Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])(=O)CCC.CCCCCC.[N:20]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.Br[CH2:39][CH2:40][CH2:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl>O1CCCC1.O>[CH2:43]([O:42][CH2:41][CH2:40][CH2:39][C:23]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21][N:20]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][CH2:24]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCCCOCc1ccccc1
Agent: Cl
Agent: [Li]C(=O)CCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.2 mL of diisopropylamine in 20 mL of tetrahydrofuran, 5.8 mL of a 1.6 mol/L butyryl lithium/hexane solution was dropped at −78° C., and the mixture was stirred at the same temperature for 1 hour. Thereto was dropped a solution of 2.0 g of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate in 2 mL of tetrahydrofuran, and the mixture was stirred for 1 hour. Thereto was added 1.7 mL of benzyl 3-bromopropyl ether, and the temperature of the reaction mixture was increased to room temperature and the mixture was stirred for 10 hours. The mixture was charged with water and adjusted to pH 2.0 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=10:1 to obtain 2.0 g of 1-tert-butyl 4-ethyl 4-(3-(benzyloxy)propyl)piperidine-1,4-dicarboxylate as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:23]([O:25]CC)=O.C(O)(=O)C.[CH:32]([NH2:34])=[NH:33]>CN1CCCC1=O>[Cl:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:21])[C:14]=1[C:13]([NH:12][C:7]1[C:6]2[N:5]=[CH:4][C:3]3[C:23](=[O:25])[NH:34][CH:32]=[N:33][C:2]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:22]
Reactant: N=CN
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O=C(Nc1cccc2c1ncc1c(=O)[nH]cnc12)c1c(Cl)cccc1Cl
Temperature: 130 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (200 mg), formamidine acetate (246 mg) and N-methylpyrrolidone was stirred for 4 hours at 100° C., for 45 minutes at 120° C. and for 6 hours at 130° C. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and evaporated in vacuo. The residue was crystallized from isopropyl alcohol and collected by filtration to give 7-(2,6-dichlorobenzoylamino)-3,4-dihydropyrimido[5,4-c]quinolin-4-one (116 mg).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH:4]([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]([CH:2]=[P:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC(C)C(=O)CCl
Solvent: ClC(Cl)Cl
Product: CCCCC(C)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 29.9 %

Procedure:
A solution of 1-chloro-3-methylheptan-2-one (49.4 g.) and triphenylphosphine (79.5 g.) in chloroform (250 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo and the residue (crude 3-methyl-2-oxoheptyltriphenylphosphonium chloride) was added portionwise to a solution of sodium carbonate (109 g.) in water (1500 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 60°-80° C.) to give 2-methylhexanoylmethylenetriphenylphosphorane (35.2 g.), m.p. 107°-109° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[CH:10]=[CH:11][C:12](=[O:14])[O:13][C:8]=2[CH:7]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]1[CH:27]=[CH:26][NH:25][CH2:24][CH2:23]1>CN(C=O)C>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]3[CH:10]=[CH:11][C:12](=[O:14])[O:13][C:8]=3[CH:7]=2)[CH2:24][CH:23]=1
Reactant: C1=CC(c2cccs2)CCN1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCN3CC=C(c4cccs4)CC3)cc2o1

Procedure:
A 2.9 g (0.012 mole) sample of 7-(3-chloropropoxy)-2H-1-benzopyran-2-one as prepared in Example 1 above, 2 g (0.012 mole) 4-(2-thienyl)tetrahydropyridine, and 5 g NaHCo3 in 80 ml DMF is stirred at 80°-90° C. for seven hours at room temperature overnight then filtered and evaporated in vacuo. The residue in methylene dichloride is washed with NaHCO3, dried (MgSO4) and evaporated in vacuo. 7-[3-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]propoxy]-2H-1-benzopyran-2-one as 4.3 g of dark oil was obtained. The oil was dissolved in 20 ml of 2-propanol and treated with 3 ml of 20% 2-propanolic hydrogen chloride solution to give 2.4 g of the monhydrochloride salt, mp 235-7° C.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[C:34]([Cl:35])=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[Cl:36]>>[Cl:35][C:34]1[CH:33]=[C:30]([C:31]#[N:32])[CH:29]=[C:28]([Cl:36])[C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Product: CCc1cc2c(C(=O)Nc3c(Cl)cc(C#N)cc3Cl)cnc(OC)c2o1
Yield: 44.7 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.10 g) and 4-amino-3,5-dichlorobenzonitrile (0.12 g). Purification by column chromatography on silica with 20% then 30% then 50% ethyl acetate in hexane to give the title compound (0.051 g) as a cream solid.
Reaction SMILES: C([O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:52]1[N:53]=[C:54]([NH:57][C:58](=[O:63])[C:59]([F:62])([F:61])[F:60])[S:55][CH:56]=1)[C:21]([NH:23][CH:24]1[C:50](=[O:51])[N:26]2[C:27]([C:34]([O:36]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:35])=[C:28]([CH2:31][S:32][CH3:33])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[C:15]([CH2:17][O:18][N:19]=[C:20]([C:52]1[N:53]=[C:54]([NH:57][C:58](=[O:63])[C:59]([F:60])([F:62])[F:61])[S:55][CH:56]=1)[C:21]([NH:23][CH:24]1[C:50](=[O:51])[N:26]2[C:27]([C:34]([OH:36])=[O:35])=[C:28]([CH2:31][S:32][CH3:33])[CH2:29][S:30][C@H:25]12)=[O:22])([OH:16])=[O:14]
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 117.7 %

