Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH2:8][C:9]3[C:14]([C:15]4([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38]>CCOCC.O.N1C=CC=CC=1>[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38].[C:22]([O:1][C:2]1[C:7]2[CH2:8][C:9]3[C:14]([C:15]4([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC2(CC1)c1ccccc1Cc1c(O)cccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)Oc1cccc2c1Cc1ccccc1C21CCN(C)CC1

Procedure:
4-Hydroxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine (0.9 g.) is added to pyridine (7 ml.) and acetic anhydride (5 ml.) and the solution is warmed on the steam bath for 1 hour. It is then poured into water, basified with solid sodium carbonate, and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried (MgSO4), and evaporated to give an oil to which is added an excess of a saturated solution of citric acid in ether. The resulting solid is filtered off and recrystallised three times from methanol-ether to give 4-acetoxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine citrate m.p. 156°-159°C.
Reaction SMILES: [C:1]([C@:3]1([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16])#[N:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:1]([C@:3]1([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[O:16][C:22](=[O:24])[CH3:23])#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OC[C@@]1(C#N)O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@@]1(C#N)O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1OC(C)=O

Procedure:
A solution of 2'-deoxy-4'-cyano-5'-O-acetyl uridine (24 mg, 0.08 mM) and acetic anhydride (20μl) in pyridine (0.2 ml) was stirred at room temperature for 5 h. The solvent was removed by evaporation and the residue was chromatographed on silica gel eluting with 5% CH3OH/CH2Cl2 to give 2'-deoxy-4'-cyano-3'O,5'O-diacetyl uridine (23 mg, 0.07 mM). Accurate Mass Calcd. for C14H15N3O7 : 337.0910. Found: 337.0911
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][O:7][C@@H:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23]/[CH:24]=[C:25]1/[C:26]2[CH:39]=[C:38]([C:40]([OH:43])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:27]=2[O:28][CH2:29][C:30]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][O:7][CH:8]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:23][CH:24]=[C:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[N:35][C:30]=4[CH2:29][O:28][C:27]4[CH:36]=[CH:37][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:39][C:26]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: Clc1ccc(CO[C@@H]2CCNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(OCc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-3-(4-chloro-benzyloxy)-pyrrolidine (0.88 mmol, 2.0 eq) in acetonitrile:water (4:1) was added potassium carbonate (0.88 mmol, 2.0 eqv) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by Reverse Phase HPLC. 1H-NMR (CDCl3) δ: 1.40 (6H, s), 1.15-1.35 (1H, m), 1.85-2.05 (1H, m), 2.20-2.40 (1H, m), 2.35-2.65 (8H, m), 3.90-4.10 (1H, m), 4.30-4.50 (2H, d), 5.10-5.30 (2H, br, s), 6.05 (1H, t), 6.50 (1H, dd), 7.10-7.50 (4H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 505 (M+1), UV retention time: 1.52 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1-c1ccccc1

Procedure:
10.1 g (34 mmol) of 2-(4-fluorophenyl)-5-methyl-1-phenylhexane-1,4-dione (Example 2) and 9.3 g (102 mmol) of aniline are heated under reflux for 24 hours in a water separator in 150 ml of toluene with the addition of 500 mg of p-toluenesulphonic acid. After cooling and diluting with ethyl acetate, the mixture is washed with 1N hydrochloric acid and then with sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated in vacuo. The residue is then chromatographed over silica gel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(=O)[CH2:34][C:35](=[O:37])[CH3:36]>CS(C)=O.[Cu]I>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[N:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:3][CH:4]=3)=[N:9]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Reactant: CC(=O)CC(C)=O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 110 °C
Yield: 35.3 %

