Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([OH:16])=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]#[N:15])=[CH:6]1)[CH3:2].[Na].C(O)=O>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]#[N:15])[CH2:6]1)=[O:16])[CH3:2]
Reactant: CCOC(O)=C1C=C(C#N)c2ccccc21
Agent: [Pd]
Agent: [Na]
Solvent: CCO
Solvent: O=CO
Product: CCOC(=O)C1CC(C#N)c2ccccc21
Yield: 87 %

Procedure:
A solution of 3-(ethoxy-hydroxy-methylene)-3H-indene-1-carbonitrile, sodium salt, (1.00 g, 4.70 mmol) in ethanol (40 mL) in a pressure reactor was purged with nitrogen for 5 minutes and charged with 5% palladium on carbon (1.00 g, 0.230 mmol) and formic acid (0.180 mL, 4.70 mmol), pH=5 at reaction initiation. The pressure reactor was purged with nitrogen and evacuated three times, then purged with hydrogen and evacuated three times before charging the bomb with hydrogen at a pressure of 50 psi (3.4 atmospheres) and mechanically shaking. After 2 hours the reactor was evacuated and purged with nitrogen three times before filtering the reaction mixture through a nylon disk. Azeotropic removal of formic acid in vacuo with ethanol and concentrating in vacuo afforded 3-cyano-indan-1-carboxylic acid ethyl ester as a light yellow solid (880 mg, 87%). 1H NMR (400 MHz, CD3CN) δ 7.47–7.45 (m, 2H), 7.37–7.35 (m, 2H), 4.28 (t, 1H, J=8.0), 4.20 (m, 2H), 4.16 (t, 1H, J=3), 2.80 (m, 1H), 2.60 (m, 1H), 1.27 (t, 3H, J=7.2); 13C NMR (100 MHz, CD3CN) δ 172.3, 140.8, 138.5, 129.0, 128.7, 125.4, 124.7, 117.6, 61.3, 48.9, 33.4, 33.3, 13.8; 13C NMR (100 MHz, d4-MeOH) δ 172.6, 140.4, 138.1, 129.0, 128.8, 125.4, 124.7, 120.9, 61.4, 48.9, 33.2, 33.1, 13.4; IR (ATR, neat) 1732, 1478, 1457, 1370, 1324, 1263, 1208, 1180, 1035, 747.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl>CS(C)=O.O>[CH2:7]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCNCCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-butylamine (0.32 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 8 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to oily compound which was later crystallized by benzene hexane to get N-(n-butyl)-(4-(naphthalen-2-yloxy)butyl)amine, solid. m.p. oil, (yield 0.56 gm, 96.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56][CH2:55]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56][CH2:55]2)=[O:33])[C:25]=1[CH3:34])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: NCCN1CCC(O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (100 mg, 0.19 mmol), DIPEA (115 mg, 5 eq.) and 1-(2-amino-ethyl)-piperidin-4-ol TFA salt (88 mg, 1.2 eq.) in 2 mL) was stirred at rt for 45 mins. To the mixture was added HATU (83 mg, 1.1 eq.). After stirring for 18 hours, the reaction was concentrated and purified on a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:30][CH2:29][CH:28]([O:27][C:26]5[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=5)[CH2:33][CH2:32]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-fluoro-phenoxy)-piperidine (Table No.1, SM 5) in ethanol essentially as described above in Example 21. Purity by LC/MS=86%, [M+H]+=481 and 8%, [M+H]+=573.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[O:7][N:6]=[C:5]([CH:8](O)[CH2:9][CH3:10])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(OCC)C>[Br:34][CH:8]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:12])[F:1])[O:7][N:6]=1)[CH2:9][CH3:10]
Reactant: CCC(O)c1cc(C(F)(F)F)on1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCC(Br)c1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
1.63 g of 1-(5-trifluoromethyl-isoxazol-3-yl)propanol was dissolved in 45 ml of diethyl ether, and 4.20 g of triphenylphosphine and 5.31 g of carbon tetrabromide were then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography to obtain 1.00 g of 3-(1-bromopropyl)-5-trifluoromethylisoxazole.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].[CH:24](OCC)(OCC)[O:25][CH2:26][CH3:27]>>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([N:1]=[CH:24][O:25][CH2:26][CH3:27])=[C:3]([S:21]([CH3:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CCOC(OCC)OCC
Product: CCOC=Nc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (4.92 g) in triethyl orthoformate (100 ml) was heated under reflux for two hours, then stirred at 20° C. for 16 hours and evaporated. Trituration with boiling hexane gave 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(ethoxymethylene)amino]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (4.05 g), m.p. 93-95° C. By proceeding in a similar manner the following compound was prepared:
Reaction SMILES: C(O[CH:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]C)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=O)C1C=CC=CC=1.C([O-])(=O)[CH:31](C)[OH:32].C([O-])(=O)C(C)(C)C.C([O-])(=O)CCCCCCC>>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:31][OH:32])[CH2:10][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCC(CCCCCCCC)OC(=O)c1ccccc1
Reactant: CC(O)C(=O)[O-]
Agent: CC(C)(C)C(=O)[O-]
Agent: CCCCCCCC(=O)[O-]
Product: CCCCCCCCCCC(CO)CCCCCCCC

