Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([O:28]CC)=O)[C:8]2=[O:31])[CH2:3][CH2:2]1.[CH3:33][NH2:34]>>[CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([NH:34][CH3:33])=[O:28])[C:8]2=[O:31])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Reactant: CN
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(cyclopropylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methanolic methylamine employing methods similar to those described in Example 245. The crude material was triturated with a mixture of MeOH and 1N HCl to afford the product as a white solid: 1H NMR (d6-DMSO) δ 9.99 (1H, d, J=5 Hz), 8.53 (1H, s), 8.23 (1H, d, J=4 Hz), 7.74 (1H, s), 7.32 (2H, dd, J=8.6, 5.7 Hz), 7.11 (2H, t, J˜9 Hz), 4.79 (2H, s), 4.13 (2H, s), 2.88 (3H, d, J=5 Hz), 2.57 (1H, m), 0.59 (2H, m), 0.34 (2H, m); HRMS calcd for C22H21FN4O4+H+: 425.1625. Found: 425.1623.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]3[N:14]=[C:13]2[CH2:23][CH3:24])=[CH:8][C:7]=1[Cl:25])=[N+]=[N-].[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:25][C:7]1[CH:8]=[C:9]([N:12]2[C:16]3=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]3[N:14]=[C:13]2[CH2:23][CH3:24])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][NH2:1]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN=[N+]=[N-])c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)c(Cl)c1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of methyl 3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 10, 430 mg, 1.2 mmol) in ethanol/water (4/1) were added Fe (335 mg, 6.0 mmol) and NH4Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 h under reflux temperature. The solvent was removed and the residue was diluted with CH2Cl2.The mixture was washed with brine, dried (MgSO4) and concentrated to give 390 mg of title compound as orange oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([CH:31]3[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][CH2:36][OH:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:37][CH2:36][CH2:35][NH2:34])[N:18]=[C:17]([CH:31]3[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C2CC2)nc1OCCN

Procedure:
According to the procedure described in Example 4b) 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide was reacted with 2-aminoethanol to give 1.28 g 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide. LC-MS: tR=4.04 min, [M−1]−=511.50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[OH2:21]>>[NH2:20][C:19]([CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:21]
Reactant: CCOC(=O)C(C#N)CCCCCc1ccc(Cl)cc1
Reactant: O
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(N)=O
Yield: 78 %

Procedure:
12 g (41 mmol) of ethyl 7-(4-chlorophenyl)-2-cyanoheptanoate and 96 g of polyphosphoric acid are heated for 3 hours at 100° C. with stirring. Then the mixture is diluted with 200 ml of water and extracted thrice with methylene chloride. The combined extracts are washed with water, dried and concentrated. 10 g (78% of theory) of ethyl 2-(aminocarbonyl)-7-(4-chlorophenyl)heptanoate is obtained, M.P. 110°-111° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[OH:14])=[O:4].[C:15]([O:19][C:20](=[O:28])[CH2:21][NH:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:28])[CH2:21][N:22]([C:8](=[O:10])[C:7]1[C:6](=[C:5]([C:3](=[O:4])[CH2:2][Cl:1])[CH:13]=[CH:12][CH:11]=1)[OH:14])[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: O=C(O)c1cccc(C(=O)CCl)c1O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(C(=O)c1cccc(C(=O)CCl)c1O)C1CCCC1

