Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:19])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH:26]=O.[O-:28][CH2:29][CH3:30].[Na+]>C(OCC)(=O)CC>[Cl:18][C:16]1[CH:15]=[C:14]([C:13]([O:12][CH2:11][CH3:10])=[O:19])[C:30]2[C:29](=[O:28])[CH:26]([C:22]3[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:8][C:9]=2[CH:17]=1
Reactant: CC[O-]
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cc(Cl)cc21
Reactant: Cn1ccnc1C=O
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cc(Cl)cc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.6 %

Procedure:
To a solution of (E)-4-(benzylideneamino)-6-chloroisobenzofuran-1(3H)-one (720 mg, 2.66 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (330 mg, 3 mmol) in ethyl propionate (40 mL) was added sodium ethoxide (650 mg, 9.6 mmol). The mixture was stirred at room temperature for 3 hr. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=20:1 to 1.5:1) to give the title compound as a solid (170 mg, yield 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>>[C:13]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:14])[CH3:12]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
The mixture of 100 g (4-amino-phenyl)-acetic acid and 200 ml acetanhydride is heated at the steam cone for 15 minutes and evaporated. The residue is stirred with 500 ml hot water until complete dissolution occurs. The solution is cooled and the precipitate formed filtered off, to yield the (4-acetamido-phenyl)acetic acid melting at 168°-170°.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:20]=3)[S:18][C:14]=2[C:13]=1OS(C(F)(F)F)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.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>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:20]=3)[S:18][C:14]=2[C:13]=1[C:50]1[CH:51]=[CH:52][C:47]([Cl:46])=[CH:48][CH:49]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)n3)sc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a 10 mL reaction vial, (S)-ethyl 2-tert-butoxy-2-(5-methyl-2-(6-(1-methyl-1H-indazol-5-yl)pyridin-2-yl)-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate (33 mg, 0.050 mmol) and p-chlorophenyl boronic acid (48 mg, 0.20 mmol) were dissolved in dioxane (2.5 mL) under argon atmosphere. The solution was bubbled with argon for 5 min. Then potassium carbonate (45 mg, 0.32 mmol) and Pd(PPh3)4 (10 mg, 0.0075 mmol) were added sequentially. The reaction mixture was sealed and heated in oil bath at 120° C. for 4.5 h. Reaction was then diluted with EtOAc (10 mL) and filtered to remove solid. The filtrate was concentrated and purified on silica gel column with 0-40% EtOAc/Hex to afford product. LCMS-ESI+: calc'd for: C35H33ClN4O3S: 625.2, 626.2, 627.2 (M+H+); found: 625.1, 626.2, 627.1 (M+H+).
Reaction SMILES: [CH3:1]I.[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH:7]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[H-].[Na+].[Na+].[Cl-]>CN(C)C=O>[CH3:1][O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH:7]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1SC(c2cccnc2)N(CCO)C1=O
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(C)SC1c1cccnc1
Yield: 48.1 %

Procedure:
Methyl iodide (0.72 g, 5.0 mmol) was added to a solution of 3-(2-hydroxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (1 g, 4.2 mmol) in dry dimethylformamide (5 ml), and 40% sodium hydride (176 mg, 4.4 mmol) was added portionwise to the mixture under ice-cooling. Then, the mixture was kept cooling for 1 hour. The resulting mixture was poured into aqueous NaCl, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and subjected to medium-pressure chromatography (hexane-acetone), giving 3-(2-methoxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (0.51 g, 48% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH2:42]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([N:52]2[CH2:53][CH2:54][N:49]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:50][CH2:51]2)=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N4CCN(Cc5ccccc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzylpiperazine (90 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (93 mg, yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7](SC2C=CC=CC=2Cl)[CH2:6]1)=[O:4].[CH:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20](C(OO)=O)[CH:19]=1.[S:29](=[O:32])(O)[O-:30].[Na+]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([S:29]([C:23]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:24])(=[O:32])=[O:30])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(Sc2ccccc2Cl)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1CCC(S(=O)(=O)c2ccccc2Cl)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of 3-(2-chloro-phenylsulfanyl)-cyclopentanecarboxylic acid methyl ester (0.24 g, 1.0 eq) in dichloromethane (10 mL) was treated at 0° C. with a solution of MCPBA (1.1 g, 5.0 eq) in dichloromethane (7 mL), which was added dropwise. The mixture was stirred at 0° C. for 3 h, then treated with 20% sodium bisulfite and stirred at RT for 15 min. The mixture was filtered, washing with chloroform. The organic phase was washed with saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel with a heptane/ethyl acetate gradient, yielding the title compound as a colorless oil (0.25 g, 90%). MS (ESI): m/z=303.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH:11]12[O:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][NH:13][CH2:12]2.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:12][CH:11]3[O:18][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:13]2[CH2:12][CH:11]3[O:18][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:3]=1
Reactant: C1CC2CNCC1O2
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1cc(Cl)nc(N2CC3CCC(C2)O3)n1
Product: Clc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %
Yield: 83 %