Procedure:
Octyldodecyl Benzoate, Lactate, Neopentanoate or Octanoate
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].OS(O)(=O)=O.O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Yield: 61 %

Procedure:
To a solution of 1-(4-(benzyloxy)-3-methoxyphenyl)ethanone (5.0 g, 19.5 mmol, Alfa Aesar Company) in dichloromethane (75 mL) at ice bath temp. was added slowly HNO3 (1.5 mL of 90% nitric acid) followed by conc H2SO4 (1.8 mL of 96.2% acid) at 0° C. with stirring. After 1 h at 0° C. additional HNO3 (0.5 mL) was added and the reaction mixture was stirred for 20 minutes at 0° C. To the reaction mixture was added dichloromethane (25 mL) and the mixture was poured into water (60 mL), the organic layer was separated which was washed with water (2×60 mL) followed by aq NaHCO3 (2×60 mL), dried over Na2SO4 and concentrated in vacuo. The residue was mixed with DMF (˜3 mL) and ether (70 mL), stirred for a while and the solid was filtered, washed with a small amount of ether and dried to obtain the desired product (3.6 g, 61%) as a yellow solid. 1H NMR (CDCl3) δ 7.64 (s, 1H), 7.42-7.35 (m, 5H), 6.76 (s, 1H), 5.21 (s, 2H), 3.93 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([Cl:12])[CH:10]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C1CCC(=O)N1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(Cl)c1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-methyl-benzoic acid (6.45 g, 30 mmol,), N-chlorosuccinimide (4.67 g, 35 mmol), and palladium (II) acetate (0.675 g, 3 mmol) in dry DMF (35 mL) was heated under a nitrogen atmosphere at 100° C. for 36 h. After this time, the reaction mixture was cooled to ambient temperature and poured into water. The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic extracts washed with aqueous sodium thiosulphate (30 mL) and then brine (30 mL). The remaining organic solution was dried over anhydrous MgSO4, filtered, and concentrated to give 4-bromo-2-chloro-6-methyl-benzoic acid. The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:17][CH:16]=[CH2:15])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
A mixture of 1-bromo-4-nitro-2-(trifluoromethyl)benzene (1.0 g, 3.7 mmol), Allyl Tri-n-butyltin (1.4 mL, 4.4 mmol), Lithium Chloride (470 mg, 11 mmol), and Palladium Tetrakis (210 mg, 0.18 mmol) in toluene (30 mL) was heated to reflux for 16 hours under nitrogen. TLC showed complete reaction at that point. The reaction was diluted with ethyl acetate, adsorbed onto silica gel, and purified by silica gel chromatography to afford the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[CH:10]=1
Reactant: COc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: COc1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and anisole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)[C@H:14]([CH3:25])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:30]4[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=4)[N:21]=[CH:20][N:19]=3)[C@H:14]([CH3:25])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(Cl)ncn3)[C@H](C)C2)c(Cl)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)c(Cl)c4)ncn3)[C@H](C)C2)c(Cl)c1
Temperature: 80 °C

Procedure:
Bubble nitrogen through a mixture of 5-chloro-6-[4-(6-chloro-pyrimidin-4-yl)-3-(R)-methyl-piperazin-1-yl]-nicotinic acid ethyl ester (226 mg, 0.57 mmol), 3-chloro-4-fluorophenylboronic acid (99 mg, 0.57 mmol), K3PO4 (2M aqueous, 570 μL) and Pd(PPh3)4 (33 mg, 0.03 mmol) in dioxane for 10 min. Heat the mixture to 80° C. for 16 h under a nitrogen atmosphere. Cool the mixture and partition between EtOAc and water. Dry (Na2SO4) the organic layer and concentrate under reduced pressure to yield the crude product. Purify the residue with preparative plate chromatography (2×2 mm thick) using 40% EtOAc/hexanes as the eluent to afford the title compound as a foam. 1H NMR (400 MHz, CDCl3): δ1.38 (m, 6H, 2×CH3), 3.16 (m, 1H), 3.31 (dd, 1H, J=11 Hz), 3.51 (m, 1H), 4.12 (d, 1H, J=12.8 Hz), 4.21 (d, 1H, J=13 Hz), 4.39 (m, 3H), 4.77 (Br s, 1H), 6.82 (s, 1H), 7.25 (m, 1H), 7.89 (m, 1H), 8.07 (d, 1H, J=7 Hz), 8.18 (s, 1H), 8.71 (s, 1H), 8.79 (s, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.C(Cl)(Cl)Cl.N>O1CCCC1>[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][C:13]([Br:1])=[CH:12][N:11]=1
Reactant: COC(=O)c1cccc2nc(-c3cccnc3N)oc12
Reactant: O=C1CCC(=O)N1Br
Agent: N
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cccc2nc(-c3cc(Br)cnc3N)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
1-bromopyrrolidine-2,5-dione (233 mg) was added to a stirred solution of methyl 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carboxylate (335 mg) dissolved in tetrahydrofuran (10 ml) over a period of 5 minutes. The resulting solution was stirred at 25° C. for 2 hours. The solvent was evaporated and the mixture was washed with water and dried over phosphorus pentoxide under reduce pressure to afford a brown solid. The mixture was adsorbed on silica gel with chloroform and methanolic ammonia (7N). The crude product was purified by flash chromatography on silica gel eluting with 0 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazole-7-carboxylate (405 mg) as a pale brown solid. NMR Spectrum: (DMSOd6) 3.99 (s, 3H), 7.56 (dd, 1H), 7.85 (bs, 2H), 7.97 (d, 1H), 8.12 (d, 1H), 8.29 (s, 1H), 8.35 (s, 1H); Mass spectrum: M+H+ 348-350.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].O>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Yield: 81 %

