Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[O:9][CH:8]([CH2:12]OC(=O)C)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH:5]1[CH2:6][CH2:7][CH:8]([CH3:12])[O:9][C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CCC(OC(C)=O)C(=O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC1CCC(C)OC1=O
Temperature: 50 °C
Yield: 70 %

Procedure:
Acetic acid 5-acetoxy-6-oxo-tetrahydro-pyran-2-ylmethyl ester (2.3) (2.30 g, 10.0 mmol) was dissolved in ethyl acetate (50 mL) and added to the Parr reactor, followed by Pd/C (5%, 0.2 g) and triethylamine (4.3 mL, 30.0 mmol). The mixture was stirred under hydrogen (5×106 Pa) and heated at 50° C. for 1 day. The product was filtered through celite and the solvent removed under vacuum. The crude product was dissolved in CH2Cl2 (200 mL) and washed with water (3×200 mL). The solvent was removed and the resulting product dried under vacuum. The resulting syrup was sublimed under vacuum, at 50° C., affording white crystals (1.20 g, 7.0 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ 5.46 (1H, dd, 3JH—H=10.56 Hz, 3JH—H=8.87 Hz, H-2), 4.60 (1H, m, H-5), 2.36 (1H, m, H-3), 2.20 (3H, s, COCH3), 2.12-2.00 (1H, m, H-4), 2.00-1.88 (1H, m, H-3′), 1.88-1.75 (1H, m, H-4′), 1.42 (3H, d, 3JH—H=6.22 Hz, H-6) ppm. 13C {1H} NMR (125 MHz, CDCl3) δ 169.9, 169.6 (COCH3, C-1), 74.2 (C-5), 66.0 (C-2), 27.8 (C-4), 23.0 (C-3), 21.0 (C-6), 20.8 (COCH3) ppm. m/z (CI-ammonia gas): 190 [M+NH4+]. Anal. Calcd for C8H12O4: C, 55.81; H, 7.02. Found: C, 55.81; H, 7.05.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19](Cl)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:25][S:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:30]4[CH:31]=[CH:32][C:27]([S:26][CH3:25])=[CH:28][CH:29]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(Oc2ccnc3c(Cl)cccc23)CC1
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: CCOC(C)=O
Product: CSc1ccc(-c2cccc3c(OC4CCN(C(=O)OC(C)C)CC4)ccnc23)cc1

Procedure:
In a 25 mL round-bottomed flask equipped with a reflux condenser and N2 inlet septum was placed a stir bar, 4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (198 mg, 0.57 mmol), 4-methylthiophenylboronic acid (287 mg, 1.7 mmol), tetrakis(triphenylphosphine)palladium (98 mg, 0.085 mmol), 2M sodium carbonate (0.6 mL) and toluene (4 mL). The mixture was refluxed 36 h under N2. The resulting mixture was diluted with ethyl acetate and extracted with H2O. The organic extract was dried and concentrated to give the crude product. The crude product was purified by column chromatography to using 50% EtOAc/Hexane and preparative HPLC to give the desired product. 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H), 2.04 (m, 2H), 2.17 (m, 2H), 2.55 (s, 3H), 3.59 (m, 2H), 3.83 (m, 2H), 4.97 (m, 1H), 5.09 (m, 1H), 7.14 (s, 1H), 7.41 (m, 4H), 7.81 (t, 1H), 7.90 (d, 1H), 8.38 (d, 1H), 9.11 (s, 1H). Exact mass calculated for C25H28N2O3S 436.18, found 437.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:27]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>C(O)(C)C>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14](=[O:15])[NH2:27])=[CH:12][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CC(C)O
Product: Cc1cc(C(N)=O)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a suspension of 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid (8.00 g, 28.7 mmol) in isopropanol (100 mL), HOBt (4.27 g, 31.6 mmol) followed by EDC hydrochloride (6.34 g, 33.1 mmol) is added. After stirring at rt for 1 h, 25% aq. ammonia (16.1 mL) is added. Stirring is continued for 30 min before the isopropanol is evaporated under reduced pressure. The remaining solution is diluted with isopropyl acetate (200 mL), washed three times with approximately 0.5 N aq. NaHCO3 solution (100 mL) followed by water (50 mL), dried over MgSO4, filtered, concentrated and dried to give 3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid tert-butyl ester (7.5 g) as an off-white solid.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH:13]=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[P:15]([O-:32])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:24][P:15]([CH:13]([OH:14])[CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:32])[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: O=CCCc1cccc2ccccc12
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=P(OCc1ccccc1)(OCc1ccccc1)C(O)CCc1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(naphthalen-1-yl)propanal (2.3 g, 12.5 mmol) in DMF (6 mL) under nitrogen is added dibenzyl phosphite (3.3 g, 12.5 mmol), followed by potassium fluoride (0.94 g, 16.2 mmol). After 2 hours, the stirred suspension is diluted with ethyl acetate (60 mL) and washed with water (3×20 mL). The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane (30% to 40% ). Concentration of the pure fractions in vacuo yields [1-hydroxy-3-(naphthalen-1-yl)-propyl]phosphonic acid dibenzyl ester as an oil which solidifies on standing.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@H:28]3[CH2:32][C@@H:31](O)[C@H:30]([OH:34])[C@@H:29]3[OH:35])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:36][OH:37]>[Pd]>[OH:35][C@H:29]1[C@@H:30]([OH:34])[C@H:31]([O:37][CH3:36])[CH2:32][C@@H:28]1[O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:26]=1
Reactant: CO
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C[C@@H](O)[C@H](O)[C@@H]3O)c3ccccc3n2)CC1
Agent: [Pd]
Product: CO[C@@H]1C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,2S,3S,4R)-(2,3,4-trihydroxycyclopentan-1-yl)oxy]quinazoline [cf. Example 33(4)] (1.00 g) in methanol (15 ml) is added 10% palladium/carbon (200 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 3 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure, and the residue is dissolved in ethanol (35 ml) and thereto is added fumaric acid (242 mg). The precipitated crystals are dissolved by adding water to the mixture. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure, and the resulting residue is recrystallized from water-ethanol to give 4-[(1S,2S,3S,4R)-(2,3,4-trihydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline 1/2 fumarate (390 mg) as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5](SC)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)(=O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: CSC1=Nc2ccccc2N(C)c2cscc21
Reactant: CN1CCNCC1
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3ccccc3N(C)c3cscc32)CC1