Procedure:
To a solution of benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-{2-(2,2,2-trifluoroacetamido)-thiazol-4-yl}acetamido]-3-methylthiomethyl-3-cephem-4-carboxylate (syn isomer) (5.6 g) and anisole (5.6 ml) in methylene chloride (11.2 ml) was added trifluoroacetic acid (11.2 ml) at 10° C. The mixture was stirred for 1.5 hours at ambient temperature and then poured into a mixture of diisopropyl ether (400 ml) and petroleum ether (100 ml). The precipitates were collected by filtration and washed with petroleum ether to give 7-[2-carboxymethoxyimino-2-{2-(2,2,2-trifluoroacetamido)-thiazol-4-yl}acetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (4.2 g), mp 183°-186° C. (dec.).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N:17]=[C:18]=[O:19]>C(OCC)C>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:18]([NH:17][C:11]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=2[CH3:9])=[O:19])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(C)c(N=C=O)c1
Reactant: N#CC1CCNCC1
Solvent: CCOCC
Product: Cc1ccc(C)c(NC(=O)N2CCC(C#N)CC2)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 4-cyanopiperidine (11.0 g, 100 mmol) in diethyl ether (350 mL) was cooled to 0° C. with an ice-water bath. A solution of 2,5-dimethylphenyl isocyanate (14.7 g, 100 mmol) in diethyl ether (50 mL) was added into the reaction mixture over 30 minutes to give a thick precipitate. The reaction mixture was warmed to room temperature, and the resulting solids were filtered, washed with diethyl ether and air-dried to give 25.3 g of the title compound as a white powder, melting at 187-190° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([N:19]([CH2:30][C@H:31]2[C@@H:35]([F:36])[CH2:34][N:33](C(OCC3C=CC=CC=3)=O)[CH2:32]2)[C:20]([N:22]2[CH2:27][C@@H:26]([CH3:28])[O:25][C@@H:24]([CH3:29])[CH2:23]2)=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=2)[N:10]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([N:19]([CH2:30][C@H:31]2[C@@H:35]([F:36])[CH2:34][NH:33][CH2:32]2)[C:20]([N:22]2[CH2:23][C@@H:24]([CH3:29])[O:25][C@@H:26]([CH3:28])[CH2:27]2)=[O:21])[C:15]([CH3:17])([CH3:16])[CH3:18])[N:11]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=2)[N:10]=1
Reactant: C[C@@H]1CN(C(=O)N(C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2F)[C@@H](c2nc(-c3cc(F)ccc3F)nn2Cc2cccc(F)c2)C(C)(C)C)C[C@H](C)O1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(C(=O)N(C[C@@H]2CNC[C@@H]2F)[C@@H](c2nc(-c3cc(F)ccc3F)nn2Cc2cccc(F)c2)C(C)(C)C)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((2S,6R)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (35 mg, 0.047 mmol) in degassed ethanol (10 mL, 4.7 mM solution) was added Pd/C (0.99 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for overnight. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude product, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (2S,6R)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamide was obtained in 63% yield (18 mg) as a free amine 1H NMR (CD3Cl, 300 MHz): δ 7.84 (1H, m), 7.32-6.95 (6H, m), 5.79 (2H, m), 5.36 (1H, s), 4.58 (1H, m), 3.91-3.72 (3H, m), 3.65-3.50 (3H, m), 3.04 (1H, m), 2.97-2.65 (2H, m), 2.53 (1H, m), 2.36 (1H, m), 2.18 (1H, m), 1.20 (6H, s), 0.9 (1H, m), 0.84 (9H, s). LC/MS (uplc): MH+ 617.5, 1.06 min.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([F:29])([F:28])[F:27]>>[CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH:14][S:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:26]([F:29])([F:27])[F:28])[CH:18]=3)(=[O:24])=[O:23])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc(COCCC2CC2)n1
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCCC2CC2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(2-cyclopropyl-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 4-fluoro-3-(trifluormethyl)-benzenesulfonyl chloride (0.12 g) as a light yellow gum (0.08 g). MS (ESI−): 417.0 ([M−H]−).
Reaction SMILES: [C:1]1([S:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)(=[NH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19]Cl>>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][N:9]=[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: N=S(=O)(c1ccccc1)c1cccs1
Reactant: CN(C)CCCCl
Product: CN(C)CCCN=S(=O)(c1ccccc1)c1cccs1
Yield: 38 %

