Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(CCC(=O)Cl)cc1
Temperature: 25 °C

Procedure:
3-(4-Methylphenyl)propanoic acid (0.055 moles, 9 g) is dissolved in thionyl chloride (1.008 moles, 120 g). The mixture is stirred for 30' at r.t., then refluxed for 1 h 30', evaporated under vacuum to an oil and taken up with toluene and hexane, each time evaporating to dryness. Yield: 12.4 g
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1.II.[OH-].[Na+]>CCOCC.CCCCCC.O>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Clc1ccc(Br)cc1
Agent: II
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a solution of 15.3 g (80 mmol) of 4-bromochlorobenzene in 100 ml of ether cooled to -25° was added 60 ml of a 1.6M solution of butyl lithium in hexane in three portions while maintaining the temperature below -20°. This mixture was allowed to warm to -5° during 15 min. It was then recooled to -20°, and a solution of 11.45 g (70 mmol) of 4-chloroquinoline in 40 ml of ether was added while maintaining the temperature at -20°. A yellow suspension formed. It was allowed to warm to 0° for 15 min, and was then stirred for a further 20 min at 0°-10°. To the reaction mixture was then added 20 ml of water and 20 g of iodine. After 20 min of stirring 40 ml of 3N sodium hydroxide solution was added and stirring was continued for a further 15 min. This mixture was then cooled to 10°, and the solid collected to give 17.65 g of product, mp 119°-122°.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:45]([O:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][NH:58][CH2:59][C:60]1[O:61][C:62]2[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=2[CH:64]=1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>O1CCCC1>[C:45]([O:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][N:58]([CH2:59][C:60]1[O:61][C:62]2[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=2[CH:64]=1)[C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:51])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2o1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(Cc2cc3ccccc3o2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC

Procedure:
Experimental condition analogous to Example 1, from 3,4,5-trimethoxy benzoic acid 72 mg (0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride 75 mg (0.39 mmol), 1-hydroxybenzotriazole 45 mg (0.33 mmol), triethylamine 0.05 mL (0.39 mmol), and 2-(S)-{[(benzofuran-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 100 mg (0.3 mmol) in 3 mL tetrahydrofuran. The compound was purified through silica gel chromatography elution with ethyl acetate: methanol 9:1, gave 93 mg of white oily compound.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([Br:19])[CH:13]=1.O>C1COCC1>[CH2:1]([O:8][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[C:14]([Br:19])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
Benzylalcohol (9.7 mL, 94 mmol) was added dropwise to a suspension of NaH (4.0 g of a 60% suspension in mineral oil, 100 mmol) in THF (150 mL) at room temperature and the mixture was stirred at room temperature for 1 h before 1,3-dibromo-5-fluorobenzene (15.9 g, 62.5 mmol) was added. The reaction was stirred at room temperature for 12 h. Water was added carefully and the THF was evaporated under reduced pressure. The residue was extracted with iso-hexane (×3) and the combined organic extracts were washed with NaOH solution (1M aq), water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 1-benzyloxy-3,5-dibromobenzene as a colourless liquid, 14.7 g 69% yield. 1H NMR (CDCl3) δ 7.45-7.33 (m, 5H), 7.30-7.28 (m, 1H), 7.10-7.08 (m, 2H), 5.02 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[C:7]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:6][CH:5]=[C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:3]=2)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 78.7 %