Procedure:
A solution of 1.2 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 6 ml. of N-methylpiperazine is treated with 2-3 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentratedto dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled, and made alkaline with concentrated ammonium hydroxide solution. The precipitate is collected, washed with water and dissolved in chloroform. The chloroform solution is dried and concentrated to an oil, which slowly crystallizes. Recrystallization from ethanol gives yellow crystals, m.p. 83°-85° C.
Reaction SMILES: [C:1](N1C(N)=C(C2C=CN=CC=2)C=N1)(=N)N.[C:16]([N:19]1[C:23]([NH2:24])=[C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[CH:21]=[N:20]1)(=[NH:18])[NH2:17]>>[NH2:18][C:16]1[N:19]2[N:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)=[C:23]2[N:24]=[CH:1][N:17]=1
Reactant: N=C(N)n1ncc(-c2ccncc2)c1N
Reactant: N=C(N)n1ncc(-c2ccncn2)c1N
Product: Nc1ncnc2c(-c3ccncn3)cnn12
Yield: 80 %

Procedure:
By replacing the 1-amidino-4-(4-pyridyl)-5-aminopyrazole in Example 1C with an equivalent quantity of 1-amidino-4-(4-pyrimidinyl)-5-aminopyrazole there is obtained an 80% yield of 4-amino-8-(4-pyrimidinyl)-pyrazolo-[1,5-a][1,3,5]triazine which separates from boiling dimethylformamide in crystals melting at about 340° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH3:18])[C:11]=2[CH:19](O)[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(S(F)(F)[F:33])CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH3:18])[C:11]=2[CH:19]([F:33])[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccncc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(F)c1ccncc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of 200 mg of 4-[[5-(3,5-dichloro-phenylsulfanyl)-1-isopropyl-3 methyl-1H-pyrazol-4-yl]-hydroxy-methyl]-pyridine in 5 mL of dichloromethane was added 68 μL of diethylamino sulfur trifluoride. The reaction mixture was stirred for 1 hour at −78° C. then quenched with saturated aqueous sodium hydrogen carbonate. The aqueous phase was extracted three times with 10 mL of dichloromethane and combined extracts were washed with brine, dried, filtered and evaporated to give a blue gum which was purified by flash chromatography on silica gel using diethyl ether/hexane (1:2 then 1:1) for the elution to give 118 mg of 4-[[5-(3,5-Dichloro-phenylsulfanyl)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-fluoro-methyl]-pyridine as a colourless oil. Mass spectrum (ES) m/z 410 [M+H]+, 451 [M+H+MeCN]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>>[CH2:17]([NH:20][C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:18]=[CH2:19]
Reactant: C=C(C)CNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC(=C)C)c2scc(C)c2n1
Yield: 32.8 %