Procedure:
2,4,6-Trichloropyrimidine (8, 6.325 mL, 55 mmol) was dissolved in 220 mL EtOH at 0° C. 8-Oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (2, 8.23 g, 55 mmol) was added followed by the addition of NEt3 (23.1 mL, 165 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour at ambient temperature. The mixture was concentrated, dissolved in EtOAc and washed with saturated NaHCO3. The aqueous phase was extracted with EtOAc the combined organic phases were dried (MgSO4), filtered, and concentrated. The mixture was purified by silica gel chromatography (10-80% EtOAc in hexanes) to give 11.807 g (45 mmol, 83%) of 3-(2,6-dichloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (9) along with 1.631 g (6.2 mmol, 11%) of 3-(4,6-dichloro-pyrimidin-2-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (10).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4]1.[C:12]([NH:19][CH2:20][CH2:21]Br)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)C(C)C)(C)C>CO.C(#N)C>[N:7]1([CH:5]2[CH2:6][N:3]([CH2:21][CH2:20][NH:19][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: C1CCN(C2CNC2)C1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN1CC(N2CCCC2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
595 mg of 1-(azetidin-3-yl)pyrrolidine dihydrochloride (Example 219A, 2.75 mmol, purity about 92%, 1 equivalent) were reacted in 3 batches. To obtain the free base, the 1-(azetidin-3-yl)pyrrolidine dihydrochloride was passed over a StratoSpheres™ SPE column. To this end, the column was initially moistened with 1 ml of methanol. 1-(Azetidin-3-yl)pyrrolidine dihydrochloride, dissolved in 3 ml of methanol, was then passed over the column and the column was rinsed with 3 ml of methanol. The solution obtained was concentrated (the column retains about 0.9 mmol of salt). The free base was then initially charged in 26.8 ml of acetonitrile, 656 mg of 2-(Boc-amino)ethyl bromide (2.9 mmol, 1.05 equivalents) and 1.45 ml of N,N-diisopropylethylamine (8.25 mmol, 3 equivalents) were added and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated and purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 5:1; dichloromethane/methanol 10:1; dichloromethane/methanol 4:1 and dichloromethane/1 N ammonia in methanol 4:1). This gave 463 mg (67% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46]([N:48]=[C:49]=[S:50])=[O:47])=[CH:41][CH:40]=1.C1(C)C=CC=CC=1.CCO>C1(C)C=CC=CC=1.CCO.CCOCC>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:49]([NH:48][C:46](=[O:47])[CH2:45][C:42]4[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=4)=[S:50])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Solvent: CCO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.6 %

