,1H), 7.1-7.4 (m,14H), 7.44 (t,8Hz,1H), 7.52 (t,8Hz,1H), 7.71 (d,8Hz,1H). FAB-MS: calculated for C37H36F3N3O4 643; found 644 (M+H,55%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19](OCC)=[O:20])[CH2:7]2.C([O-])(=O)C.[NH4+:30]>C(O)(=O)C>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:12]=[CH:11][C:10]2[C:9]3[NH:30][C:19](=[O:20])[C:15]4[N:14]([CH:18]=[CH:17][N:16]=4)[C:8]=3[CH2:7][C:6]=2[CH:5]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nccn1C1Cc2cc(OC(F)(F)F)ccc2C1=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)Cc1cc(OC(F)(F)F)ccc1-2
Temperature: 20 °C
Yield: 75.9 %

Procedure:
0.76 g of 5-trifluoromethoxy-2-(2-ethoxycarbonyl-1H-imidazol-1-yl)indanone and 19 g of ammonium acetate in 30 ml of acetic acid are heated at reflux for 45 minutes. After cooling to a temperature in the region of 20° C., the precipitate formed is filtered, washed with water and dried under reduced pressure (1 mm Hg, 0.13 kPa) at 40° C. There is obtained 0.5 g of 8-trifluoromethoxy-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a beige powder, the melting point of which is greater than 260° C. (Analysis C14H8F3N3O2.0.9AcOH, % calculated C: 54.73, H: 2.62, F: 18.55, N: 13.68, % found C: 55.0, H: 2.6, F: 18.3, N: 13.8).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:42]([OH:45])(=[S:44])[CH3:43]>CN(C)C=O.ClCCl>[CH3:1][N:2]1[CH2:6][C@@H:5]([S:44][C:42](=[O:45])[CH3:43])[CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9]
Reactant: CN1C[C@H](O)C[C@H]1C(N)=O
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](C(N)=O)N(C)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
(2S,4R)-1-Methyl-2-aminocarbonyl-4-hydroxypyrrolidine (540 mg) was dissolved in dry dimethylformamide (10 ml), and triphenylphosphine (1.78 g) was added thereto. To the resultant mixture, diethyl azodicarboxylate (1.07 ml) was added under nitrogen steam while ice-cooling, and the mixture was stirred for 35 minutes. Thioacetic acid (0.76 ml) was added to the mixture under ice-cooling, and stirring was continued for 30 minutes under ice-cooling and at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2S,4S)-1-methyl-2-aminocarbonyl-4-acetylthiopyrrolidine.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]3=[N:13][O:14][N:15]=[C:11]3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[C@@H:29]1[CH2:31][O:30]1>>[N:13]1[O:14][N:15]=[C:11]2[CH:10]=[C:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][N:4]([CH2:31][C@@H:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:24](=[O:28])[O:25][CH2:26][C:27]=5[C:19]=4[CH3:18])[OH:30])[CH2:3][CH2:2]3)[CH:17]=[CH:16][C:12]=12
Reactant: c1cc2nonc2cc1CCN1CCNCC1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2CCN(CCc3ccc4nonc4c3)CC2)ccc2c1COC2=O

Procedure:
5-[(1R)-2-{4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one was prepared in a similar fashion as to the synthesis described in EXAMPLE 12 starting from 5-[2-(piperazin-1-yl)ethyl]-2,1,3-benzoxadiazole and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one. LC/MS: [(M+1)]+=423.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][CH2:8][CH2:9][C@H:10]([NH2:11])[C@H:4]2[O:3]1.[CH3:13][C:14]1([CH3:39])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26]3[N:31]=[C:30]([N:32]4[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]4)[CH:29]=[CH:28][CH:27]=3)[CH:17]=[CH:16][C:15]1=2>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][CH2:8][CH2:9][C@H:10]([NH:11][CH:35]3[CH2:34][CH2:33][N:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:18]5[CH:17]=[CH:16][C:15]6[C:14]([CH3:39])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=6[CH:19]=5)[N:31]=4)[CH2:37][CH2:36]3)[C@H:4]2[O:3]1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Reactant: CC1(C)O[C@H]2[C@H](CCC[C@@H]2N)O1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](NC3CCN(c4cccc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)n4)CC3)CCC[C@@H]2O1