Procedure:
2-Amino-5-iodopyridine (1.0 g) and 2-bromo-4′-cyanoacetophenone (1.02 g) were dissolved in ethanol (30 mL), and sodium hydrogencarbonate (382 mg) was added to the solution, followed by refluxing for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was left to cool. The precipitated matter was recovered through filtration and dried, to thereby yield the title compound (1.27 g).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][N:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:24][CH2:25]O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].O.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:25][CH2:24][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:17]1[CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(CCN2CCCCCC2CCO)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(CCN2CCCCCC2CCBr)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4 ml of phosphorus tribromide are added dropwize to 2.9 g (9.4 mmol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-(2-hydroxyethyl)-hexahydro-azepine in 100 ml of carbon tetrachloride, whilst cooling with ice, and the mixture is stirred for 15 hours at ambient temperature. Then water is added, whilst cooling with ice water is continued, and the mixture is made slightly alkaline with 2 molar sodium hydroxide solution. The aqueous/alkaline solution is separated off and extracted twice with methylene chloride. The combined organic solutions are dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 3.6 g (100% of theory).
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[CH:6]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Sc1cc2ccccc2s1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCN(c3cc4ccccc4s3)CC2)cc1
Yield: 46.5 %

Procedure:
To a solution of 2-mercaptobenzothiophene (1.8 g, 10.8 mmol) in toluene under nitrogen was added N-benzylpiperazine (1.88 ml, 10.8 mmol) and the mixture heated at reflux for 1.5 h. Left to cool, concentrated in vacuo and product recrystallised from diethyl etherhexane to yield the title compound (1.55 g), m.p. 160°-161° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[C:4]1([CH2:1][CH:2]=[N:18][C@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C[C@H](N=CCc1ccccc1)c1ccccc1
Yield: 100.8 %

Procedure:
At first, zinc chloride (0.14 g, 1 mmol) was added to a toluene solution (100 ml) containing 12.0 g (100 mmol) of acetophenone (1a) as a ketone and 13.3 g (110 mmol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine, followed by heating under reflux for 20 hr and by removing water (formed as a by-product) with a Dean-Stark tube during the reaction. Then, the reaction liquid after the reaction was washed with a 1N NaOH, followed by washing with 1N ammonium chloride aqueous solution, then drying with sodium sulfate anhydride, then filtration, then concentration, and then drying under vacuum, thereby obtaining 22.5 g of (S)-N-(phenylethylidene)-1-phenylethylamine ((S)-3aa, purity: 99%, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[CH:29][C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 57%).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.Cl[CH:19]([O:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(O)(C)(C)C.[I-].[K+]>[N:14]1[C:15]2[C:10](=[CH:9][C:8]([O:7][CH:19]([O:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CCOC(=O)C(Cl)OCC
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(OCC)Oc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Potassium t-butoxide (3.15 g) was dissolved in t-butyl alcohol (20 ml) and stirred for 10 minutes at ambient temperature. 6-Hydroxyquinoline (3.0 g) was added, the resulting dark green solution was stirred for 15 minutes, and then ethyl 2-chloro-2-ethoxyacetate (4.22 g, 90% pure) added, followed by a catalytic amount of potassium iodide (0.005 g). The mixture was stirred for 18 hours, poured into water and extracted with chloroform. The organic fraction was washed with brine, water, and dried over magnesium sulphate. The solvent was evaporated to give a brown oil, which was purified by flash chromatography on silica gel, eluting with a gradient of ethyl acetate:hexane (1:2 to 4:1) to give ethyl 2-(6-quinolinyloxy)-2-(ethoxy)acetate as a pale brown oil (3.68 g).
Reaction SMILES: Cl[C:2](Cl)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20]>CCOC(C)=O>[CH3:18][S:19]([N:22]=[C:2]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])=[O:20]
Reactant: CS(N)(=O)=O
Reactant: ClC(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Yield: 34.7 %

Procedure:
Dichlorodiphenoxymethane (2 g, 7.46 mmol) and methylsulfonamide (1.56 g, 16.41 mmol) were dissolved in EtOAc (15 ml) and heated to reflux for 12 hours. The mixture was allowed to cool and was concentrated under vacuum. Purification of the crude mixture by flash chromatography (20% EtOAc/hexanes) afforded diphenyl methylsulfonylcarbonimidate (0.75 g, 2.59 mmol, 35%).