Procedure:
3-Chloroacetylsalicylic acid was combined with N-cyclopentylglycine t-butyl ester and N,N1 -dicyclohexylcarbodiimide at 0° C. in methylene chloride as described in Example I. Similar workup gave crude N-(3-chloroacetylsalicyloyl)-N-cyclopentylglycine t-butyl ester, which was cleaved to N-(3-chloroacetylsalicyloyl)-N-cyclopentylglycine using iodotrimethylsilane prepared in situ as described in Example I. Hydrolysis with aqueous sodium hydroxide (Example IV) provided the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[CH:10][S:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][OH:26].O>C1(C)C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[CH:6][C:7]3[CH:11]=[CH:10][S:9][C:8]=3[CH:12]=2)[O:26][CH2:25][CH2:24][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccc2ccsc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc3ccsc3c2)OCCO1
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 6-acetyl benzo[b]thiophene (10.57 g, 60 mmole), p-toluenesulfonic acid (1.65 g) and ethylene glycol (33 ml) was heated to reflux in toluene (250 ml) for 2 hours with the continuous removal of H2O using a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature. Then extracted with 20% saturated NaHCO3 (150 ml) and H2O (2×150 ml). After drying over Na2SO4, the solvent was evaporated in vacuo and the residue was crystallized from hexanes (50 ml) yielding 9.66 g (73%) of product.
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:18][CH2:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].C([BH3-])#N.[Na+].O>O1CCCC1>[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]([N:18]([CH2:1][CH3:2])[CH2:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC=O
Reactant: CCN[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
150 μl (2.4 mmol) of acetaldehyde are added to 369 mg (1.5 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-ethylaminopropanoate in 5 ml of tetrahydrofuran then stirred for 30 minutes at ambient temperature. After cooling to 0° C., 189 mg (3 mmol) of sodium cyanoborohydride are added and the reaction medium is stirred at ambient temperature for 36 h. Water is added and the medium is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered then concentrated. The crude residue obtained is purified by chromatography over silica gel eluted with a 70/30 heptane/ethyl acetate mixture. 150 mg (38%) of methyl (S)-3-tert-butoxycarbonylamino-2-diethylaminopropanoate are obtained in the form of a colourless oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][C@@H:10]([C:24](O)=[O:25])[C@@H:11]([O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:12]([OH:14])=[O:13])=[O:8])=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>>[O:25]=[C:24]1[C@H:10]([O:9][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C@@H:11]([O:15][C:16](=[O:17])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12](=[O:13])[O:14]1
Reactant: O=C(O[C@@H](C(=O)O)[C@@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O[C@H]1C(=O)OC(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
To a 3-necked 5 L round bottom flask fitted with a mechanical stirrer and a teflon coated thermocouple was added (−)-2,3-dibenzoyl-L-tartaric acid (1000 g, 2.79 mol) followed by acetic anhydride (2 L). The suspension was stirred and heated to 85° C. for 2 h during which time the starting material gradually dissolved. A short time thereafter, the product began to crystallize in the reaction mixture and the suspension was then cooled to 25° C. The product was collected by filtration, washed with 10% acetone in hexane (2×1 L), and dried in a vacuum oven at 50° C. overnight to afford the title compound (22) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.0 (s, 2H), 7.45 (app. t, 4H), 7.65 (app. t, 2H), 8.05 (d, 4H).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C@H:8]1[O:15][CH:14]2[C@:10]([CH3:18])([O:11][C:12]([CH3:17])([CH3:16])[O:13]2)[CH2:9]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[CH3:16][C:12]1([CH3:17])[O:11][C@:10]2([CH3:18])[CH2:9][C@@H:8]([CH2:7][OH:6])[O:15][CH:14]2[O:13]1
Reactant: CC1(C)OC2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@@]2(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OC2O[C@H](CO)C[C@@]2(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyldiphenyl(((5S,6aR)-2,2,6a-trimethyl-tetrahydrofuro[3,2-d][1,3]dioxol-5-yl)methoxy)silane (from step 7) (7.2 g, 0.0169 mol) in 50 mL of anhydrous THF at 0° C., TBAF (20.28 mL, 0.0203 mol) was added and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. Purified by column chromatography using hexane and ethyl ether as a gradient mixture to give 2.72 g of the title compound in 82% yield.
Reaction SMILES: Br[C:2]1[C:3]([F:26])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][C:19]4[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.[CH3:27][C:28]([OH:32])([CH3:31])[C:29]#[CH:30].C(NC(C)C)(C)C>CN(C=O)C>[F:26][C:3]1[C:2]([C:30]#[C:29][C:28]([OH:32])([CH3:31])[CH3:27])=[CH:25][C:6]2[C:7]3[N:8]([C:12]([CH2:18][C:19]4[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: Cn1nccc1Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Yield: 23 %