Procedure:
305 mg (1.2 mmol) of 2-chloro-7-methyl-4-(2-methyl-2-propenylamino)thieno[3,2-d]pyrimidine and 1.14 g (19.2 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 108 mg (yield: 32.7%) of the title compound.
Reaction SMILES: C([O:8][N:9]([CH2:12][CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=O)[CH:10]=[O:11])C1C=CC=CC=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[O:27][CH:28]=[CH:29][N:30]=1>>[OH:8][N:9]([CH2:12][CH:13]([C:14]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:26]1[O:27][CH:28]=[CH:29][N:30]=1)=[O:16])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=[O:11]
Reactant: c1coc([C@@H]2CCCN2)n1
Reactant: CCCCC(CN(C=O)OCc1ccccc1)C(=O)O
Product: CCCCC(CN(O)C=O)C(=O)N1CCCC1c1ncco1

Procedure:
The title compound is prepared from 2-[(benzyloxy-formyl-amino)-methyl]-hexanoic acid D-7 (R=n-butyl) and 2-(S)-pyrrolidine-2-yl-oxazole E-5 (prepared as described in Procedure E) according to General Procedure D.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[CH2:23][C:24]#[N:25].C[O-].[Na+]>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[C:24]=1[NH2:25]
Reactant: N#CCc1ccc(C(F)(F)F)cc1F
Reactant: COc1ccc(N=[N+]=[N-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To an ice-cooled solution of 1-azido-4-methoxy-benzene (0.450 g, 3.0171 mmol) and commercial 2-fluoro-4-(trifluoromethyl)phenyl acetonitrile (0.736 g, 3.6205 mmol) in absolute ethanol (10 ml) and under a nitrogen flow, sodium methoxide (0.2445 g, 4.5257 mmol) in absolute ethanol (5 ml) is added drop-wise and the resulting mixture is allowed to attain room temperature spontaneously overnight. The reaction mixture is evaporated and the solid residue is dissolved in dichloromethane (80 ml) and the organic solution is washed with water (60 ml), brine (60 ml), dried over MgSO4, filtered and evaporated (˜1 g). This crude residue is purified by crystallization from a mixture of dichloromethane and petroleum ether, to afford the title compound as a yellow solid (0.570 g, 53% yield). M.p. 164.6-165.5° C. LC-ESI-HRMS of [M+H]+ shows 353.1028 Da. Calc. 353.102548 Da, dev. 0.7 ppm.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3.[OH-].[Na+].Cl>C(O)C.O>[CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)c1cn2c(ccc3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(ccc3ccccc32)n1

Procedure:
0.5 g of ethyl imidazo-[1,2-a]-quinoline-2-carboxylate was dissolved in 50 ml of ethanol and then a solution of 0.12 g of sodium hydroxide in 10 ml of water was added thereto. The mixture was heated on a steam bath for 2 hours and was subsequently acidified to a pH of 2 with concentrated hydrochloric acid. The mixture was evaporated to dryness under reduced pressure and 50 ml of methanol were added to the residue. The solution was filtered to remove inorganic material and the filtrate was evaporated to dryness under reduced pressure. The residue was crystallized by trituration in chloroform to give imidazo-[1,2-a]-quinoline-2-carboxylic acid in the form of the hydrochloride salt.
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][S:16][C:4]=12)=O.[C:17](#[N:21])[CH2:18][C:19]#[N:20].[OH-].[K+]>C(O)C>[C:19]([C:18](=[CH:1][C:3]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][S:16][C:4]=12)[C:17]#[N:21])#[N:20]
Reactant: N#CCC#N
Reactant: CCCn1c(=O)c(C=O)c2n(c1=O)CCS2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(=O)c(C=C(C#N)C#N)c2n(c1=O)CCS2
Temperature: 60 °C
Reaction time: 7 h
Yield: 19.2 %