Procedure:
A solution of tert-butyl (trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (150 mg, 0.364 mmol), 4-chlorophenylboronic acid (67.3 mg, 0.432 mmol) and K2CO3 (149 mg, 1.09 mmol) in acetonitrile:water (4:1) was degassed for 20 min. Tetrakis triphenylphosphine palladium (4.2 mg, 0.00364 mmol) was added and the reaction mixture was heated at reflux for 16 h. After completion, the reaction mixture was poured into ice water (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4 filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using EtOAc:Pet ether (1:9) to afford tert-butyl (trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (140 mg, 79%) as white solid.
Reaction SMILES: ClC1C=CC(O[C:9]([N:11]2[CH2:15][CH2:14][N:13](C)[C:12]2=[C:17]([N+:28]([O-:30])=[O:29])[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:19])=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[CH3:9][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[C:17]([N+:28]([O-:30])=[O:29])[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:19]
Reactant: CN1CCN(C(=O)Oc2ccc(Cl)cc2)C1=C(C(=O)Oc1ccc(Cl)cc1)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCNC1=C(C(=O)Oc1ccc(Cl)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred mixture of 3.62 g of 2A, 1.19 g of sodium carbonate, 20 ml of dimethyl sulfoxide, and 4 ml of water was kept at 100° C. for 1.5 hours. The mixture was cooled to room temperature and diluted with 10 ml of water. After ice-bath cooling, a white solid, 2, m.p.: 211°-212° (with decomposition) was isolated by filtration.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].Cl[CH2:11][C:12]#[C:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1COCC1>CO.O>[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][S:6][CH2:11][C:12]#[C:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCSCC#CCCl
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCSCC#CCSCC(=O)OC
Reaction time: 0.5 h

Procedure:
2.03 ml of a 30% solution of sodium methoxide in methanol were added dropwise (such that the temperature did not exceed 15° C.) to a solution of 980 μl of methyl thioglycolate in 10 ml of methanol at 10° C., under an inert atmosphere. The mixture was maintained under stirring for 30 min and then added to a solution of 2.5 g of 1-chloro-5-thia-2-tridecyne in a mixture of 7 ml of methanol with 3 ml of THF under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained was chromatographed on a silica gel column (CH2Cl2) providing 2.3 grams of methyl 3,8-dithia-5-hexadecynoate in the form of a pale orange-colored oil (yield 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([N:30]([CH3:32])[CH3:31])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Li].C(Cl)CCl.CCN(C(C)C)C(C)C.[O:47]1[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][C@@H:55]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([S:71]([NH2:74])(=[O:73])=[O:72])=[CH:67][C:66]=2[S:75]([C:78]([F:81])([F:80])[F:79])(=[O:77])=[O:76])[CH2:56][S:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:49][CH2:48]1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CO.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([N:30]([CH3:32])[CH3:31])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:74][S:71]([C:68]4[CH:69]=[CH:70][C:65]([NH:64][C@H:55]([CH2:54][CH2:53][N:50]5[CH2:51][CH2:52][O:47][CH2:48][CH2:49]5)[CH2:56][S:57][C:58]5[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=5)=[C:66]([S:75]([C:78]([F:81])([F:79])[F:80])(=[O:77])=[O:76])[CH:67]=4)(=[O:72])=[O:73])=[O:26])=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)[O-])cc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Li]
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Reaction time: 0.25 h
Yield: 35 %

Procedure:
(R)-4-(4-((4′-chlorobiphenyl-2-yl)(dimethylamino)methyl)piperidin-1-yl)benzoate, lithium salt (EXAMPLE 36, STEP 1, 0.105 g, 0.23 mmol), DMAP (56 mg, 0.46 mmol), and EDC (0.176 g, 0.92 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (4.5 ml) and DIPEA (0.08 ml, 0.46 mmol) were added, and the solution was stirred at r.t for 15 minutes. (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 0.127 g, 0.23 mmol) was added to the solution and the reaction mixture was stirred at r.t overnight. The reaction mixture was diluted with DCM and washed with 1N sodium bisulfate (aq.) followed by saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue which was purified by reverse phase HPLC (Gilson column, eluting with 30→50% H2O/ACN with 0.1% formic acid for 10 minutes) to provide a solid. The solid was dissolved in MeOH and the mixture was treated with 2N HCl in diethylether. Evaporation of the volatiles under reduced pressure provided the title compound (85 mg, yield: 35% for 2 steps).
Reaction SMILES: [OH:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>ClCCl.O>[NH2:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([CH3:17])([OH:1])[CH2:3][CH2:4]1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]
Reactant: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(O)CCC(CN)CC1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 376A (0.75 g) in dichloromethane (3 mL) was added a few drops of water followed by trifluoroacetic acid (1.19 mL) and the reaction stirred at room temperature. After stirring for 2 h added additional trifluoroacetic acid (0.5 mL). After an additional 4 h the reaction was concentrated and dried under high vacuum. The resulting oily solid was triturated with diethyl ether with sonication. Filtration and washing with diethyl ether gave the title compound as a trifluoroacetic acid salt and a mixture of cis and trans isomers.
Reaction SMILES: [CH:1](/[B-](F)(F)F)=[CH:2]\[CH3:3].[K+].C(Cl)Cl.Br[C:13]1[O:17][N:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]=1[CH3:23].C(N(CC)CC)C>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][C:14]1[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][O:17][C:13]=1/[CH:1]=[CH:2]/[CH3:3]
Reactant: CCOC(=O)c1noc(Br)c1C
Reactant: C/C=C/[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C/c1onc(C(=O)OCC)c1C
Temperature: 90 °C

