Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24]#[N:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:6])[CH3:5])[CH3:2].C(N(CC)CC)C.[SH2:33]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24](=[S:33])[NH2:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:5])[CH3:6])[CH3:2]
Reactant: S
Reactant: CCN(CC(C)N1c2ccccc2Sc2ccc(C#N)cc21)C(C)C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCN(CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21)C(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 10-{(2RS)-1-[N-ethyl-N-(1-methylethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (2.3 g) and triethylamine in anhydrous pyridine (46 cc) is treated with hydrogen sulphide and stirred for 16 hours at a temperature in the region of 20° C. The greenish solution obtained is purged with nitrogen, poured into distilled water (200 cc) and extracted with ethyl acetate (200 cc and then 100 cc). The combined organic phases are washed with distilled water (3×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (4 g) is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (75:25 by volume) (750 cc) of ethyl acetate and cyclohexane and collecting 60-cc fractions. The combined fractions 6 to 10 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-((2RS)-1-[N-Ethyl-N-(1-methylethyl)-amino]-2-propyl}-2-phenothiazinecarbothioamide (2.5 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:18]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][O:20][CH2:19]1>>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:9]([C:22]([CH2:21][O:20][CH2:19][C:18]([OH:25])=[O:24])=[O:23])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNCCCCCCCC
Reactant: O=C1COCC(=O)O1
Product: CCCCCCCCN(CCCCCCCC)C(=O)COCC(=O)O

Procedure:
In Examples 2, 3 and 4 wherein a ratio of the amount (B mmol) of dioctylamine to the amount (A mmol) of diglycolic anhydride is 1.0≦B/A≦1.2, the DODGAA's were obtained in high yields while their Nd/Pr separation factor indicative of the separation ability of a metal extractant and the phase separation were satisfactory.
Reaction SMILES: C(OC(=O)[NH:7]C1CCC(NCC2C=C(C3C=NC=CC=3)C=CC=2OC)CC1)(C)(C)C.C(OC(=O)N[CH2:38][CH:39]1[CH2:44][CH2:43][CH:42]([N:45]([C:61]([C:63]2[S:64][C:65]3[C:72]([F:73])=[CH:71][CH:70]=[C:69]([F:74])[C:66]=3[C:67]=2[Cl:68])=[O:62])[CH2:46][C:47]2[CH:52]=[C:51]([C:53]3[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=3)[CH:50]=[CH:49][C:48]=2[O:59][CH3:60])[CH2:41][CH2:40]1)(C)(C)C.Cl>CCO>[CH3:60][O:59][C:48]1[CH:49]=[CH:50][C:51]([C:53]2[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=2)=[CH:52][C:47]=1[CH2:46][N:45]([C:42]1([NH2:7])[CH2:41][CH2:40][CH:39]([CH3:38])[CH2:44][CH2:43]1)[C:61]([C:63]1[S:64][C:65]2[C:72]([F:73])=[CH:71][CH:70]=[C:69]([F:74])[C:66]=2[C:67]=1[Cl:68])=[O:62]
Reactant: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(CNC(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(-c2cccnc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1(N)CCC(C)CC1
Temperature: 5 °C
Reaction time: 4.5 h

Procedure:
To a 3 L 3-neck RB flask with a mechanical stirrer, addition funnel, temperature probe and N2 inlet is added {4-[(3-chloro-4,7-difluorobenzothiophene-2-carbonyl)-(2-methoxy-5-pyridin-4-ylbenzyl)amino]cyclohexyl}methylcarbamic acid tert-butyl ester P6 (54.92 g, 83.70 mmol) and EtOH (1.5 L). The resulting beige slurry is cooled to 5° C. and concentrated HCl (800 mL) is added over 1 h. The cold bath is removed and the solution is stirred for 4.5 h at room temperature. The reaction mixture is concentrated by removing 1.5 L solvent in vacuo and H2O (500 mL) is added. The mixture is extracted with CH2Cl2 (2×350 mL). The aqueous layer is cooled to 2° C. and 50% NaOH (300 mL) is added to pH=13. The mixture is extracted with CH2Cl2 (3×600 mL) and the combined organic layers are washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 3-chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid (2-methoxy-5-pyridin-4-ylbenzyl)-(4-methyl-aminocyclohexyl)amide n (46.5 g, 99%) as a tan foam.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][CH:27](OCC)OCC)[CH3:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1C=CC=CC=1>[CH2:15]([O:14][C:12]([C@H:11]1[O:17][CH:27]([O:26][CH2:24][CH3:25])[N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:10]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H]1OC(OCC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1

