Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2=[CH:11][C:12]3[N:13]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][C:17](B1OC(C)(C)C(C)(C)O1)=[CH:16][CH:15]=4.Br[C:40]1[CH:41]=[C:42]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:53])[CH:47]=2)[CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O>[C:52]([C:48]1[CH:47]=[C:46]([C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C:12]3[CH:11]=[C:10]5[C:2]([CH3:1])([CH3:38])[C:3]6[C:8]([C:9]5=[CH:21][C:20]4=3)=[CH:7][CH:6]=[CH:5][CH:4]=6)[CH:41]=2)[CH:51]=[CH:50][CH:49]=1)(=[O:53])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2c2cc3c(cc21)C(C)(C)c1ccccc1-3
Reactant: O=C(c1ccccc1)c1cccc(-c2cccc(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1c2ccc(-c3cccc(-c4cccc(C(=O)c5ccccc5)c4)c3)cc2c2cc3c(cc21)C(C)(C)c1ccccc1-3

Procedure:
16.8 g (33.0 mmol) of tert-butyl 12,12-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-12H-10-azaindeno[2,1-b]fluorene-10-carboxylate, 13.4 g (40 mmol) of (3′-bromobiphenyl-3-yl)phenylmethanone and 11.6 g of sodium carbonate are suspended in 900 ml of dioxane, 900 ml of toluene and 400 ml of water. 4.2 g (3.6 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 7 h. After cooling, the precipitated solid is filtered off with suction and washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene. Yield: 14.7 g (23 mmol), 70% of theory.
Reaction SMILES: [Na].[C:2]1([O:9][CH3:10])[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]1([CH:17](Cl)[CH:18]=[CH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH3:10][O:9][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:18]=[CH2:19]
Reactant: C=CC(Cl)c1ccccc1
Reactant: COc1ccccc1O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(Oc1ccccc1OC)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 5 g of guaiacol sodium salt in 60 ml of dimethylformamide, 1-phenylallyl-chloride (5.22 g) (J.C.S. 1959, p. 2720) was added under a nitrogen atmosphere. The whole was stirred for 4 hours at room temperature and for two hours at 50° C., poured into water and extracted with ethyl ether. After standard working up, followed by chromatographic separation, 3-(2-methoxy-phenoxy)-3-phenyl-propylene (8.1 g; 98%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[C:8]([Cl:20])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Cl:20])[C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: [H][H]
Reactant: OCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: OCCOc1c(Cl)cc(O)cc1Cl
Yield: 92.3 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step B, by the treatment of 16.0 grams (0.051 mole) of 2-[2,6-dichloro-4-(phenylmethoxy)phenoxy]ethan-1-ol with hydrogen gas in the presence of a catalytic amount of 10% palladium on carbon in about 400 mL of ethanol using a Parr hydrigenaton apparatus. Following the theoretical uptake of hydrogen, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:2 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 10.5 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N+](C1C=CC=CC=1O)([O-])=O.[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.CC(C)N=C=NC(C)C.[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([NH:43][CH3:44])[CH2:39][CH2:38]1.[Cl:45]CC(Cl)C>CN(C=O)C>[ClH:45].[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:43]([CH3:44])[CH:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:20])=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CNC1CCN(C)CC1
Reactant: CC(Cl)CCl
Agent: CC(C)N=C=NC(C)C
Agent: O=[N+]([O-])c1ccccc1O
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Cc2ccc(-c3ccccc3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
To the polymeric nitrophenol (1.5 g, approx. 1 mmol) was added a filtered solution of 4-biphenylylacetic acid (1.10 g, 5.18 mmol) in a mixture of 1,2-dichloropropane (18 ml) and DMF (2 ml), followed by the addition of a solution of DIC (0.63 g, 4.99 mmol) in 1,2-dichloropropane (5 ml). The mixture was shaken at room temperature for 15 hours, filtered, and the polymer was extensively washed with DCM, DMF, and 1,2-dichloropropane. To the polymer was added 1,2-dichloropropane (5 ml) and a solution of 1-methyl-4-methylaminopiperidine (0.10 g, 0.78 mmol) in 1,2-dichloropropane (10 ml). The resulting mixture was shaken at room temperature for 21 hours and then at 60° C. for one hour, filtered, and the polymer was carefully washed with DCM and methanol. The combined filtrates were concentrated to yield the crude product, which was purified by column chromatography (silicagel, gradient elution with DCM/methanol). The amine was mixed with ethanol and 1 molar aqueous hydrochloric acid, concentrated, and the residual hydrochloride was recrystallized from acetone. 120 mg (42%) of the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:10][CH:11]2[CH:15]([CH:16]=1)[CH2:14][C:13](=[O:17])[CH2:12]2)#[N:2].[OH-:18].[K+]>C(O)(C)(C)C>[O:17]=[C:13]1[CH2:12][CH:11]2[CH:15]([CH2:16][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]([NH2:2])=[O:18])[CH2:10]2)[CH2:14]1
Reactant: N#Cc1ccccc1C1=CC2CC(=O)CC2C1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccccc1C1CC2CC(=O)CC2C1
Yield: 111 %