Procedure:
A suspension of potassium trans-1-propenyltrifluoroborate (9.86 g, 66.7 mmol), PdCl2(dppf).DCM adduct (907 mg, 1.11 mmol), ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (13 g) and triethylamine (7.7 mL) in EtOH (250 mL) was degassed under vacuum and back-filled with nitrogen before heating at 90° C. for 18 h. After cooling to room temperature, the reaction was partitioned between EtOAc and brine, separated, dried over MgSO4 and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 5-10% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=3)=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].O.[Cl-].[NH4+]>O1CCOCC1.[Zn]>[NH2:32][C:28]1[CH:27]=[C:26]([C:13]2[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=3)=[CH:16][N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
400 mg (0.87 mmol) of N-tert-butyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridin-2-amine were dissolved in 15 ml of dioxane and 4 ml of water and 227 mg (3.48 mmol) of metallic zinc and 461 (8.7 mmol) of ammonium chloride were added. The mixture was stirred at 100° C. for 4 hours, then filtered through a celite pad. The filtrate was evaporated and the residue partitioned between dichloromethane and aqueous sodium hydrogenocarbonate. The organic phase was then dried and evaporated and the residue purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 from 9/1 to 7/3), giving 180 mg (48%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:19]=[N:20]2)=[CH:15][CH:14]=1)=O)(C)(C)C.C[O-].[Na+]>O1CCCC1>[CH3:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][C:18]1[N:19]=[N:20][C:21]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)[CH:22]=2
Reactant: C[C@@H]1CCCN1CCc1cc2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2nn1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1cc2ccc(-c3ccc[nH]3)cc2nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of the product from Example 187 (0.007 g, 0.017 mmol) in tetrahydrofuran (2 mL), was added NaOMe (0.03 mL, 25% in methanol) and stirred at r.t. for 3 hours. The reaction mixture was then concentrated under reduced pressure, re-dissolved in water (2 mL), extracted with ethyl acetate (2 mL), dried with Na2SO4, and concentrated to afford the product in 76% yield as a yellowish solid. 1H NMR (CD3OD, 300 MHz) δ 8.31 (m, 1H), 8.02 (dd, J=3, 9 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J=9 Hz, 1H), 6.89 (m, 1H), 6.71 (m, 1H), 6.18 (m, 1H), 3.33–3.19 (m, 4H), 2.53–2.22 (m, 3H), 1.96–1.87 (m, 1H), 1.77–1.64 (m, 2H), 1.43–1.37 (m, 1H), 1.06 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 307.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([OH:32])[CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([Zn][CH2:36][CH3:37])C.ICI.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CCCCCC>[CH2:24]([O:23][CH2:22][CH:21]([OH:32])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:10][CH:11]1[CH2:12][CH:13]1[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCC(O)COCCCCCCCC
Reactant: CC[Zn]CC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: ICI
Product: CCCCCCCCOCC(O)COCCCCCCCCC1CC1CC1CC1CCCCC
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-2-ol in DCM (166 ml) in a 1 L flask under nitrogen was cooled in an ice/IPA bath (−15° C.) and then 1 M diethylzinc in hexane (199 ml, 199 mmol) added, followed by diiodomethane (24.05 ml, 298 mmol). The mixture was allowed to stir in the cooling bath overnight to gradually come up to room temperature. Reaction was quenched by addition of excess saturated ammonium chloride. Washed reaction into 2 L separatory funnel with hexane and water and added excess hexane, shook vigorously. Discarded lower aqueous layer, dried organic layer with sodium sulfate and evaporated to 1-(octyloxy)-3-[(8-{2-[(2-pentylcyclopropyl)methyl]cyclopropyl}octyl)oxy]propan-2-ol (15.5 g, 32.2 mmol, 97% yield) as a yellow oil. Material was used with no further purification. MS (ESI): 481 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(OCC)(=O)C.CO>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C=CC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Yield: 88.6 %