Procedure:
To a suspension of intermediate 13 (5.53 g, 10.55 mmol) in toluene (80 mL) and EtOH (80 mL) was added 2-(4-fluorophenyl)acetyl isothiocyanate (2) (3.09 g, 15.83 mmol) in a minimum of toluene-EtOH mixture (1:1). The reaction mixture was stirred at r.t. for 45 min then concentrated. The residue was purified by flash column chromatography (eluent EtOAc), followed by two triturations: first one in a mixture Et2O-EtOAc-hexanes and second one in Et2O, to afford intermediate 14 (4.68 g, 62% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.49 (s, 1H), 11.84 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.04 (d, J=11.6 Hz, 1H), 7.79 (dd, J=8.2, 2.2 Hz, 1H), 7.55-7.54 (m, 2H), 7.38 (dd, J=8.6, 5.8 Hz, 2H), 7.18 (t, J=8.8 Hz, 2H), 6.69 (d, J=5.6 Hz, 1H), 4.48 (s, 2H), 3.84 (s, 2H), 3.43-3.34 (m, 4H), 3.23 (s, 3H), 1.44-1.34 (m, 9H). MS (m/z): 720.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#[CH:2].[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]\I)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16][C:2]#[C:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH3:12]
Reactant: C#Cc1ccc(C#N)cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc(C#N)cc1

Procedure:
The general procedure was used to convert 4-Ethynyl-Bezonitrile and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow solid (380 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.64-7.59 (m, J=8.5, 4H), 6.37-6.34 (d, J=11.3, 1H), 6.24-6.21 (d, J=11.3, 1H), 4.28-4.23 (q, J=7.1, 2H), 1.34-1.30 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.40, 132.39, 132.03, 130.08, 127.49, 121.74, 118.25, 112.37, 98.34, 89.94, 60.57, 14.23. Anal. Calcd. for C14H11NO2: C, 74.65; H, 4.92, N, 6.22; Found C, 74.45; H, 4.84, N, 6.06. m.p.: 69.5°-71.5° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1>C(O)C>[CH:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][N:7]=[N:6][C:5]=2[NH:2][NH2:3])[CH:10]=1
Reactant: Clc1nncc2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nncc2ccccc12
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a 2-L, 3-necked, round-bottom flask fitted with a temperature probe and condenser were charged 700 mL of ethanol and 7.6 mole equivalents (630 mL) of hydrazine hydrate, and the solution was cooled to <10° C. One (1) mole equivalent (280 g) of 1-chlorophthalazine (solid) was added in portions at a rate to maintain the solution temperature at <20° C. The solution was stirred and heated to 60-70° C. After 1 hour at temperature, the hot solution was filtered to remove any insoluble by-products, and the filtrate was cooled to 0-5° C. A light yellow solid formed in the cold solution, and was isolated by filtration and washed with cold ethanol. The resulting product, hydralazine free base, was dried to constant mass and characterized. Typical yields were in the range 77-80%. The hydralazine thus obtained could be used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]#[CH:16].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:1][C:2]1[C:3](=[CH:9][C:10](=[N:13][CH2:16][C:15]#[CH:14])[CH2:11][CH:12]=1)[NH:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)Nc1cc(N)ccc1F
Reactant: C#CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C#CCN=C1C=C(NC(=O)OC)C(F)=CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 80.9 %

Procedure:
under an atmosphere of nitrogen, compound methyl 2-fluoro-5-aminoaniline formate (72.5 mg, 0.39 mmol) was dissolved in dried DMF (5 mL), then propargyl bromide (44 μL, 0.59 mmol) and DIPEA (140 μL, 0.78 mmol) were added. The resulting solution was stirred for 6 h at 60° C., and diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with saturated saline solution (15 mL×3), dried with anhydrous Na2SO4, concentrated and then loaded on chromatography column (PE/EtOAc=6:1-4:1) to produce a product of methyl 2-fluoro-5-(N-propargyl-imino)-aniline formate (70.1 mg, 81%);
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3][CH2:4]C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3][CH3:4]
Reactant: Sc1ccccc1
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COP(C)(=O)c1cc(Sc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
To a mixture of ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol) and thiophenol (40.0 mmol) in 20 ml of ethanol is added sodium hydroxide (60.0 mmol) in 1 ml of water. The mixture is heated under reflux for 24 hours. The reaction mixture is poured into water, acidified with dilute HCl and extracted with methylene chloride (2×). The combined extracts are washed with brine, dried and evaporated to dryness. The resulting oily residue is treated with diazomethane in methanol, concentrated and purified by preparative TLC to yield methyl P-methyl-2-nitro-5-phenylthiophenylphosphinate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[N:17]=1)=[O:14].CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)O1.[O:45]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH2:48][CH2:47][CH2:46]1>>[O:45]1[CH2:50][CH2:49][CH2:48][C:47]([C:18]2[N:17]=[C:16]([NH:15][C:13]([NH:12][C:7]3[C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[O:14])[CH:21]=[CH:20][CH:19]=2)=[CH:46]1
Reactant: O=C(Nc1cccc(I)n1)Nc1ccnc2c(F)cccc12
Reactant: CC1(C)OB(C2=COCCC2)OC1(C)C
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: O=C(Nc1cccc(C2=COCCC2)n1)Nc1ccnc2c(F)cccc12