Procedure:
5-(2-Cyano-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one, ethylene ketal (0.25 g, 0.935 mmol) and powdered potassium hydroxide (0.5 g, 8.9 mmol) in t-butanol (5 mL0 were refluxed for 2 hours. After concentration, the reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 0.296 g (111%) 2-(5-oxo-octahydro-pentalen-2-yl)-benzamide, ethylene ketal as light yellow oil which solidified upon standing. A portion was triturated with hexanes to give a dull yellow solid which had the following properties: mp 111-1 12.5° C.; NMR (CDCl3) δ 7.66 (dd, J1=7.5 Hz, J2=1.5 Hz, 1H), 7.36-7.18 (m, 3H), 6.56 (br s, 2H),5.71 (t, J=2.1 Hz, 1H), 3.88-3.82 (m, 4H), 3.44-3.33 (m, 1H), 3.03-2.87 (m, 2H), 2.63-2.49 (m, 1H), 2.11-1.93 (m, 2H), 1.78-1.67 (m, 2H); 13C NMR (CDCl3) δ 171.65, 141.48, 136.24, 134.20, 133.69, 130.33, 129.10, 128.96, 127.33, 118.19, 64.43, 64.11, 49.78, 43.68, 42.80, 39.83, 39.19; IR(KBr) 3386, 3171, 2967, 2940, 2897, 1666, 1387, 1325, 1111, 781, 771, 631; Anal. calculated for C17H13NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.39; H, 6.85; N, 4.92.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(CCO)[CH2:27][CH2:26]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH2:20][CH:25]3[CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1CC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 14.5 h

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 0.17 g (0.72 mmol) of tetraethyl orthotitanate and 7.5 g of 2-cyclopropyl-ethanol is stirred at 130° for 14.5 hours, about 2 ml of solvent being distilled off after 0.5 hour. The mixture is subsequently evaporated to dryness in vacuo, the residue is taken up in chloroform and chromatographed on silica gel while eluting with ethyl acetate. After crystallization of the resulting oil from ethyl acetate/n-hexane, there is obtained 2-cyclopropylethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 163°-164°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][CH:24]([NH:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCC(N)CC2)nc1N
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCC(NS(C)(=O)=O)CC2)nc1N

Procedure:
The similar procedure as described in Example 60 was used, starting from [4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 345) and methanesulfonyl chloride (Aldrich) to give N-[4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-methanesulfonamide. MS (M+H)+, 452.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[C:12]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C1COCC1.CCOC(C)=O.CN(C=O)C>[C:12]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of phenol (0.40 g, 4.23 mmol) in 10 mL of THF at 0° C. was added sodium hydride (0.226 g, 5.65 mmol), and the mixture was warmed to room temperature. The mixture was stirred 10 minutes (until evolution of hydrogen gas ceased) and cooled to 0° C. A solution of (S)-(+)-N-Boc-2-(4-toluenesulfonyloxymethyl)pyrrolidine (1.0 g, 2.8 mmol) in 2 mL of THF was added dropwise and the resulting mixture was refluxed overnight. To the mixture was added 5 mL of DMF and the mixture was heated at 100° C. overnight. To the mixture was added EtOAc and the organic layer was washed thrice with water, thrice with 1N NaOH, and twice with water. The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by silica gel chromatography with 7% EtOAc/Hexanes to give the title compound as a colorless oil (0.55 g, 71%). ES (+) MS m/e=278 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
To a solution of 4-chloro-3-fluorobenzaldehyde (8 g, 50.5 mmol) and ammonium acetate (9.72 g, 126 mmol) in acetic acid (168 mL) was added nitromethane (8.16 mL, 151 mmol). The reaction mixture was heated at reflux for 5 h and cooled down. Water (100 mL) was added, and the mixture was stirred at room temperature for 1 h. The solid was filtered, washed by water, and dried under vacuum. The solid was purified by flash chromatography (0-20% EtOAc/heptane) to yield clean product 4.2 g in 41% yield. 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (d, J=13.7 Hz, 1H), 7.54 (d, J=13.8 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.33 (dd, J=2.0, 9.3 Hz, 1H), 7.31-7.28 (m, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12]>C(O)(=O)C>[CH3:16][C:15]1[CH:14]=[CH:13][C:11]([NH:12][C:5]([CH3:6])=[O:7])=[CH:10][C:9]=1[CH3:8]
Reactant: Cc1ccc(N)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C)c(C)c1