Procedure:
The preparation is carried out analogously to FS1008 in THF starting from 62 mg (0.360 mmol) of (3aR,4S,7aS)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-ylamine and 145 mg (0.360 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The purification is carried out by means of flash chromatography on silica gel.
Reaction SMILES: [NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>CO>[NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: C[C@H](CCc1ccc(C#CCCCc2ccccc2)s1)C(N)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCc1ccc(C(=O)CCCCc2ccccc2)s1)C(N)O
Temperature: 0 °C
Yield: 82 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol (387 mg, 1.18 mmol) obtained in Example 49 was dissolved in methanol (4 ml), and 6N sulfuric acid (4 ml) was added thereto followed by heating under reflux for 4 hours. The reaction solution was cooled to 0° C. and made alkaline (pH 14) with a 1N aqueous sodium hydroxide solution, and the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacua. The residue was purified by chromatography on a silica gel column (Chromatorex NH (100-200 mesh)) (elution solvent; dichloromethane:methanol=1:0-50:1) to afford (2R)-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol (336 mg, 82% yield). This compound was dissolved in methanol, and oxalic acid (88 mg, 0.97 mmol) was added thereto to precipitate crystals. The crystals were recrystallized from methanol to afford the tide compound (332 mg, 78% yield) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Mg]Cl)[CH2:12][CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:11][CH2:12][CH3:13])=[C:4]([F:10])[CH:3]=1
Reactant: CCC[Mg]Cl
Reactant: O=Cc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a −78° C. solution of 4-bromo-2-fluorobenzaldehyde (600 mg, 3 mmol) in tetrahydrofuran (10 mL) was added n-propylmagnesium chloride (2.22 mL, 4.43 mmol) dropwise over 20 minutes. The reaction was warmed to 0° C. and stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), dried over sodium sulfate, filtered, and concentrated. Purification by preparatory thin layer chromatography gave (+/−)-1-(4-bromo-2-fluorophenyl)butan-1-ol (440 mg, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.26-7.30 (m, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 4.90 (t, J=5.6 Hz, 1H), 1.53-1.79 (m, 2H), 1.30-1.45 (m, 2H), 0.85 (s, J=5.6 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:11]=3[O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([S:20]([N:23](CC4C=CC(OC)=CC=4OC)[C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:22])=[O:21])=[C:15]([F:40])[CH:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:11]=3[O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([S:20]([NH:23][C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:21])=[O:22])=[C:15]([F:40])[CH:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4[nH]cnc4c3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccc3[nH]cnc3c2)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 4-(2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.149 g, 0.22 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at 0° C. The reaction mixture was stirred for 2 h at 0° C. The mixture was concentrated in vacuo and the residue was suspended in methanol (20 mL) and filtered. The filtrate was concentrated in vacuo and the residue triturated in diethyl ether (5 mL) and suspended in water (2 mL). Lyophilization affored 4-(2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzene-sulfonamide as the corresponding beige trifluoroacetate salt in 75% yield (0.11 g): 1H NMR (300 MHz, DMSO-d6) δ9.11 (s, 1H), 8.37 (s, 1H), 7.84 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.64 (dd, J=10.2, 6.5 Hz, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.49 (dd, J=8.7, 2.5 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H), 7.11 (dd, J=10.4, 6.5 Hz, 1H), (NH not observed); 19F NMR (282 MHz, DMSO-d6) δ−76.6 (s, 3F), −113.0 (d, J=15.8 Hz, 1F), −139.0 (d, J=15.9 Hz, 1F); MS (ES+) m/z 519.7 (M+1), 521.7 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C:15]2[C:16](Cl)=[N:17][C:18]([Cl:22])=[CH:19][C:20]=2[CH3:21])=[O:13])[C:5]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH:9]3[CH2:11][CH2:10]3)[C:16]3[N:17]=[C:18]([Cl:22])[CH:19]=[C:20]([CH3:21])[C:15]=3[NH:14][C:12](=[O:13])[C:4]=2[CH:3]=1
Reactant: Cc1cc(Cl)nc(Cl)c1NC(=O)c1cc(Br)cnc1NC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2c1NC(=O)c1cc(Br)cnc1N2C1CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
A solution of 5-bromo-2-(cyclopropylamino)-N-(2,6-dichloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide (105 mg, 0.254 mmol) in pyridine (3.0 mL) was heated to 50° C. while a 1 M solution of NaHMDS in THF (0.53 mL, 0.53 mmol) was added. The resulting solution was stirred at 50° C. for 3 h. The reaction was quenched with aqueous saturated NH4Cl, diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (hexane:EtOAc, 7:3) to give the title compound (32 mg, 33% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[P:21](Cl)([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][P:21]([NH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3)(=[O:22])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: CCOP(=O)(Cl)OCC
Reactant: NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Solvent: CN(C)C=O
Product: CCOP(=O)(NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2)OCC
Yield: 50 %