Procedure:
[R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (1.16 mmol) is suspended in benzene (10 ml), and triethoxymethane (3.44 mmol) and PPTS (72 mg) are added. Heating to reflux provides the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3(C(F)(F)F)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCCC1.CS(N)(=O)=O.[CH3:52][O:53][CH2:54][CH2:55][S:56]([NH2:59])(=[O:58])=[O:57]>>[CH:16]1([CH2:15][O:14][C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:12][C:8]([C:9]([NH:59][S:56]([CH2:55][CH2:54][O:53][CH3:52])(=[O:58])=[O:57])=[O:10])=[C:7]([F:13])[CH:6]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with 2-methoxyethanesulfonamide, the title compound was obtained (0.16 g, 40%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.70-8.59 (m, 1H), 7.58-7.51 (m, 1H), 6.61-6.51 (m, 1H), 3.90-3.74 (m, 6H), 3.31 (s, 3H), 2.11-1.99 (m, 1H), 1.95-1.67 (m, 6H), 1.41-1.04 (m, 5H), 0.98-0.89 (m, 2H), 0.69-0.61 (m, 2H); MS (ES−) m/z 412.3 (M−1);
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][OH:32])[CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:25]=[C:26]([CH2:30][CH2:31][OH:32])[CH:27]=[CH:28][CH:29]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: NC(=NO)c1cccc(CCO)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cccc(CCO)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was obtained following procedure described for example 54 step 1 but starting from Intermediate 28 (149.42 mg; 0.58 mmol) and Intermediate 73 (100.00 mg; 0.60 mmol). Purification by column chromatography (cHex/EtOAc from 9:1 to 8:2) gave the title compound as a colorless oil. 1H NMR (DMSO-d6, 300 MHz) δ 8.32 (d, J=1.5 Hz, 1H), 8.16 (dd, J=7.9, 1.8 Hz, 1H), 7.98-7.93 (m, 2H), 7.54-7.47 (m, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.15-7.13 (m, 1H), 4.71 (t, J=5.2 Hz, 1H), 4.22 (d, J=12.7 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.24 (s, 3H), 2.85 (t, J=6.7 Hz, 2H), 2.03 (s, 3H). LC/MS (Method B): 401.2 (M+H)+. HPLC (Method A) Rt 5.17 min (Purity: 98.2%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6](=[N:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC.CCOCC>[C:7]1([CH:6]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:1][CH2:2][CH2:3][CH3:4])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [Li]CCCC
Reactant: C(=Nc1ccncc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCC(Nc1ccncc1)c1ccccc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
0.03 Mole of butyl lithium in hexane as a 15% w/w solution was added dropwise to a stirred, cooled (-10° C.) solution of 5.46 grams (0.03 mole) of 4-benzylideneamino pyridine in 10 milliliters of dry ether. The mixture was allowed to warm to room temperature and then poured onto ice and extracted with methylene chloride. The organic phase was separated and extracted with 2 N hydrochloric acid. The extracts were basified with 2 N sodium hydroxide and extracted into methylene chloride. The resulting methylene chloride solution was dried (MgSO4) and decolourised with charcoal. The solvent was removed and the resulting light oil (5.75 grams) was crystallised and recrystallised from a toluene/petrol (60°-80° C.) mixture affording 2.36 grams of N-([α-phenyl]-n-pentyl)-4-pyridinamine, melting point 118°-8.5°.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(OC(=O)C)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Yield: 75.1 %