Procedure:
3-(4-Bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C52) (11 g, 29 mmol), copper(I) iodide (0.55 g, 2.9 mmol), potassium phosphate (18 g, 86 mmol), and pentane-2,4-dione (8.9 mL, 86 mmol) were dissolved in dimethylsulfoxide (120 mL) in a 500 mL round bottomed flask. The reaction was heated at 110° C. for 19 hours. The solution was cooled to room temperature and then quenched with hydrogen chloride (2 N). The excess base was removed by gravity filtration and the filtrate was extracted with ethyl acetate. The organics were washed with water, extracted, dried, and concentrated. Purification by flash column chromatography using 0-30% ethyl acetate/hexanes afforded the title compound as a pure orange solid (3.7 g, 35%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.17 (d, J=8.2 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.39 (dt, J=8.1, 1.0 Hz, 2H), 7.33 (dd, J=8.1, 0.6 Hz, 2H), 3.76 (s, 2H), 2.19 (s, 3H); ESIMS m/z 361 ([M]+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:17].O>C1COCC1>[NH2:17][C:11]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F

Procedure:
A mixture of ethyl 2,4-difluoro-5-nitrobenzoate (5.00 g; 21.6 mmol) (see Example 59 (d)) in THF (100 mL) was treated with NH3 in THF (2.7 mL; 8 M; 21.6 mmol) at 0° C. and the mixture was stirred over night. Another portion of NH3 in THF (1.0 mL; 8M; 8 mmol) was added and the mixture stirred over night. Water (100 mL) was added and the mixture was concentrated. The precipitate was filtered off and dried to give the sub-title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](OB(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)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.C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CCCc1ccc(OB(O)O)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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2cc(F)cc(Cl)c2)cc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
At first, 25.8 g of 4-propylphenylboric acid (S1-1), 30.0 g of 1-bromo-3-chloro-5-fluorobenzene (S1-2), 2.5 g of tetrakis(triphenylphosphine)palladium, 50.1 g of sodium carbonate and 700 ml of a mixed solvent of toluene/ethanol/water=3/3/1 (volume ratio) were added into a reactor under nitrogen atmosphere, and then the mixture was refluxed for 5 hours. Next, the reaction solution was cooled to room temperature, added with toluene and then washed with 1N hydrochloric acid and water. Then, the resulting solution was dried over magnesium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by silica-gel column chromatography with heptane as eluent and then dried under reduced pressure to obtain 34.8 g of 4-propyl-1-(3-chloro-5-fluorophenyl)benzene (S1-3). The yield of the compound (S1-3) from (S1-1) was 97.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH:22]([NH:25][C:26]([NH:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:6][CH2:5][C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[O:2][CH3:1])[CH:16]=[CH:15]2)=[O:27])([CH3:24])[CH3:23]
Reactant: CC(C)N=C=O
Reactant: COc1ccccc1CNc1ccc2cc(N)ccc2n1
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1ccc2cc(NC(=O)NC(C)C)ccc2n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (example 10, step B, 50 mg, 0.179 mmol) was dissolved in 1 mL toluene. Isopropyl isocyanate (15 mg, 0.179 mmol) was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and the crystals were filtered off and washed with dichloromethane. The title compound was obtained as an off-white solid (24 mg, 37%), MS: m/e=365.3 (M+H+).
Reaction SMILES: CCCCCCCCCCCCCCCC(OC[C@@H](OC(CCCCCCCCCCCCCCC)=O)COC(CCC(O)=O)=O)=[O:17].ON1C(=O)CCC1=O.CN(C1C=CC=CN=1)C.[CH:65]1([N:71]=[C:72]=[N:73][CH:74]2[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]2)[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1>C(#N)C>[C:72]([NH:71][CH:65]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]1)([NH:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](COC(=O)CCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 5 h

