Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH2:16][CH:17]1[C:21](=[O:22])OC(=O)[N:18]1[CH3:24].O.CC(C)=O>C(Cl)Cl>[ClH:1].[CH3:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:15][CH2:16][CH:17]([NH:18][CH3:24])[C:21]2=[O:22]
Reactant: [Cl-]
Reactant: COc1cccc(CCC2C(=O)OC(=O)N2C)c1OC
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CNC1CCc2c(ccc(OC)c2OC)C1=O
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
12.5 g of anhydrous aluminium chloride (0.094 mole) in 200 ml of methylene chloride are placed into a 3 l round-bottomed flask, under nitrogen atmosphere, cooling to 0° C., then 12.5 g of 4-[2-(2,3-Dimethoxyphenyl)-ethyl]-N-methyl -2,5-oxazolidindione dissolved in 200 ml of methylene chloride are added in about 10 minutes, keeping T<10° C. The mixture is stirred for 30 minutes at T<10° C., then for 1 hour a room temperature. The mixture is cooled again at 0° C. and 200 ml of water are dropped therein, keeping T<20° C., then the mixture is stirred at room temperature for about 1 hour and the organic phase is separated and extracted with water (3×400 ml). The combined aqueous phases are slowly alkalinized with 400 ml of a 20% KHCO3 solution and extracted with 3×400 ml of chloroform. The organic phase is then dried over sodium sulphate, filtered, markedly acidified with methanolic HCl (1M) and evaporated to dryness to obtain a waxy compound, which is taken up into 150 ml of acetone a 50° C., stirred for one hour under stirring and left to stand overnight, then is filtered and dried under vacuum at room temperature. Yield: 8.2 g, 67% (moles); TLC: methylene chloride/methanol, 90/10; Rf=0.35; M.p.=208°-209° C.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3]CC[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCCCCCCC/C=C\CCCCC[CH2:30][CH2:31][C:32]([O:34][CH2:35]C(O)[C@H]1OC[C@H](O)[C@H]1O)=[O:33]>C(OCC)(=O)C>[CH2:11]([CH:10]([CH2:9][CH2:8][CH2:7][CH3:6])[CH2:35][O:34][C:32](=[O:33])[CH:31]=[CH2:30])[CH3:12].[C:1]([OH:14])(=[O:13])[CH:2]=[CH2:3]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Product: C=CC(=O)O
Product: C=CC(=O)OCC(CC)CCCC

Procedure:
With 20 parts of lauric acid, 4 parts of polyoxyethylene sorbitan monooleate and 3 parts of sorbitan monooleate were mixed for dissolution 46 parts (as the solid portion) of a copolymer solution (C) obtained by conventional polymerization of 93 parts of acrylic acid 2-ethylhexyl ester and 7 parts of acrylic acid in ethyl acetate as the solvent to give a lipophilic phase.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[BrH:20].BrBr>C(O)(=O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([Br:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: Br
Reactant: NS(=O)(=O)c1ccc(CC(=O)c2ccccc2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(C(Br)C(=O)c2ccccc2)cc1
Yield: 80 %

Procedure:
To a mixture of 14.4 g (52 mmol) of 2-(4-aminosulfonylphenyl)-1-phenylethanone in 240 mL of glacial acetic acid stirred under nitrogen, a solution of 24 mL of hydrobromic acid in glacial acetic acid (33%) was added. To the reaction mixture was added slowly 8.4 g (52 mmol) of bromine. It was stirred at room temperature until complete loss of the colour. After concentration, the resulting residue was dissolved in ethyl acetate (500 mL). The organic layer was washed twice with 5% aqueous sodium bicarbonate solution (2×350 mL) and with brine (350 mL). The organic layer was dried, filtered and concentrated in vacuum. The residue was swished in hexane to give 14.9 g (80%) of the desired solid as a white powdered solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3Br)[C:12](=[O:22])[NH:11][C:10](=[O:23])[CH:9]=2)[CH2:3]1.[I:24]C1C=CC=CC=1CCl>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[I:24])[C:12](=[O:22])[NH:11][C:10](=[O:23])[CH:9]=2)[CH2:3]1
Reactant: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2Br)C1
Reactant: ClCc1ccccc1I
Product: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2I)C1