Procedure:
After 20 g of 4-nitroimidazole was put in a flask, 144.5 mL of acetic anhydride was added thereto and while the temperature was kept at 25° C., 14.5 mL of 69 mass % nitric acid was added dropwise thereto. After the addition of nitric acid was completed, the resultant mixture was stirred at 25° C. for 3 hours. The reaction solution was added into 100 g of iced water and extracted with 300 mL of dichloromethane. The organic layer was washed with 300 mL of a saturated sodium hydrogen carbonate aqueous solution and dried over 30 g of magnesium sulfate. The organic layer was filtered and the solvent was evaporated under reduced pressure to obtain 21 g of 1,4-dinitroimidazole (yield 75.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(N1C=CN=C1)(N1[CH:17]=[CH:16]N=C1)=O.C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccnc(Cl)c1
Yield: 95.9 %

Procedure:
In 400 ml of tetrahydrofuran was dissolved 31.5 g of 2-chloroisonicotinic acid, and 32.5 g of 1,1′-carbonyldiimidazole was added thereto. The mixture was stirred under ice-cooling for an hour. To the solution was added 50 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated, and extracted by adding ethyl acetate and water. The organic layer was dried over magnesium sulfate, and the residue was vacuum dried, to give 35.6 g of ethyl 2-chloroisonicotinate as shown in Table 132 below.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][C:8]([NH:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[C:37]([Cl:38])=[C:36]([C:39](Cl)=[O:40])[S:35][C:34]=2[CH:42]=1)=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[C:37]([Cl:38])=[C:36]([C:39](=[O:40])[N:16]([C:8]3[CH:9]=[CH:10][C:11]4[S:12][C:13]5[C:4](=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=5)[C:5](=[O:18])[C:6]=4[CH:7]=3)[CH3:17])[S:35][C:34]=2[CH:42]=1)=[O:29]
Reactant: CNc1ccc2sc3ccc(Br)cc3c(=O)c2c1
Reactant: COC(=O)c1ccc2c(Cl)c(C(=O)Cl)sc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(Cl)c(C(=O)N(C)c3ccc4sc5ccc(Br)cc5c(=O)c4c3)sc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To 0.51 g (1.6 mmol) of 2-bromo-7-methylamino-thioxanthen-9-one (14) and 10 mL of triethylamine in 15 mL of anhyd CH2Cl2 was added 0.61 g (2.1 mmol) of 3-chloro-2-chlorocarbonyl-benzo[b]thiophene-6-carboxylic acid methyl ester (12) dissolved in 10 mL of anhyd CH2Cl2 at 5-8° C. in an ice bath. A catalytic amount of DMAP was added. The reaction mixture was warmed at room temperature and stirred for 48 h under N2. The reaction mixture was filtered to remove triethylamine hydrochloride salt, the filtrate was washed three times with aq saturated NaHCO3, H2O, three times with aq. 2N HCl to remove unreacted amines, H2O, brine, dried over Na2SO4, and concentrated in vacuo to give crude ester 10. The crude ester 10 was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane to give 0.55 g (60% yield) of NMR pure 10 (LG−=Cl−) as a brown powder, mp 237-239° C. Found: C, 52.09; H, 2.64; N, 2.47%; calcd for C25H15NO4S2ClBr: C, 52.40; H, 2.62; N, 2.44%; 1H-NMR (400 MHz, CDCl3): 3.61 (3H, s), 3.92 (3H, s), 7.35-7.54 (3H, m), 7.66-7.80 (2H, m), 8.02 (1H, d, J=8.2 Hz), 8.40 (1H, s), 8.51 (1H, s), 8.69 (1H, s); 13C-NMR (100 MHz, CDCl3): 38.3, 52.6, 120.8, 120.9, 122.8, 124.9, 126.3, 127.3, 127.4, 127.8, 128.6, 129.6, 130.0, 131.0, 132.7, 134.1, 135.8, 136.1, 137.6, 138.7, 141.4, 162.5, 166.5, 178.1.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[Li+:9].[Li+].[Li+].[NH2-:12].CN(C=O)C>COCCOC>[N-:12]([S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4].[Li+:9]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: [NH2-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
22 ml of trifluoromethanesulfonyl chloride were added to a suspension of 3.5 g of lithium nitride in 100 ml of a mixture of DMF and DME (50/50). The nitride dissolved in a few minutes with stirring at ambient temperature. The reaction took place according to the following reaction scheme:
Reaction SMILES: [Br:1][C:2](=[CH:9]OCC)[C:3](=O)[C:4]([F:7])([F:6])[F:5].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][NH2:23].Br>C(O)C>[Br:1][C:2]1[C:3]([C:4]([F:5])([F:6])[F:7])=[N:23][N:22]([C:15]2[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[CH:9]=1
Reactant: CCOC=C(Br)C(=O)C(F)(F)F
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Agent: Br
Solvent: CCO
Product: FC(F)(F)c1nn(-c2c(Cl)cc(Cl)cc2Cl)cc1Br
Yield: 30.4 %