Procedure:
95 ml of acetic anhydride was added to a stirred solution of 3,4-dimethylaniline in 300 ml of glacial acetic acid at such a rate the temperature of the mixture slowly rose to 60° C. The resulting mixture was stirred while the temperature dropped to room temperature, then evaporated to dryness. A mixture of water and ice was added to the residue, followed by methylene chloride. The resulting mixture was stirred and treated with solid sodium bicarbonate until neutral. The organic phase was separated, and dried (MgSO4), and the solvent was evaporated to give 3,4-dimethylacetanilide (9A).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])C.[CH3:16][NH:17][NH2:18]>CCO>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[CH:5]=[C:4]([OH:3])[N:17]([CH3:16])[N:18]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Solvent: CCO
Product: Cn1nc(-c2ccccc2F)cc1O
Yield: 76.7 %

Procedure:
To a solution of ethyl-2-fluorobenzoylacetate (4.3 ml, 24 mmol) in EtOH (48 ml) was added methylhydrazine (1.32 ml, 25 mmol) under N2 at RT. The reaction was heated at reflux for 18 h. The mixture was then evaporated, and the off white solid residue taken up in hot EtOAc. The mixture was cooled down, and the white solid not dissolved was collected via filtration and washed with hexane, then dried under reduced pressure to yield 5-(2-fluorophenyl)-2-methyl-2H-pyrazol-3-ol (intermediate XXVIIIa, 3.54 g, 77% yield). M+=193.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(OP(OCC)OCC)C.[H-].[Na+].[CH3:26][O:27][CH2:28][O:29][C:30]1[C:37]([CH3:38])=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[CH3:39]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][O:27][CH2:28][O:29][C:30]1[C:37]([CH3:38])=[CH:36][C:33](/[CH:34]=[CH:2]/[C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:32][C:31]=1[CH3:39]
Reactant: COCOc1c(C)cc(C=O)cc1C
Reactant: CCOC(=O)c1cccc(CCl)c1
Agent: CCOP(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(/C=C/c2cc(C)c(OCOC)c(C)c2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
Ethyl 3-(chloromethyl)benzoate (1.192 g, 6 mmol) and triethylphosphite (1.273 mL, 7.2 mmol) were heated to 150° C. for 4 hours. The reaction mixture was cooled to 0° C. and then DMF was added. NaH (60% in oil, 0.252 g, 6.3 mmol) was added to the solution at 0° C. After stirring for 20 minutes, the solution of 4-(methoxymethoxy)-3,5-dimethylbenzaldehyde (4-MOMO-3,5-dimethylbenzaldehyde; 0.583 g, 3 mmol) in DMF was added to the mixture dropwise at 0° C. After 18 hours, the mixture was diluted with ethyl acetate (EtOAc) and the solution was washed with 10% citric acid and brine. After drying on Na2SO4, the organic layer was filtered and concentrated under reduced pressure. The compound was purified by column chromatography (9.5:0.5 Hexane:EtOAc) to afford (E)-ethyl 3-[4-(methoxymethoxy)-3,5-dimethylstyryl]-benzoate (0.726 g, 71%).
Reaction SMILES: [N:1]1[C:8](Cl)=NC(Cl)=NC=1Cl.[OH-].[Na+].[CH3:12][C:13]([CH3:15])=O>>[C:8](#[N:1])[C:12]1[C:12](=[CH:13][CH:15]=[CH:15][CH:13]=1)[C:8]#[N:1]
Reactant: CC(C)=O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccccc1C#N
Reaction time: 2 h

Procedure:
A solution of intermediate D (32.7 g) in acetone (500 ml) was added to cyanuric chloride (18.5 g) in acetone (150 ml) at 0° C. and stirred at this temperature for 2 hours, maintaining the pH at 6 with 0.5M sodium hydroxide solution. The precipitated solid was filtered off, washed with ice cold water (2×250 ml) and dried to give the damp product (65.2 g).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)C=O.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 25 °C