Procedure:
In a manner analogous to that described in Example 1, Stage 3, by the reaction of phenyl-(2-thienyl)-sulphoximide with 3-dimethylaminopropyl chloride, there is obtained, in a yield of 38% of theory, N-(3-dimethylaminopropyl)-S-phenyl-S-(2-thienyl)-sulphoximide, the fumarate of which, after recrystallisation from ethyl acetate/isopropanol, melts at 125° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11]([O:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:17]([O:16][C:15]([N:14]([O:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[C:1](=[O:4])[CH:2]=[CH2:3])=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A solution of acryloyl chloride (700 μL; 779.8 mg; 8.6 mmole) dissolved in dry dichloromethane (20 mL) was cooled at 0° C. with an ice bath. A mixture of tert-butyl N-(tert-butoxycarbonyloxy)carbamate (31) (2.0038 g; 8.6 mmole) and triethylamine (1.32 mL; 958.3 mg; 9.5 mmole) in dry dichloromethane (20 mL) was slowly added over a period of 1 hour to the cooled solution. The ice bath was removed after 4 hours and the reaction mixture was left stirring overnight while its temperature warmed up gradually to room temperature. Water (100 mL) was added to the reaction and the layers were separated. The organic solution was washed with a 10% ammonium chloride solution (3×80 mL), water (2×100 mL), and finally brine (1×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate (90:10) to elute the product. The purification gave 690 mg (28%) of N-(tert-butoxycarbonyl),N-(tert-butoxycarbonyloxy)acrylamide (32) as a colorless oil.
Reaction SMILES: [C:1]([OH:17])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(Cl)([Cl:20])=O>C1CCCCC1>[C:1]([Cl:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCC(=O)O
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCC(=O)Cl
Temperature: 80 °C
Yield: 63.6 %