Procedure:
2.3 g (0.01 mole) of 3-bromo-4-ethoxy-1,1,1-trifluorobut-3-en-2-one are added to a solution of 4.2 g (0.02 mol) of 2,4,6-trichlorophenyl-hydrazine in 100 ml of ethanol which contains 0.01 mole hydrogen bromide. The mixture is refluxed for 5 hours and then concentrated under reduced pressure, and ice water is added to the residue. Extraction with dichloromethane, washing with saturated sodium chloride solution until neutral, clarification over anhydrous sodium sulphate and concentration gives 4.6 g of a crude product, which is chromatographed on 120 g of silica gel using toluene/petroleum ether (ratio 1:1). 1.2 g of 4-bromo-1-(2,4,6-trichloro-phenyl)-3-trifluoromethylpyrazole of melting point 93°-94° C. (from petroleum ether) are obtained.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][C:14](=[O:23])[C:15]1[C:20](F)=[CH:19][N:18]=[C:17]([Br:22])[CH:16]=1)[CH3:12].O>O1CCCC1>[CH2:11]([O:13][C:14](=[O:23])[C:15]1[C:20]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][N:18]=[C:17]([Br:22])[CH:16]=1)[CH3:12]
Reactant: CCOC(=O)c1cc(Br)ncc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(Br)ncc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
To a solution of benzylalcohol (1.5 g) in tetrahydrofuran (30 mL) was added sodium hydride (55%, 0.3 g) under ice cooling, and this mixture was stirred at same temperature for 5 minutes. To this reaction mixture was added a solution of 2-bromo-5-fluoroisonicotinic acid ethyl ester (2.9 g) in tetrahydrofuran (30 mL), and this mixture was stirred at room temperature for 2 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (2.4 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:18][CH2:17][CH2:16][O:15]1.[C:28]([O:32][C:33]([NH:35][CH:36](O)[CH3:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:28]([O:32][C:33]([NH:35][CH2:36][CH2:37][O:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:14]2([CH3:13])[O:18][CH2:17][CH2:16][O:15]2)=[CH:22][CH:23]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC1(COc2ccc(O)cc2)OCCO1
Reactant: CC(O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(OCC2(C)OCCO2)cc1
Reaction time: 64 h
Yield: 56 %

Procedure:
Diethyl azodicarboxylate (3.8 ml) was added dropwise to a stirred solution of 4-[(2-methyl-1,3-dioxolan-2-yl)methoxy]phenol (3.4 g), N-t-butoxycarbonylaminoethanol (5.2 g) and triphenylphosphine (6.3 g) in anhydrous tetrahydrofuran (100 ml), at ice-bath temperature, under argon. The reaction mixture was left for 64 hours at 25° C. and then the solvent was removed under reduced pressure. The residue was dissolved in ether (100 ml) and the ethereal solution washed with 2N aqueous sodium hydroxide (2×50 ml), water (2×50 ml) and saturated brine (50 ml). The aqueous washings were in turn extracted with ether (50 ml). The ethereal solutions were combined, dried, and the ether removed under reduced pressure. The residue was purified by chromatography using 11/2% tetrahydrofuran in dichloromethane as eluent. The appropriate fractions were combined and evaporated to yield 1-t-butoxycarbonylamino-2-[4-((2-methyl-1,3-dioxolan-2-yl)-methoxy)phenoxy]ethane as a light yellow solid (3.2 g) m.p. 80°-82° C. (from cyclohexane); microanalysis: found C, 61.3; H, 7.7; N, 3.8%; required for C18H27NO6 : C, 61.2; H, 7.6; N 4.0%.
Reaction SMILES: [F:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C(C(OO)=[O:18])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]2[O:18][CH:7]2[CH:6]=1
Reactant: O=C(OO)c1ccccc1
Reactant: FC=CCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: FC=CCC1=CC2OC2C=C1
Reaction time: 120 h
Yield: 52 %