Procedure:
A solution of 8-formyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione(1 g), malononitrile (0.31 g) and ethanol (20 ml) containing 10% aqueous solution of potassium hydroxide (0.1 ml), were stirred at 60° C. for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform. After washing with water and drying, the organic solution was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystallized from ethyl acetate-isopropyl ether to give pale yellow-red needles (0.23 g, 19%).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][CH:38]1[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]1.O>CN(C=O)C>[CH3:27][N:26]([CH2:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[S:25]([N:20]1[C:21]2([CH2:23][CH2:22]2)[CH2:24][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:18][CH2:19]1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)C1
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 45 °C
Reaction time: 16 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.71 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (1.42 mmol) and tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (0.85 mmol). Stirred at 45° C. for 16 h and then added H2O (2 mL). Extracted with EtOAc (3×2 mL) and the combined organic phases were concentrated in vacuo. The residual oil was treated with a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol: 2,2,2-trifluoroethanol (3:1, 4 mL) at 150° C. for 2 h. The crude reaction mixture was concentrated on celite in vacuo and purified by standard column chromatography using methanol in DCM as eluent. The obtained compound was recrystallized in methanol:EtOAc affording the title compound as solid.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:18]([C:10]1[CH:9]=[C:8]2[C:17]3=[C:16]4[C:5](=[CH:4][CH:3]=[C:2]([C:26]5[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=5)[C:15]4=[CH:14][CH:13]=[C:12]3[CH:11]=1)[CH:6]=[CH:7]2)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc2ccc3ccc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
Then, a mixed solution of 106.9 g of 1-bromo-7-t-butylpyrene, 54.5 g of 4-chlorophenylboronic acid, 0.223 g of bis(triphenylphosphine)dichloropalladium, 350 ml of an aqueous 2M sodium carbonate solution and 1586 ml of 1,2-dimethoxyethane was heated and stirred for about 5 hours under a nitrogen stream and under refluxing. After the mixture was cooled to room temperature, 640 ml of water was added, and this was extracted with 1170 ml of toluene. The organic layer was washed with 640 ml of water two times, dried with magnesium sulfate, and evaporated, 270 ml of toluene and 1350 ml of methanol were added, and the mixture was stirred for about 2 hours, and filtered. After the resultant was vacuum dried, 105.16 g of 7-t-butyl-1-(4-chlorophenyl)pyrene was obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CS(C)=O>[F:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:21][CH:20]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Fc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)nc1
Yield: 34.5 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (5.8 g), dimethylsulfoxide (20 ml), potassium carbonate (4.8 g) and 6-fluoro-3-(bromomethyl)pyridine (6.7 g) according to the similar method described in Production Example 4 was obtained 3.3 g of 2-((6-fluoro-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (13)).
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:17](Br)[CH2:18][CH:19]([CH3:21])[CH3:20]>O1CCCC1>[CH3:20][CH:19]([CH2:18][CH2:17][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:21]
Reactant: CC(C)CCBr
Reactant: CCCCCCCCCC/C=C\CCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCC/C=C\CCCCC(C)C
Temperature: 0 °C
Yield: 37.5 %

Procedure:
In a 1-liter reactor, a Grignard reagent was prepared from 5.0 g (0.206 mole) of magnesium and 46 g (0.2 mole) of 1-chloro-cis-3-tetradecene in exactly the same manner as in Example 4. Next, 30 g of tetrahydrofuran, 30 g (0.2 mole) of isoamyl bromide and 0.6 g of cuprous iodide were placed in another 1-liter reactor and cooled to 0° C. Then, the above-described Grignard reagent was added dropwise thereto so that the temperature did not exceed 20° C. After completion of the reaction, the reaction product was distilled in exactly the same manner as in Example 4 to obtain 20 g of 2-methyl-cis-7-octadecene (purity 96.0%, yield 77%, b.p. 155°-158° C./2 mmHg). MS(m/e): 56(100%), 266 (M+, 27%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1F>O1CCOCC1>[C:8]1([P:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[P:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1ccccc1Nc1ccccc1F
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(P(c2ccccc2)c2ccccc2Nc2ccccc2P(c2ccccc2)c2ccccc2)cc1

Procedure:
A 100-mL Schlenk flask equipped with a condenser was flashed with nitrogen thoroughly. To this flask was added KPPh2 (20 mL, 0.5 M in THF solution, Aldrich, 10 mmol). THF was removed in vacuo and a solution of di(2-fluorophenyl)amine (1.00 g, 4.88 mmol) in 1,4-dioxane (8 ml) was added with a syringe. The transparent, ruby reaction solution was heated to reflux with stirring. The reaction condition was monitored by 31P{1H} NMR spectroscopy, which revealed the completion of reaction in 2 d. The resulting yellow solution was evaporated to dryness in vacuo. The residue was treated with degassed deionized water (50 mL) and the product was extracted with deoxygenated dichloromethane (15 mL). The dichloromethane solution was separated from the aqueous layer, from which the product was further extracted with dichloromethane (15 mL×3). The combined organic solution was dried over MgSO4 and filtered; All volatiles were removed in vacuo to yield the product as a pale yellow crystalline solid; yield 2.1 g (80.15%). 1H NMR (CDCl3, 300 MHz) δ 7.10-7.23 (m, 24, Ar), 6.69-6.76 (m, 5, Ar and NH). 31P{1H} NMR (CDCl3, 121.5 MHz) δ-19.58. 31P{1H} NMR (Et2O, 121.5 MHz) δ-18.62. 13C NMR (CDCl3, 75 MHz) δ 146.51 (JCP=21.1), 135.78 (JCP=8.0), 134.14, 133.72 (JCP=21.1), 129.64, 128.53 (JCP=12.0), 128.46 (JCP=7.5), 126.34 (JCP=10.1), 121.51, 118.16. Anal. Calcd. for C36H29NP2: C, 80.43; H, 5.44; N, 2.61. Found: C, 80.04; H, 5.56; N, 2.69.