Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:21](Cl)(=[O:23])[CH3:22]>C(=S)=S>[F:16][C:2]([F:1])([F:15])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:21](=[O:23])[CH3:22])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccccc2C1)C(F)(F)F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 0 °C
Yield: 57.9 %

Procedure:
2-(Trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (140 mmol, 32.00 g) was introduced into CS2 (190 ml). Aluminum trichloride (837 mmol, 111.60 g) was added thereto in portions at room temperature. Acetyl chloride (419.12 mmol, 32.90 g) was then added dropwise in such a way that gentle refluxing took place, and the mixture was heated to reflux for a further hour. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic phase was dried, filtered with suction and concentrated and then stirred with isopropanol. 22 g of the title compound were obtained with a melting point of 80° C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].CCN(CC)CC.[P:33]([O-:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([O:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:2]([P:33]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:40])=[C:3]([CH:14]=1)[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOP([O-])OCC
Reactant: CN(Cc1cc(NC(=O)OC(C)(C)C)ccc1Br)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 48 h
Yield: 53.3 %

Procedure:
A solution of 12B (25 mg, 0.060 mmol), bis(tri-t-butylphosphine)palladium (0) (3.08 mg, 6.02 μmol), Et3N (0.042 mL, 0.301 mmol) and diethyl phosphite (0.039 mL, 0.301 mmol) in toluene (0.6 mL) was degassed with Ar by evacuating and filling (4×). The sealed vessel was stirred for 2 days at 105° C. The reaction mixture was concentrated and purified by column chromatography (0 to 30% EtOAc in hexanes) to yield 12C (15 mg, 0.032 mmol, 52.7% yield).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](F)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>CN(C)C1C=CN=CC=1.C(#N)C.O>[CH2:21]([N:24]([CH2:25][CH2:26][CH3:27])[S:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]([OH:18])([CH3:17])[C:2]([F:20])([F:19])[F:1])=[CH:8][CH:9]=1)(=[O:15])=[O:14])[CH2:22][CH3:23]
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Reactant: CCCNCCC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: CCCN(CCC)S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Temperature: 22 °C
Yield: 34.8 %

Procedure:
A solution of 3,3,3-trifluoro-N-[4-(fluorosulfonyl)phenyl]-2-hydroxy-2-methylpropanamide (0.2 g), di-n-propylamine (0.25 g), and 4-dimethylaminopyridine (13.0 mg) in dry acetonitrile (3 ml) was heated at reflux for 4 days. The reaction mixture was cooled to 22° C., diluted with water (30 ml) and extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with 1N HCl, brine, dried and evaporated to give an oil. The oil was purified by chromatography (12:1 CHCl3 : diethyl ether) to yield an oil which crystallized from hexane to produce the title compound as a colourless crystalline solid (87.5 mg); mp 132°-134° C.; MS: m/z=397(M+1); NMR (250M Hz): 0.77-0.83 (t,6), 1.41-1.49 (m,4), 1.58 (s,3), 2.96-3.02 (t,4), 7.54 (s,1), 7.72-7.75 (m,2), 7.96-7.98 (m,2), 10.36 (s,1). Analysis for C16H23 F3N2O4S: Calculated: C, 48.47; H, 5.85; N, 7.07; Found: C, 48.84; H, 5.90; N, 6.89.
Reaction SMILES: [OH:1][C@H:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:3]([NH:5][CH2:6][C:7]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1)[CH3:4].C(N(C(C)C)CC)(C)C.[O:43]1CCOC[CH2:44]1>>[CH3:4][C@H:3]1[C@@H:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:1][C:44](=[O:43])[N:5]1[CH2:6][C:7]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: C1COCCO1
Reactant: C[C@H](NCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1)[C@H](O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(3-{2-[((1S,2R)-2-Hydroxy-1-methyl-2-phenyl-ethylamino)-methyl]-4-trifluoromethyl-phenoxy}-phenyl)-acetic acid (0.15 g, 0.33 mmol), N,N′-carbonyldiimidazole (0.065 g, 0.4 mmol), and diisopropylethylamine (1 mL) were combined in 1,4-dioxane (5 mL) and stirred at 80° C. overnight. After work-up, the crude material was purified by preparative HPLC to give the desired product (0.04 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:9]=3)[N:14]=[C:13]([CH3:18])[C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 43.1 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (40 mg, 0.039 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (37 mg, 0.078 mmol) and cesium carbonate (952 mg, 2.92 mmol). 6-Bromo-4-(4-chloro-phenyl)-3-methanesulfonyl-2-methyl-quinoline (compound of example 16) (800 mg, 1.95 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.204 g, 2.33 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (350 mg, 43%). MS: m/z=417 (M+H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]2[C:15](=[O:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([F:32])[CH:20]=3)[O:18][C:13]=2[C:12]([F:34])=[CH:11][C:10]=1[F:35])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]2[C:15](=[O:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[C:21]([F:32])[CH:20]=3)[O:18][C:13]=2[C:12]([F:34])=[CH:11][C:10]=1[F:35]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCN=[N+]=[N-])c(F)cc(F)c3o2)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCN)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.6 %