Procedure:
To a solution of compound 49(0.5 mmol) in anhydrous DMF (20 mL) was added diethyl chlorophosphate (1.5 mmol). After 3 hours solution was concentrated in vacuo, and 50 mL of water was added. The aqueous layer was extracted with 30 mL of EtOAc twice. Organic layers were combined and washed with 30 mL of brine. Organic layer was dried with MgSO4. Solvent was removed to afford a white solid, which was recrystallized in 10% of EtOAc in hexanes to afford a white solid 54 in 50% yield. MS (ES−): 400; Mp: 222.3-224.5° C.; 1H-NMR (CDCl3, 400 MHz): 10.21 (s, 1H), 8.10 (d, J=2.5 Hz, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.5 and 2.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 4.12 (m, 6H), 1.32 (t, J=6.5 Hz, 6H); Anal. Calcd. for C19H20N3O5P·(0.3H2O): C, 56.10; H, 5.10; N, 10.33. Found: C, 56.00; H, 5.03; N, 10.13.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([N:11]1[N:10]=[N:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[N:12]1)[CH3:15]
Reactant: Cc1ccc(-c2nnn[nH]2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1nnc(-c2ccc(C)cc2)n1
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A solution of 20.0 grams (0.125 mole) of 5-(4-methylphenyl)-1,2,3,4-tetraazole in 230 mL of acetonitrile was stirred and 48.7 grams (0.312 mole) of iodoethane, followed by 17.3 grams (0.125 mole) of potassium carbonate were added. Upon completion of addition, the reaction mixture was warmed to reflux, where it stirred for two hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:4 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 18.8 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:13]=[CH2:14].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C1(C=CC(O)=CC=1)O.O>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14][NH:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)=[CH:29][CH:28]=1
Reactant: CN1CCN(c2ccc(CN)cc2)CC1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: CCCCO
Product: COc1cc(CCNCc2ccc(N3CCN(C)CC3)cc2)c(Cl)cc1[N+](=O)[O-]
Yield: 42.8 %

Procedure:
A mixture of 1-chloro-4-methoxy-5-nitro-2-vinylbenzene (0.42 g, 1.95 mmol), 4-(4-methyl-piperazin-1-yl)-benzylamine (1.2 g, 5.85 mmol) and quinol (0.043 g, 0.39 mmol) in n-butanol (8 mL) was heated to reflux for 12 hours under a N2 atmosphere. Water (100 mL) was added and the reaction mixture extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 3-5% methanol in DCM to give the title compound (0.35 g, 43%) as a solid.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([N:12]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N
Reactant: O=c1ccocc1
Product: CC(C)(C)n1ccc(=O)cc1