Procedure:
7 g of p-fluoroallylbenzene was added to 800 ml of chloroform solution containing perbenzoic acid prepared from 46 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 5 days. The resulting mixture was washed with sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was distilled under reduced pressure to give 4.1 g (yield 52%) of p-fluoroallylbenzene oxide as colorless liquid.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8]O)[O:6][CH:7]=1.OS(O)(=O)=O.[BrH:16].[OH-].[Na+]>>[Br:16][CH2:8][C:5]1[O:6][CH:7]=[C:2]([OH:1])[C:3](=[O:10])[CH:4]=1
Reactant: O=c1cc(CO)occ1O
Reactant: Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(CBr)occ1O
Temperature: 4 °C
Reaction time: 18.5 h

Procedure:
In a 250 mL round-bottomed flask 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (10.0 g, 70.36 mmol) was added to concentrated H2SO4 (30 mL). The solution was cooled to 4° C. and bromohydric acid (40 mL) was added dropwise for 1.5 h. HBr vapors were trapped using a NaOH 0.5 N solution. The reaction was stirred at 70° C. for 18.5 h. After cooling ice (220 g) was added with continuous stirring for for 1.5 h to obtain a white precipitate. The solid was filtered off and dissolved in ethyl acetate and the solution was dried with MgSO4, filtered and evaporated. 2-(Bromomethyl)-5-hydroxy-4H-pyran-4-one 21 was obtained as a pale yellow solid (9.1 g, 63% yield).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccc3cn[nH]c3c12
Solvent: CN(C)C=O
Product: Clc1ccnc2ccc3cn[nH]c3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A mixture of 9-hydroxy-1H-pyrazolo[3,4-f]quinoline (2.97 g, 16.0 mmol) and phosphorus oxychloride (24.58 g, 160 mmol) at 0° C. was treated with dimethylformamide (DMF) (15.4 ml) dropwise. After addition was complete, the viscous reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was then poured onto ice and the resulting dark brown solution was treated with decolorizing carbon and filtered, and the brown filtrate neutralized with 10M NaOH. The light brown solid which resulted was collected by filtration and air dried giving 9-chloro-1H-pyrazolo[3,4-f]quinoline (1.73 g, 53%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[NH:14][CH2:13][CH2:12][CH:11]2[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26].[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C(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>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH2:18][CH:11]1[C:10]2[C:15](=[N:16][CH:17]=[C:8]([C:37]3[CH:36]=[N:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)[CH:9]=2)[NH:14][CH2:13][CH2:12]1
Reactant: Fc1ccc(F)c(CC2CCNc3ncc(Br)cc32)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)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: CCO
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Cc3cc(F)ccc3F)CCN4)cn2)CC1
Yield: 26 %

Procedure:
Na2CO3 (2N, 53 μL) (4.0 eq) was added to a mixture of 6-bromo-4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (9.0 mg) (1 eq), 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (11.3 mg) (1.4 eq), and Pd(PPh3)4 (3.0 mg, 0.1 eq) in toluene/ethanol (4:1, v/v, 2 mL). The reaction was heated at 90° C. for six (6) hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (15 mL) and washed with water (15 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent to give the title compound as a yellow foam (26% yield). LCMS: m/z=436 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.7-2.0 (m, 2H), 2.37 (s, 3H), 2.55-2.60 (m, 4H), 2.81 (dd, J=9.1 and 13.3 Hz, 1H), 2.98 (dd, J=6.4 and 13.3H, 1H), 3.08-3.18 (m, 1H), 3.40-3.50 (m, 1H), 3.53-3.70 (m, 5H), 5.18 (bs, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.81-6.87 (m, 1H), 6.89-6.96 (m, 1H), 6.98-7.06 (m, 1H), 7.16 (d, J=1 Hz, 1H), 7.50 (dd, J=2.5 and 8.8 Hz, 1H), 8.05 (d, J=1 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H).