Procedure:
332 mg (0.682 mmol) of the above 5-(4-azidobutylamino)-6, 8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 20 mL of tetrahydrofuran, 272 mg (1.02 mmol) of triphenylphosphine and 20 mL of water were added and the mixture was stirred at room temperature for 22 hours. Ethyl acetate was added to the reaction solution, and the organic layer was separated, washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-chloroform:methanol:aqueous ammonia=9:1:1) to give 260 mg of 5-(4-aminobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:31]([CH:18]1[CH:19]=[C:14]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:13])[CH2:15][CH2:16][C:17]1=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C1=CCC(=O)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C1=CC(Cc2ccccc2)C(=O)CC1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the above ketone (33) (14.93 g) in dry THF (200 mL) at -78° C. under Ar was added a solution of lithium bis-trimethylsilylamide (55 mL, 1N in THF). After stirring for 20 min benzylbromide (35 mL) was added and the reaction stirred for an additional 6 h at -78° C. then allowed to slowly warm to room temperature. The reaction was taken up in ethyl acetate, washed with 1N HCl, saturated NaCl, dried over MgSO4 and evaporated. The product (34) was obtained by flash chromatography on silica gel eluted with 20 to 25% ethyl acetate in n-hexane (6.09 g, 31%): TLC Rf 0.17 (20% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ1.12 (3H, d, J=7 Hz), 2.0-3.2 (7H, m), 4.18(1H, q), 5.1(2H, s), 5.33(1 H, dd), 5.55(1H, br s), 7.22 (5H, m), 7.32 (5H, s).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=O.O.[NH2:13][NH2:14]>C(C(CCCC)CO)C>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[N:13][NH2:14]
Reactant: NN
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CCCCC(CC)CO
Solvent: O
Product: NN=C1Nc2ccccc2C1=O
Reaction time: 1 h

Procedure:
400.6 g of isatin (2.72 mol, purity 98.2%) were initially charged into a 2 l double jacket vessel and 2000 ml of 2-ethylhexanol were added. With stirring (KPG, 250 rpm), 131 ml of hydrazine hydrate (135.2 g, 2.70 mol, purity 100.6%) were added within 15 minutes, which caused the temperature to increase from 23° C. to 45° C. and an intensely orange suspension to form. The reaction mixture was heated further and held at 50° C. for 60 minutes to form isatin hydrazone (yellow suspension). 61.2 g of DABCO (0.55 mol, 98%) were then added and the reaction solution continuously heated up to 130° C. which resulted in the onset of nitrogen cleavage above about 100° C. At the same time, the water (reaction water+hydrate water+2-ethylhexanol, 114.7 g altogether) was discharged. This resulted in refluxing and foaming of the reaction mixture. The reaction mixture was held at 130° C. until complete conversion (5 h). 1500 ml of 2-ethylhexanol were then distilled off at 90-95° C. (20-30 mbar, contained 0.02% by weight of hydrazine), the reaction solution was cooled to 50° C. and admixed with 732 g of MTBE and then cooled slowly with stirring to crystallize the 2-oxindole (from 130° C. to 50° C. in 3 h, then left to stand overnight at room temperature). The crystals were filtered off, washed with 3×50 ml of cold MTBE (5° C.) and sucked to dryness. 328.1 g of damp product were obtained which was dried for about 48 hours in a vacuum drying cabinet (80-90° C. and 50-65 mbar) to constant weight. Altogether, 298.7 g of dry 2-oxindole product (light brown) were obtained which corresponded to an overall yield of 83.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:22])[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([C:19](N)=[O:20])[CH:16]=[CH:15][N:14]=1.Cl.[CH3:28][OH:29]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:22])[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([C:19]([O:29][CH3:28])=[O:20])[CH:16]=[CH:15][N:14]=1
Reactant: COc1ccccc1OCCN(C)CCCNc1nccc(C(N)=O)n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccnc(NCCCN(C)CCOc2ccccc2OC)n1