Procedure:
9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(2-methylpyrazol-3-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-9-fluoro-3-[(2-methylpyrazol-3-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 2.5 mg (23% yield). M+1=424.2.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH2:2][C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[C:6]([CH3:13])[CH:5]=2)=[O:3])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(C(N)=O)c(C)c1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(N)=O
Temperature: 60 °C
Reaction time: 25 h
Yield: 78.3 %

Procedure:
0.35 g of 4-acetyl-2-methylbenzoic acid amide, 0.49 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.72 g of toluene and 0.19 g of tri-n-butylamine were fed and the mixture was stirred for 25 hours at 60° C. The mixture was left to cool to room temperature and the slurry-state reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 0.65 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid amide as a light yellow solid was obtained by drying under reduced pressure.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1.[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>C(Cl)(Cl)Cl>[CH2:11]([O:10][P:9]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Cc1cc(CCl)on1
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cc1cc(C)no1)OCC
Reaction time: 4 h

Procedure:
445 g of 5-chloromethyl-3-methylisoxazole and 674 g of triethyl phosphite are slowly heated to 150° C. and left at this temperature for 4 hours. After distillation, 546 g (69% of theory) of (3-methylisoxazol-5-yl)-methanephosphonic acid diethyl ester of boiling point 118°-121° C./0.3 mm Hg are obtained. 1H-NMR spectrum (CHCl3, with TMS as internal standard): τ=3.85 (d, J=3 Hz, 1H), 4.17 (m, J=8 Hz, 4H), 6.67 (d, J=22 Hz, 2H), 7.72 (s, 3H), 8.67 (t, J=8 Hz, 6H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: [Br-]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.1 %

Procedure:
m-Nitroacetophenone (20 g) was dissolved in acetic acid (150 mL) under argon. Pyridinium tribromide (38.7 g) was added at once; the reaction was allowed to stir at room temperature for 1 hour and then quenched with water (250 mL). The product was filtered and air dried to give the title compound (25 g, 84%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O.O1CCOCC1.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>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(Br)s1
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: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Temperature: 80 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
Under a nitrogen atmosphere, to a mixed solvent of ethyl 5-bromothiophene-2-carboxylate (2.4 g, 10 mmol), 3-(trifluoromethyl)phenylboronic acid (2.9 g, 15 mmol) and sodium carbonate (2.1 g, 20 mmol) in water/1,4-dioxane (v/v=1/1, 10 mL) was added tetrakistriphenylphosphinepalladium (1.1 g, 1.0 mmol), and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (petroleum ether/ethyl acetate=60/1) to give the title compound (2.5 g, 83%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5](=[CH:9][C:10]1[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:13]=[CH:12][C:11]=1[O:31][CH3:32])[C:6](=O)[CH3:7])[CH3:2].Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][S:44][C:45](=[NH:47])[NH2:46])=[CH:39][CH:38]=1.C([O-])(=O)C.[Na+]>CN(C)C=O.CCOCC>[CH2:1]([O:3][C:4]([C:5]1[CH:9]([C:10]2[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:13]=[CH:12][C:11]=2[O:31][CH3:32])[N:46]=[C:45]([S:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)[NH:47][C:6]=1[CH3:7])=[O:33])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C=C(C(C)=O)C(=O)OCC
Reactant: COc1ccc(CSC(=N)N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C1N=C(SCc2ccc(OC)cc2)NC(C)=C1C(=O)OCC
Temperature: 70 °C