Procedure:
The starting material may be prepared as follows: A solution of 4-pyrone (730 mg.) in t-butylamine (3.0 ml.) was set aside for 3 days. The excess t-butylamine was evaporated under reduced pressure and the residue was purified by chromatography on Kieselgel 60 (20 g.) eluting with methylene chloride/MeOH 100:0 to 90:10 v/v to give 1-t-butyl-4-pyridone (530 mg.) N.m.r. in solvent A:-1.55(s, 9H); 6.4(d, 2H); 7.6(d, 2H). This material was chlorinated as described in the second part of Example 56 to give 4-chloro-1-t-butylpyridiniumtoluene-p-sulphonate.
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[C:16](O)([CH:17]([CH3:19])[CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:7]1)=[O:5])C.C(O)(=O)C.Cl.C(=O)([O-])O.[Na+]>O>[CH:17]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:7][C:6]=1[C:4]([OH:5])=[O:3])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C1(C(=O)OCC)OC(=O)c2ccccc2C1(O)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1c(C(=O)O)oc(=O)c2ccccc12
Temperature: 0 °C
Yield: 40 %

Procedure:
A stirred mixture of crude 3,3-bis(ethoxycarbonyl)-4-hydroxy-4-isopropyl-3,4-dihydroisocoumarin (76 g), glacial acetic acid (500 ml) and concentrated hydrochloric acid (800 ml) was refluxed for 18 hours. The cooled mixture was added to ice/water (3500 ml) and the precipitated solid filtered off and washed with water to give an off-white solid. This was treated with a solution of sodium hydrogen carbonate (40 g) in water (400 ml) and the resultant solution was extracted with diethyl ether (150 ml). The aqueous phase was acidified to pH1 with concentrated hydrochloric acid and the white precipitate filtered off, washed with water and dried at 70° C. to give 4-isopropylisocoumarin-3-carboxylic acid (20.16 g) in the form of a white solid [Elemental analysis: C, 67.4; H, 5.2%; calculated: C, 67.2; H, 5.17%; NMR (in DMSO-d6): 1.45 (6H, d, J=8 Hz), 3.85 (1H, sept, J=8 Hz), 7.6-8.4 (4H, m)].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:16][C:17]1[C:22]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Oc1cccnc1Br
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cccnc3Br)c2cc1OC
Temperature: 140 °C
Reaction time: 2 h
Yield: 5.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (226 mg), 2-bromo-3-pyridinol (250 mg), and 4-dimethylaminopyridine (400 mg) were suspended in o-dichlorobenzene (10 ml), and the suspension was stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (21 mg, yield 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][C:13]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:18][S:40]([CH3:39])(=[O:42])=[O:41])=[O:17])=[CH:14][C:13]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1cnc(C2CC2)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)ccc1Oc1cnc(C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution of 4-(5-chloro-6-cyclopropylpyridin-3-yloxy)-3-(2-methoxypyridin-3-yl)benzamide (Preparation 40, 437 mg, 1.10 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen was added 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (4.40 mL, 4.40 mmol). The solution was stirred 30 minutes at room temperature then methane sulfonyl chloride (340 μL, 4.40 mmol) was added and the reaction mixture was stirred 2 hours at room temperature. Water (50 mL) was added and the solution was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with Feb. 10, 1990 acetic acid/ethyl acetate/dichloromethane to afford the title compound as a white solid (230 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:19][C:18](=[O:20])[CH2:17][N:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: CC(=O)CN1CCOCC1
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C=CC(=O)CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
Condensation 13.6 g (0.1 mole) of p-methoxybenzaldehyde is dissolved in 14.3 g (0.1 mole) of morpholinoacetone and this solution is added dropwise to 100 cm3 of a solution of 1 N sodium hydroxide cooled in an ice-containing water bath. The temperature is allowed to return to ambient temperature while stirring for 5 hours. The precipitate obtained is filtered and rinsed several times with water. 18.8 g of 1-(p-methoxyphenyl)-4-morpholino-1-buten-3-one is obtained.
Reaction SMILES: [CH3:1][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]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=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(C)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccc(F)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-methylphenylacetylene (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-methylstyryl 4-fluorobenzylsulfide. The title compound was obtained in 69% yield following oxidation. 1HNMR (CDC13) δ 2.46 (3H, s),4.62 (2H, s), 6.78 (1H, d, JH,H=11.98), 7.18-7.59 (9H aromatic+1H ethylenic).