Procedure:
12.7 g (35.3 mmol) of 2-[[3-[[2-(2-methoxyphenoxy)ethyl]methylamino]propyl]amino]pyrimidine-4-carboxamide and 300 ml of methanol are introduced into a 0.5 l round-bottomedflask, a stream of gaseous hydrochloric acid is passed through for a few minutes and the mixture is heated at the reflux temperature of the methanol for 4 h.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:8][C@H:7]2[C@:5]([C:9]3[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=3)([O:6]2)[CH2:4][CH2:3]1>[Ni].C(O)(C)C>[F:15][C:2]1([F:1])[CH2:8][C@H:7]([OH:6])[C@@H:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: Cn1nccc1[C@@]12CCC(F)(F)C[C@@H]1O2
Agent: [Ni]
Solvent: CC(C)O
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1O
Yield: 42.1 %

Procedure:
A solution of the 5-[(1S,6S)-4,4-difluoro-7-oxabicyclo[4.1.0]hept-1-yl]-1-methyl-1H-pyrazole (50 mg, 0.233 mmol) prepared in Example 102b and Raney nickel (500 mg) in isopropanol (20 mL) was stirred for 3 hours under a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, and the residue was then purified with silica gel chromatography to yield the title compound (21.2 mg, 42%) as a colorless oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O[C@H]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+].Br[C:19]1[CH:32]=[C:31]2[C:22]([O:23][C:24]3[C:25]([F:41])=[CH:26][C:27]([O:39][CH3:40])=[CH:28][C:29]=3[C@@:30]32[CH2:37][CH2:36][O:35][C:34]([NH2:38])=[N:33]3)=[CH:21][CH:20]=1.CN[C@@H]1CCCC[C@H]1NC>CCOC(C)=O.[Cu]I.O>[N:1]([C:19]1[CH:32]=[C:31]2[C:22]([O:23][C:24]3[C:25]([F:41])=[CH:26][C:27]([O:39][CH3:40])=[CH:28][C:29]=3[C@@:30]32[CH2:37][CH2:36][O:35][C:34]([NH2:38])=[N:33]3)=[CH:21][CH:20]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N=[N+]=[N-])ccc1O2
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A resealable vessel was flushed with argon and loaded with copper(I) iodide (0.138 g, 0.726 mmol), sodium azide (0.708 g, 10.90 mmol), and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (0.072 g, 0.363 mmol). A solution of (S)-7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine (1.428 g, 3.63 mmol) in dmso (20 mL) was degassed and transferred via cannula into the resealable vessel. Water (4 mL) was added. The vessel was flushed with argon, and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.163 mL, 1.090 mmol) was added. The vessel was sealed and heated in a 90° C. oil bath. After 4 h, the reaction mixture was taken up in EtOAc (600 mL) and the organic layer was extracted with quarter-saturated brine (2×70 mL), half-saturated brine (70 mL), and saturated brine (70 mL), dried over MgSO4 and concentrated to afford crude (S)-7′-azido-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine, which was used without purification in the next step. MS m/z=356 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[CH:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[CH:24]([N:26]1[CH2:31][CH2:30][N:29]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: O=CN1CCNCC1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(c2ccc(OC)cc2)N2CCN(C=O)CC2)cc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 105.9 %

Procedure:
1.22 g of the above-mentioned compound (1) and 1.01 g of triethylamine were dissolved in 15 ml of dichloromethane. 5 ml of a dichloromethane solution containing 630 mg of methanesulfonyl chloride was then dropped thereon over a period of 10 minutes, at -15° C. After stirring for 30 minutes at the same temperature, 5 ml of a dichloromethane solution containing 1.14 g of N-formylpiperazine was dropped thereon into the first solution, over a period of 10 minutes, followed by stirring for 1 hour at -5° C. The reaction solution was made alkaline by the addition of saturated sodium bicarbonate solution and then was extracted with dichloromethane (10 ml×3). Next, after washing with saturated brine, the reaction solution was dried with anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain 1.80 g of residue. This was then purified with silica gel column chromatography (elution solvent: ethyl acetate) to obtain 1.68 g of the target compound. Yield: 98%
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]#[CH:13].[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:13]([O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]#[CH:11]
Reactant: OCCc1ccccc1
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: C#CCOCCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of benzenethanol (12.2 g), 3-bromo-1-propyne (12.0 ml), 40% aqueous sodium hydroxide (20 ml) and tetrabutylammonium bisulphate (1 g) was stirred overnight. Water (100 ml) was added and the mixture was extracted with ER (2×100 ml). The organic extracts were washed with water and brine, dried and concentrated to a dark oil which was purified by FCC eluting with CX-ER (19:1) to give the title compound as a pale yellow oil (12.3 g) T.l.c. (CX-ER 19:1) Rf 0.50.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[C:15](=[O:16])[C:14]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]3[C:12]2=[O:17])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccc([N+](=O)[O-])cc1O