Procedure:
The reaction mixture containing 2-[[2-methoxy-6-pentadecyl phenyl]methylene]-3-oxobutanoic acid ethyl ester (3 g, 6.6 mmol), 2-((4-methoxyphenyl)methyl)-2-thiopseudourea hydrochloride (1.2 g, 6.6 mmol), and sodium acetate (0.6 g, 7 mmol) in dimethylformamide (30 mL) was heated at 70° C. for 4 h. The reaction was cooled to room temperature, diluted with ether, and filtered. The filtrate was washed with water, sodium bicarbonate, and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the compound was obtained as brown viscous liquid.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([OH:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30].N1C=CN=C1>ClCCl>[Si:1]([O:31][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCCCCCCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#CCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
tert-Butyldiphenylsilyl chloride (TBDPSCl, 8.70 g, 31.65 mmol) was slowly added to a 0° C. solution of dodec-11-yn-1-ol (4.80 g, 26.37 mmol) and imidazole (3.23 g, 47.47 mmol) in anhydrous dichloromethane (100 mL). After stirring at room temperature for 3 h, the reaction mixture was washed with water (75 mL), brine (50 mL), and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 3% EtOAc/hexanes as eluent to give 12-(tert-butyldiphenylsilyloxy)dodec-1-yne (9.75 g, 88%) as a colorless oil. TLC: 6% EtOAc/hexanes, Rf≈0.7; 1H NMR (CDCl3, 300 MHz) δ 7.65-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.65 (t, J=7.3 Hz, 2H), 2.18 (dt, J=7.0, 2.4 Hz, 2H), 1.94 (t, J=1.9 Hz, 1H), 1.20-1.60 (m, 16H), 1.04 (s, 9H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[S:22][CH:21]=[C:20]([N:23]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:29]4[C:24]3=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]=2[CH:36]=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.O1CCCC1>[S:22]1[CH:21]=[C:20]([N:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]2[CH:36]=[C:15]([N:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:16]=[CH:17][C:18]1=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Clc1ccc2scc(-n3c4ccccc4c4ccccc43)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc2scc(-n3c4ccccc4c4ccccc43)c2c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
In a 250 mL 2-neck round flask, 5 mL of tetrahydrofuran (THF) was poured to carbazole (0.75 g, 4.5 mmol). Then, a 2.5Mn-butyllithium/hexane solution (1.8 ml) was gradually added to the mixture in an ice bath. This mixture solution was stirred at room temperature for minutes, and then 9-(5-chlorobenzothiophen-3-yl)carbazole (1.5 g, 4.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (Pd(pph3)4) (0.024 g) were poured to the mixture solution, the resulting mixture was dissolved in and tetrahydrofuran, and reacted at 80° C. After the reaction, the precipitate was filtered and recrystallized with dichloromethane and methanol, thereby giving 1.71 g of a product (82%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[CH:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[O:3]1.[OH-:23].[Na+].Cl>CS(C)=O.CN(C=O)C>[OH:23][C:4]1([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH2:11][CH:2]([CH3:1])[O:3]1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)OC(C)C2
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(O)(c1ccc([N+](=O)[O-])cc1)OC(C)C2
Reaction time: 5 h

Procedure:
A solution of 16 (1.3 g) in 4 ml of DMSO and 24 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over Na2SO4. Removal of the solvent afforded 17 as a syrup (1.6 g), which was used directly for the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: O=C(CCCl)Nc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cccc(F)c2N1
Temperature: 160 °C
Yield: 70.8 %

Procedure:
A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with 3-chloro-N-(2-fluoro-phenyl)-propionamide (5.33 g, 26.5 mmol) and aluminium chloride (5.30 g, 39.7 mmol). In a pre-heated oil bath, the flask was heated at 160° C. for 1.5 hours. After cooling to room temperature, the mixture was treated slowly with ice-water and extracted with EtOAc. The organic layer was washed with water and brine in sequence, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford title compound (3.1 g, 70%) as a solid. MS: 166.0 (M+H+)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1.O>CN(C)C=O>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
To a suspension of piperidin-4-ol (2.79 g, 28 mmol) and potassium carbonate (3.88 g, 28 mmol) in N,N-dimethylformamide (40 mL), 4-Fluoro-2-methoxy-1-nitro-benzene (4.0 g, 23 mmol) is added and stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is collected by a filtration. The resulting solid is dried in vacuo at 50° C. to afford 1-(3-methoxy-4-nitro-phenyl)-piperidin-4-ol (5.23 g) as yellow solids in 89% yield.