Procedure:
To a cooled (0 to 5° C.) solution of 1,2-dipalmitoyl-sn-glycero-3-succinate 66.8 mg, N-hydroxy-succinimide 11.5 mg, dimethylaminopyridine (DMAP) 2 mg and acetonitrile 40 mL in a 100 mL round bottom flask was added dropwise to a solution of dicyclohexyl carbodiimide (DCC) 20.6 mg in acetonitrile 10 mL. The resulting mixture was stirred for 5 hours. The solid material which formed during the reaction (dicyclohexylurea) was removed by filtration, and the filtrate was concentrated in vacuo to yield 78 mg of a white product of N-DPGS-succinimide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[CH3:27][NH:28][O:29][CH3:30]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:28]([O:29][CH3:30])[CH3:27])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (50 g, 186 mmol) in DCM (500 mL) at 0° C., was added Oxalyl chloride (30.7 g, 242 mmol) with catalytical amount of DMF (0.5 mL). After stirring for 30 min the reaction mixture was concentrated. To a suspension of N,O-dimethylhydroxylamine hydrochloride (23.5 g, 242 mmol) in DCM (300 mL) at 0° C. was added TEA (51 g, 500 mol). Then a solution of acid chloride in DCM (300 mL) was added slowly. After stirring for 1 h, the reaction mixture was poured into water (200 mL) with vigorous stirring, extracted with DCM (2×200 mL). The organic layers were washed with brine (50 mL), dried over anhydrous MgSO4 and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=20/1 to 5/1) to give the title compound (47 g, yield: 81%); m/z (ES+): 312 [M+H]+.
Reaction SMILES: [CH:1]1([C:5]([F:18])([F:17])[C:6]2[CH:16]=[CH:15][C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Li+].O>O1CCCC1>[CH:1]1([C:5]([F:17])([F:18])[C:6]2[CH:16]=[CH:15][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1ccc(C(F)(F)C2CCC2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1ccc(C(F)(F)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[cyclobutyl(difluoro)methyl]benzoate (synthesized by the method of WO2005/032465, 140 mg, 0.55 mmol) in tetrahydrofuran (5 mL) and methanol (112 μL, 2.76 mmol) was added lithium borohydride (60 mg, 2.75 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours, and then to the reaction solution was added water at 0° C., and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude {4-[cyclobutyl(difluoro)methyl]phenyl}methanol (111 mg) as a colorless oil. The resultant was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:13])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:25]([O:12][CH2:11][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:13])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: O=C(CCO)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
46.0 g (0.21 mole) of 3-(3,4-dichlorophenyl)-3-oxo-1-propanol [prepared as described in step (a) above] were dissolved in 460 ml of dimethylformamide, and 35 ml (0.25 mole) of triethylamine and 38.0 g (0.25 mole) of t-butyldimethylchlorosilane were added to the resulting solution. The mixture was then stirred for 2 hours at 0° C. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 96:4 by volume mixture of hexane and ethyl acetate as the eluent, to give 66.1 g of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[OH:9][CH2:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC(C)(C)C>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:15]2[CH:16]=[C:11]([CH2:10][OH:9])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: OCc1cccc(-c2ncc(Br)cn2)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
750 mg (0.65 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution, kept under nitrogen, of 6.11 g (21.5 mmol) of 5-bromo-2-iodopyrimidine, 3.91 g (25.7 mmol) of 3-(hydroxymethyl)benzeneboronic acid and 9.11 g (42.9 mmol) of tripotassium phosphate trihydrate in 120 ml of dioxane and 14 ml of water, and the mixture is stirred at 90° C. for 18 hours. The reaction mixture is cooled to room temperature, tert-butyl methyl ether and water are added, and the mixture is filtered through kieselguhr. The organic phase of the filtrate is separated off, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.[H-].[Na+].Cl[CH2:26][O:27][CH3:28]>CN(C=O)C>[F:21][C:19]1[CH:18]=[C:15]([CH:14]=[C:13]([C:11]2[CH:10]=[CH:9][C:4]3[N:5]([CH2:26][O:27][CH3:28])[C:6](=[O:8])[O:7][C:2]([CH3:22])([CH3:1])[C:3]=3[CH:12]=2)[CH:20]=1)[C:16]#[N:17]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3]oxazin-6-yl)-5-fluorobenzonitrile (0.150 g, 0.51 mmol) in DMF (5 mL) was treated at rt with sodium hydride (0.061 g, 1.53 mmol). The mixture was stirred for 30 minutes and treated with chloromethyl methylether (0.062 g, 7.7 mmol). Upon completion of the reaction, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3×30 mL), dried over MgSO4, and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 3-fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile as a white solid (0.11 g, 65%): mp 169-171° C.; 1H-NMR (DMSO-d6) δ8.17 (bs, 1H), 8.03 (dt, 1H, J=10.4, 2.13 Hz), 7.85-7.77 (m, 3H), 7.31 (d, 1H, J=8.49 Hz), 5.33 (s, 2H), 3.35 (s, 3H), 1.7 (s, 6H); MS (APCI) m/z 341 ([M+H]+, 50%); Anal. Calc. For C19H17FN2O3: C, 65.32; H, 5.19; N, 8.02. Found: C, 64.92; H, 4.96; N, 7.73.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH:2]=[CH2:3].[CH:8](=[O:12])/[CH:9]=[CH:10]/[CH3:11].[CH3:13][CH2:14]O>Cl>[CH2:1]([N:4]1[CH:8]([O:12][CH2:13][CH3:14])[CH2:9][CH:10]([CH3:11])[NH:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: CCO
Reactant: C=CCNC(N)=O
Reactant: C/C=C/C=O
Agent: Cl
Product: C=CCN1C(=O)NC(C)CC1OCC