Procedure:
In a one L (liter) two-necked flask were placed 160.0 g (0.66 mol) of pentadecanoic acid and 200 milliliter (mL) of cyclohexane, and the flask was equipped with a 100 mL dropping funnel containing 83.3 g (0.7 mol) of thionyl chloride and a reflux tube. Then, the pentadecanoic acid was completely dissolved under heating and stirring of the flask in an oil bath at 80° C. Thereafter the thionyl chloride was added dropwise over a period of 2 hours, and further the oil bath was maintained at 80° C. for one hour. From the resultant reaction mixture were removed the cyclohexane and the thionyl chloride under reduced pressure by means of an aspirator. The resultant crude reaction product was subjected to vacuum distillation. Thus 110.0 g (0.42 mol) of pentadecanoyl chloride was obtained in a yield of 63.9% based on the fed pentadecanoic acid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[C:12]([O:19][CH3:20])=[C:11]([O:21][CH3:22])[C:10]=1[CH3:23])(=O)=O.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+].[I-:44]>C(Cl)Cl>[I-:44].[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[C:11]([O:21][CH3:22])=[C:10]([CH3:23])[C:9]=1[CH2:8][CH2:7][CH2:6][P+:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(C)c(CCCOS(C)(=O)=O)c(OC)c(OC)c1OC
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)c(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
The crude methanesulfonate 4 (3.30 g, 9.8 mmol) was used directly in the following reaction by mixing with a freshly ground mixture of triphenylphosphine (4.08 g, 15.6 mmol) and NaI (7.78 g, 51.9 mmol) in a Kimax tube and sealed under argon. The mixture was then held at 70-74° C. with magnetic stirring for 3 hrs during which time the mixture changed from a molten thick liquid into a glassy solid. The tube was cooled to room temperature and the residue stirred with CH2Cl2 (30 mL). The suspension was then filtered and the filtrate evaporated in vacuo. The residue was dissolved in a minimum amount of CH2Cl2 and triturated with excess ether (250 mL) to precipitate the white solid. The solid was filtered and washed with ether, dried in vacuo to give pure [3-(2,3,4,5-tetramethoxy-6-methyl-phenyl)-propyl]triphenylphosphonium iodide (5) (5.69 g, 90%). 1H NMR δ 7.82-7.65 (15H, m, Ar—H), 3.88, 3.86, 3.74, 3.73 (12H, s, OMe), 3.76-3.88 (2H, m, CH2—P+), 2.98 (2H, t, J=7.0 Hz, CH2—Ar), 2.13 (3H, s, Ar-Me), 1.92-1.78 (2H, m, —CH2—) ppm. 31P NMR (121.4 MHz) δ 25.32 ppm. Anal. calcd. for C32H36IO5P: C, 59.8; H, 5.7; P, 4.8. Found: C, 59.8; H, 5.8; P, 4.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccnc(Cl)c2)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1cc(-c2cc(Cl)c3ccccc3n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 250 mL RBF was added 4.6 g (18 mmol) 2-(2-chloro-pyridin-4-yl)-quinolin-4-ol and 100 mL POCl3, and the mixture was treated with 3.1 mL DIEA (18 mmol). The mixture was was stirred at rt for 1 h, and all starting material was converted. All POCl3 was vacuumed down. The residue was dissolved in 250 mL DCM, washed with saturated NaHCO3 carefully to pH 8. The organic phase was dried over Na2SO4, concentrated and purified by column and yielded pale yellow 4-chloro-2-(2-chloro-pyridin-4-yl)-quinoline. MS (ES+): 275 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH:12]=1)[C:10]#N)([F:4])[CH3:3].[OH2:18].Cl>C(Cl)Cl>[F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH:12]=1)[CH:10]=[O:18])([F:4])[CH3:3]
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C#N)c1
Reactant: O
Agent: Cl
Solvent: ClCCl
Product: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a stirred solution of Compound 24 (1.31 g, 5.22 mmol) in dry CH2Cl2(20 ml) was added a solution of diisobutylaluminum hydride(DIBAL) (6.20 ml, 6.26 mmol, 1.01M in toluene solution) with ice-cooling. The reaction mixture was stirred at 0-C. for 3 h. To the mixture was added H2O (6 ml), followed by 6M HCl aq. (20 ml) and stirred at room temperature for 1.5 h. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with sat. NaHCO3 aq. and brine, dried(MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate (50:1-30:1) to give Compound 25 (1.17 g, 88%) as a yellow oil.
Reaction SMILES: [F-].[K+].C(O[C:6](=[O:15])[C:7](Br)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])C.[SH:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].O>CN(C)C=O>[CH2:11]([O:10][C:8]([C:7]1([CH3:13])[C:6](=[O:15])[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[S:16]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Reactant: Nc1ccccc1S
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
To a suspension of KF (3.016 g, 52 mmoles) in anhydrous dimethyl formamide (14 ml), diethyl-2-bromo-2-methyl-malonate (3.90 ml, 20 mmoles) was added and the mixture was stirred for 15 minutes at room temperature. Subsequently, 2-mercaptoaniline (2.50 g, 20 mmoles) was added and the mixture was stirred for 6 hours at the temperature of 60° C. and overnight at room temperature. The reaction mixture was admixed with a mixture of water and ice (80 ml), the product which separated was filtered off by suction and recrystallized from absolute ethanol. Thus there were obtained 3.80 g (75.7%) of the title product in the form of white crystals, m.p. 109°-111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(N(CC)CC)C>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12](=[C:15]3[C:16]4[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=4[CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=4)[CH2:13][CH2:14]2)=[CH:30][CH:31]=1)(=[O:34])[CH3:33]
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 92.3 %

Procedure:
1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) was N-acetylated by acetic anhydride using triethyl amine as base. Yield 92.3%
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5]([C:10]2[C:11](F)=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH:15]=2)[CH:4]=1)#[CH:2].[N:30]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N+:31]=[N-:32]>CN(C)C=O.C(Cl)Cl.CO.[Cu]I>[CH2:33]([N:30]1[CH:2]=[C:1]([C:3]2[N:8]=[CH:7][C:6]3[NH:9][C:11]4[N:12]=[CH:13][C:14]([C:16]5[CH:21]=[CH:20][C:19]([CH2:22][N:23]6[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]6)=[CH:18][CH:17]=5)=[CH:15][C:10]=4[C:5]=3[CH:4]=2)[N:32]=[N:31]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C#Cc1cc(-c2cc(-c3ccc(CN4CCCCC4)cc3)cnc2F)c(N)cn1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc(Cn2cc(-c3cc4c(cn3)[nH]c3ncc(-c5ccc(CN6CCCCC6)cc5)cc34)nn2)cc1
Temperature: 60 °C

Procedure:
A mixture of 6′-ethynyl-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4]bipyridinyl-3′-ylamine (60 mg, 0.16 mmol), copper (I) iodide (3.0 mg, 0.016 mmol), and azidomethylbenzene (29 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL) was heated at 60° C. for 2 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a brown residue that was taken to the next step without purification.