Procedure:
1.58 g (6.96 mmol) of N-(3-acetyl-phenyl)-N-methyl-methanesulfonamide were dissolved in 15 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.12 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl methanesulfonamide as a yellowish-white solid were obtained (yield 88.6%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH2:18]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:19].Cl.N1C=CC=CC=1.C(OCCO)C>>[CH2:18]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:22][CH:21]=1)[CH3:19]
Reactant: CCc1ccc(N)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: CCc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1
Temperature: 139 °C
Yield: 97.5 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.14 ml (1.1 mmol) of 4-ethylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 1 hour; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.325 g (97.5%) of the desired product as light cream crystals. MP 248-250° C.;: mass spectrum (electrospray, m/e,): 333.1462.
Reaction SMILES: [NH2:1]/[CH:2]=[N:3]/[C:4]1[C:9]([C:10]#[N:11])=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:7]=[C:6]([C:25]2[C:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[CH:29][CH:28]=[CH:27][C:26]=2[O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[N:5]=1.FC(F)(F)C(O)=O>CO.C1(C)C=CC=CC=1>[NH2:11][C:10]1[C:9]2[C:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)=[CH:7][C:6]([C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[CH:29][CH:28]=[CH:27][C:26]=3[O:41][CH2:42][CH:43]3[CH2:44][CH2:45]3)=[N:5][C:4]=2[N:3]=[CH:2][N:1]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(/N=C/N)n2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3c(N)ncnc3n2)cc1
Reaction time: 480 h
Yield: 14.7 %

Procedure:
To a solution of tert-butyl 3-(2-{[(1E)-aminomethylidene]amino}-3-cyano-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-1-piperidine-carboxylate (0.180 g, 0.289 mmol) in MeOH (5 mL) and toluene (5 mL) was added trifluoroacetic acid (0.01 mL). The mixture was allowed to stand for 20 days and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH 50:1 to 20:1) gave tert-butyl 3-(4-amino-7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}pyrido[2,3-d]pyrimidin-5-yl)-1-piperidinecarboxylate as a colorless oil (0.026 g, yield; 15%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[O:8])[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1(C)C(C)=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[O:32][CH2:31][CH2:30][O:8]1
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1cccnc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1ccc(CC2(c3cccnc3)OCCO2)c(Cl)c1

Procedure:
2.25 g of 2,4-dichlorobenzyl 3-pyridyl ketone, 2.2 g of p-toluenesulfonic acid monohydrate and 1.0 g of ethylene glycol are heated at reflux for 24 hours in 20 ml of xylene, the resulting water being separated in a water separator. The mixture is then cooled, poured into 2N sodium hydroxide and extracted with diethyl ether, the organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel with n-hexane/ethyl acetate (1:1) to yield 3-[2-(2,4-dichlorobenzyl)-1,3-dioxolan-2-yl]pyridine, which melts at 76°-78°.