Procedure:
231 g (1.5 mol) of 5-nitro-2-aminophenol and 444 g (3 mol) of phthalic acid anhydride were stirred together in 2.25 liters of acetic acid at boiling point for 2.5 hours. The product was suction filtered at room temperature, washed with water and dried. Yield: 420 g=98.5%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:15]1([CH2:20][CH2:21][CH2:22]O)[CH:19]=[CH:18][N:17]=[N:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH2:21][CH2:20][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCCCn1ccnn1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCCn1ccnn1
Yield: 76.2 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 15 (see note a) above), 4-chloro-6-cyano-7-hydroxyquinoline (300 mg, 1.46 mmol), (prepared as described for the starting material in Example 1), was reacted with 3-(1,2,3-triazol-1-yl)propan-1-ol (242 mg, 1.9 mmol) to give 4chloro-6-cyano-7-(3-(1,2,3-triazol-1-yl)propoxy)quinoline (349 mg, 86%).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:17][CH:18]([N:20]([CH3:22])[CH3:21])[CH3:19])[CH:8]=[CH:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:17][CH:18]([N:20]([CH3:21])[CH3:22])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=CC=CC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 81.3 %

Procedure:
1.05 g of ethyl 6,6-diphenyl-8-dimethylaminonona-2,4-dienoate was dissolved in toluene (5 ml) and evaporated to dryness twice. The oil was taken up in 95% ethanol (25 ml) and placed in a Paar shaker bottle with 10% palladium on activated carbon (Pd/C, 190 mg). Paar shaker hydrogenation was conducted at room temperature and 60 psi pressure. After 1 hour, an additional 150 mg of catalyst were added and the hydrogenation reaction continued for 3 hours. TLC indicated complete reaction. The catalyst was removed by filtration, and the filtrate was concentrated to dryness to provide 863 mg of ethyl 6,6-diphenyl-8-dimethylaminononanoate, as a clear light yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=[O:25].O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:29][C:28]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=2[Br:20])[CH2:34][CH2:35]1
Reactant: OCCN1CCOCC1
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCOCC2)c(Br)c1
Reaction time: 12 h
Yield: 56 %

Procedure:
Triphenylphosphine (6.85 g) was added to a solution of 3-bromo-4-hydroxybenzaldehye (5 g) in tetrahydrofuran (40 ml), followed by addition of 2-hydroxyethylmorpholine (3.01 ml) and then the dropwise addition of diethylazodicarboxylate (4.11 ml). After 12 hours, the reaction was concentrated under reduced pressure, poured into 2N hydrochloric acid (200 ml) and extracted with ethyl acetate (2×150 ml). The aqueous layer was basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (2×150 ml). The organic layers were dried over magnesium sulfate and concentrated to afford 4.4 g (56%) of 4-morpholinoethoxy-3-bromobenzaldehyde as a reddish oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2].S(Cl)([Cl:15])(=O)=O.C([O-])(O)=O.[Na+]>CCOCC>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([Cl:15])[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCC(=O)CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCC(=O)C(Cl)C(=O)OCC
Temperature: 0 °C
Yield: 99.4 %

Procedure:
3-oxo-hexanoic acid ethyl ester (29.7 g, 188 mmol) was dissolved in Et2O (400 ml). The solution was cooled to 0° C., and sulfuryl chloride (22.6 ml, 282 mmol) was added dropwise. The solution gradually warmed to RT over 4 h. The solution was neutralized to pH 7 with a solution of aqueous saturated NaHCO3. The organic layer was separated, washed with brine, and dried over sodium sulfate. Evaporation under reduced pressure yielded 2-chloro-3-oxo-hexanoic acid ethyl ester (intermediate Id, 36 g, 100%). 1H-NMR (CDCl3, ppm): 0.95 d (3H); 1.35 d (3H); 1.58 m (2H); 2.7 t (2H); 4.28(d (2H); 4.78 s (1H).