Procedure:
Following a related procedure, [G. Zigeuner, W. Rauter, Monatshefte fur Chemie, 96, 1950 (1965)], allylurea (24.5 g, 0.25 mol), crotonaldehyde (19.67 g, 0.29 mol) and 37% HCl (12 drops) were mixed with 140 g of EtOH at room temperature for 3d, during which all of the crotonaldehyde was consumed. The major product had a retention time near that of allylurea. The dark mixture was neutralized with Na2CO3, filtered and concentrated at reduced pressure. Part of the crude mixture was extracted with cyclohexane, decolorized with charcoal, filtered and concentrated to give a light yellow oil which produced white crystals (mp 72°-76° C.) on standing. A separate sample was submitted to kugelrohr distillation (0.05 torr) to give further products: E at 90° C., F at 145°-155° C. (solid, mp 72°-76° C.) and G at 145°-155° C. (liquid).
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:9][CH2:10][C@@H:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)[OH:12].N1C=CN=C1>CN(C=O)C>[Br:9][CH2:10][C@H:11]([O:12][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CBr)c1ccc2c(c1)COC(C)(C)O2
Temperature: 15 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Triethylsilyl chloride (205 g) was added dropwise to a stirred mixture of (1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (350 g) and imidazole (108.5 g) in DMF (875 ml) at 5° C. Upon complete addition the mixture was warmed to 15° C. and stirred, at this temperature for 1 h. N-hexane (3500 ml) was then added to the mixture which was washed with water (3×1750 ml). The organic layer was dried over anhydrous MgSO4 before being filtered and concentrated under reduced pressure to give the title compound (488.6 g) as an oil, LC RT=7.97 min, δ (DMSO-d6) 7.18 (1H, d, J 8.2 Hz), 7.10 (1H, s), 6.75 (1H, d, J 8.2 Hz), 4.83 (1H, m), 4.78 (2H, d, J 6.9 Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H, t, J 8.1 Hz), 0.51 (6H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:15][OH:16])[CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].C(N(CC)CC)C.[P:25](Cl)(Cl)([Cl:27])=[O:26].O>ClCCl>[Cl:27][P:25]1(=[O:26])[O:4][CH:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[C:2]([CH3:17])([CH3:1])[CH2:15][O:16]1
Reactant: CC(C)(CO)C(O)c1ccc2ccccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C)COP(=O)(Cl)OC1c1ccc2ccccc2c1
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 82.1 %

Procedure:
2,2-Dimethyl-1-(2-naphthyl)-1,3-propanediol (34.86 g, (0.151 mol) and triethylamine (42.9 g, 0.424 mol) were dissolved in dichloromethane (200 ml). Phosphorus oxychloride (24.3 g, 0.158 mol) dissolved in dichloromethane (50 ml) was added dropwise to the above solution under cooling to 1 to 4° C. with stirring for 1 hr 40 min. The solution was stirred at the same temperature for 1 hr, and water (60 ml) was added thereto to partition the solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained dark brown oil was added ether (50 ml) and the mixture was stirred thoroughly and left at room temperature overnight. The solidified reaction product was pulverized, filtered, washed with ether and dried to give the title compound (38.62 g, yield 82.1%).