Procedure:
The title compound was prepared as described in example 27 step 2, substituting 1-(6-bromo-quinolin-4-yl)-3-(6-trifluoromethyl-pyridin-2-yl)-urea by 1-(8-fluoroquinolin-4-yl)-3-(6-iodopyridin-2-yl)urea (example 47, step 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate by 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:8]1[CH:7]=[C:6]([CH2:10][CH3:11])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(CC)c1N
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(CC)c1N
Temperature: 25 °C
Yield: 51.4 %

Procedure:
2,6-diethylaniline (7 g, 46.9 mmol) was dissolved in 50 mL of DMF in a round-bottom flask and cooled with an ice-water bath. N-bromosuccimide (NBS) (9.18 g, 51.6 mmol) was dissolved in 100 mL of DMF and added dropwise to the flask via a dropping funnel. The reaction was warmed slowly to room temperature and reacted overnight before it was quenched by ice water. The product was extracted with dichloromethane and washed with lithium chloride solution. After evaporating solvent, the residue was purified by silica gel column chromatography. 5.5 g (51.4% yield) of product was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][OH:33]>C(O)CCC>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][O:33][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CN(C)CCO
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CN(C)CCOc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline, (100, 0.293), triethylamine (123 μL, 0.879 mmol), N,N-dimethylethanolamine (959 μL, 0.586 mmol) in n-butanol (3.0 mL) was heated in the microwave at 120° C. for 20 minutes, then concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform/7 N ammonia in methanol (0.1-5%) to afford the title compound (75 mg, 74%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(N(C)C)=O>[C:25]([N:4]1[C:3](=[O:17])[C:2]([F:1])=[CH:15][N:6]([C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:5]1=[O:16])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)n1c(=O)c(F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15 Grams of 2'-deoxy-5-fluoro uridine (FudR) was dissolved in 45 ml of dimethylacetamide. Thereto was added 9 ml of triethylamine. To the mixture being cooled with ice-water was added 8.6 g of benzoyl chloride and the whole mixture was stirred overnight. The reaction mixture was subjected to filtration. The resulting filtrate was subjected to evaporation to obtain the residue, and water was added to the residue. The aqueous solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous sodium sulfate. The dried ethyl acetate solution was concentrated and the residue was recrystallized from ethanol to obtain the desired compound. The yield was 10.5 g. M.p. 126° to 127° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][NH2:10].C(N)CN.ClCC1SC=CN=1.[CH3:22][N:23]=[C:24]=[O:25]>>[CH3:22][NH:23][C:24]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:25]
Reactant: CN=C=O
Reactant: NCCNCc1nccs1
Agent: ClCc1nccs1
Solvent: NCCN
Product: CNC(=O)NCCNCc1nccs1

Procedure:
N-(2-Thiazolylmethyl)ethylenediamine, prepared by reacting ethylenediamine with 2-chloromethylthiazole by the procedure of Example 40, is reacted with methyl isocyanate by the procedure of Example 24 to give, after concentrating and separating by column chromatography, the title compound.