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 43.7 g (0.157 mole) of oleylalcohol and 500 ml of dried dimethylformamide is flushed with nitrogen and stirred at room temperature after which 7.55 g (0.314 mole) of sodium hydride is added. The mixture is stirred at room temperature for an hour then heated to reflux. The mixture is refluxed for 92 hours after which the mixture is poured into an ice-water mixture, acidified with acetic acid and extracted with ether. The ether layer is washed with water and salt water, dried over sodium sulfate, filtered ane evaporated replacing the ether with hexane. Upon cooling a solid is formed which is recrystallized from methanol to give 5-(cis-9octadecenyloxy)-2-furoic acid, M.P. 93°-96° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][C:21](=O)[C:22](F)(F)F)[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ICC[N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][S:37]1(=[O:43])=[O:42]>CN(C)C=O.C1(C)C=CC=CC=1>[O:42]=[S:37]1(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][N:36]1[CH2:22][CH2:21][NH:20][C:11]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:10]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC(=O)C(F)(F)F
Reactant: O=S1(=O)CCCCN1CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCCS1(=O)=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 5-[(4-fluorophenyl)methyl]-3-[(trifluoroacetyl)amino]-2-pyridinecarboxylate (304 mg, 0.821 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (535 mg, 1.64 mmol) and 2-(2-iodoethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (356 mg, 1.23 mmol), respectively. The reaction mixture was stirred at 80° C. for 5 hours. Additional cesium carbonate (535 mg, 1.64 mmol) and 2-(2-iodoethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (356 mg, 1.23 mmol) were added and the reaction mixture was stirred overnight at 80° C. The reaction mixture was cooled and diluted with toluene. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5%, methanol in dichloromethane) to provide ethyl 3-{[2-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate, which was slightly contaminated and taken on to the next step.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[NH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[CH2:22][C@H:21]([CH2:23][OH:24])[CH:20]=[CH:19]2)=[C:11](Cl)[N:10]=1.[OH-].[Na+]>CO>[NH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[CH2:22][C@H:21]([CH2:23][OH:24])[CH:20]=[CH:19]2)=[C:11]([NH:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5])[N:10]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NC(CO)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(NC(CO)CO)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of serinol hydrochloride (0.765 g, 6.00 mmol) in methanol (20 mL) was stirred with basic ion exchange resin for 10 minutes. The resin was filtered off and the filtrate concentrated to a colorless oil. To this was added (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.544 g, 2.00 mmol) and methanol (10 mL). The resulting solution was stirred in a Parr bomb at 80° C. overnight. 1N NaOH (2 mL) was added and the solvent evaporated. The residue was chromatrographed on silica gel. Title compound eluted with 20% methanol-chloroform; white powder after crystallization from acetonitrile-methanol (0.404 g, 63%), m.p. 160-162° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:7]([O:6][C:4]([CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)CCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 18 %

Procedure:
Ethyl 3-bromopropionate (1.81 g, 0.01 moles) was added to a three-necked, 100 mL round bottom flask equipped with a magnetic stirrer, thermocouple and temperature controller, condenser, and heating mantle. Triphenylphosphine (2.62 g, 0.01 moles) and toluene (25 ml) was added and the mixture was heated to reflux temperature. As the temperature turned 90° C., the mixture turned slightly cloudy. After 3 hours at 115° C., the reaction mixture was cooled to room temperature, during which time a yellow colored waxy material settled to the bottom of the reaction flask. The liquid was removed and the residual waxy solid dissolved in dichloromethane (about 10 ml). Diethyl ether (about 15 ml) was added to the dichloromethane solution and a precipitate was formed. The precipitate was collected by filtration and dried under vacuum to give the required phosphonium salt (0.8 grams; 18% yield). The structure of the product was confirmed by 1H NMR analysis.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN1CCCC1=O.[F:24][C:25]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[C:31]2[C:26]=1[C:27](=[O:47])[C:28]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[CH:29][NH:30]2>C(OCC)(=O)C.O>[F:24][C:25]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[C:31]2[C:26]=1[C:27](=[O:47])[C:28]([C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)=[CH:29][N:30]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCN3CCOCC3)c12
Temperature: 55 °C
Reaction time: 45 h
Yield: 75.2 %

Procedure:
Potassium carbonate (2.1 g, 15.2 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.36 g, 7.31 mmol) were added to an N-methylpyrrolidone (NMP) solution (5 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (1.0 g, 3.05 mmol) and then stirred at 50 to 60° C. for 45 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=50:1→30:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-1-(2-morpholin-4-ylethyl)-8-propoxy-1H-quinolin-4-one (1.01 g, yield: 75%).