Procedure:
The title compound was prepared by the procedure described in the preparation of compound 8, except that 2-iodobenzyl chloride was used as the benzylating reagent. 1H-NMR (400 MHz, CDCl3—CD3OD 10:1): δ 7.76 (d, J=7.6 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 6.89 (t, J=7.2 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 5.26 (s, 1H), 4.79-4.92 (ABq, J=34.1, 6.7.0 Hz, 2H), 3.27 (m, 1H), 3.13 (s, 1H), 2.85 (d, J=11.6 Hz, 1H), 2.70 (m, 1H), 2.41 (m, 1H), 2.02 (m, 1H), 1.60 (m, 1H), 1.45 (m, 2H). MS (ES) [m+H] calc'd for C16H20IN4O2, 427.1; found, 427.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.[I:10]I.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:10])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a solution of 4-chlorophenol in THF (75 mL), and H2O (75 mL) was added a mixture of crushed iodine (78.7 mmol, 20 g) and sodium bicarbonate (78.7 mmol, 6.6 g). The reaction mixture was stirred at room temperature overnight, then quenched with sufficient 5% sodium thiosulfate solution to turn the color of the reaction mixture from deep violet to light yellow and extracted with ether (2×200 mL). The ether layer was collected, washed with H2O, and the washed ether layer was dried, filtered and the filtrate was evaporated to a crude product, which was purified by distillation to obtain 4-chloro-2-iodo phenol (7%,1.3 g); mp 79° C.-82° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C@:20]3([CH3:31])[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[N:23]([CH3:29])[C:22]([NH2:30])=[N:21]3)[CH:14]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1.CO.O>[NH2:30][C:22]1[N:23]([CH3:29])[C:24](=[O:28])[C:25]([CH3:26])([CH3:27])[C@:20]([C:15]2[CH:14]=[C:13]([NH:12][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[O:10][CH3:11])[C:3]([OH:32])=[O:2])[CH:18]=[CH:17][C:16]=2[F:19])([CH3:31])[N:21]=1
Reactant: COC(=O)c1ccc(OC)c(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-methyl-3-(3-(2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydropyrimidin-4-yl)-4-fluorophenylamino)-4-methoxybenzoate (example 122, 0.05 mmol) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH (1N, 0.1 mmole) and the reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo and the residue diluted with aqueous HCl (0.5N) until pH=5 and extracted with dichloromethane. The organic phase was dried, evaporated and the residue triturated with Et2O to give the title compound as a white solid. MS (ESI): m/z=429.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][OH:7])(=[O:4])=[O:3].[C:8](=[O:11])([O-])[O-].[Na+].[Na+].N1C=CC=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:8]([O:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:11])[CH:15]=[CH2:16]
Reactant: c1ccncc1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)CCO
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fifty grams 2-(methylsulfonyl)ethanol, 500 mg BHT, 25.61 g sodium carbonate, 0.5 mL pyridine, and 200 mL toluene were combined in a dry 500 mL 3-neck round bottom flask. The flask was outfitted with a mechanical stirrer, a disposable pipet to act as a sparge tube, and addition funnel. Oxygen was bubbled into the solution via the pipet for 30 minutes, and then slowed to a bubble every few seconds. The flask was cooled in an ice-water bath and the pipet pulled out to bring the tip above the solution surface. Fifty ml toluene and 40.1 g acryloyl chloride was added to the addition funnel. The acryloyl chloride solution was added dropwise over 90 minutes. The reaction was stirred at room temperature for two hours, and then heated to 50° C. for one hour. IR(neat): 3107, 3013, 2964, 2933, 1725, 1635, 1461, 1408, 1295, 1186, 1130, 1073, 984, 965, 809, 665, 482, 451 cm−1. 1H NMR (300 Mhz, CDCl3): δ66.40 (d), 6.10 (dd), 5.90 (d), 4.55 (t), 3.35 (t), 2.95 (s). 13C NMR (75.6 Mhz, CDCl3): δ165, 132, 127, 58, 53, 43.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+]>Cl>[NH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 22 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
5-Chloro-4-fluoro-3-nitrotrifluoromethylbenzene (50 g) was added to a cooled (5° C.) solution of stannous chloride (140 g) in concentrated aqueous hydrochloric acid (187 ml). After stirring for several hours at the ambient temperature (about 22° C.), the reaction mixture was stood overnight. After basification by the addition of sodium hydroxide, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent removed by evaporation under reduced pressure. The residual yellow oil was kugelrohr distilled under reduced pressure to give 3-amino-5-chloro-4-fluorotrifluoromethylbenzene (32 g): boiling point 105° C./11 mm Hg;
Reaction SMILES: [Li].Br[C:3]1(Br)[CH2:8][CH:7]=[CH:6][CH:5]=[C:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:16](Cl)(Cl)([Cl:18])[Cl:17]>CCCCC.CCOCC>[Cl:17][Si:16]1([Cl:18])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[C:3]1=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: BrC1(Br)CC=CC=C1c1ccccc1
Agent: [Li]
Solvent: CCCCC
Solvent: CCOCC
Product: Cl[Si]1(Cl)c2ccccc2-c2ccccc21

Procedure:
Lithium wire (3.33 g, 0.08 mol) was washed with pentane, carefully cut into small pieces, and suspended in 150 mL of Et2O. While stirring, 2,2-dibromobiphenyl (25 g, 0.08 mol) in 100 mL of diethyl ether was added dropwise over 1 hour and the contents were allowed to stir for 10 hours. The mixture was filtered through a frit to remove any unreacted Li and LiBr. The filtrate was loaded into an addition funnel and slowly dropped into a solution containing SiCl4 (50 g, 0.08 mol) in 200 mL of Et2O. After addition, the contents were stirred at room temperature for 5 hours. The solvent was removed in vacuo and 300 mL of pentane was added. The solution was filtered to remove LiCl and the solvents were again removed in vacuo. The solids were then loaded into a sublimator and allowed to sublime at 150° C. under full vacuum. Yield was 10.0 g (51%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)[CH2:11][CH2:10]1.BrB(C)C>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1(c2ccccc2OC)CC1
Agent: CB(C)Br
Solvent: ClCCl
Product: Oc1ccccc1C1(c2ccccc2O)CC1

Procedure:
1,1-Bis(2-methoxyphenyl)cyclopropane (10.0 g, 0.039 mole) was combined with 60 ml of dichloromethane and the mixture was cooled in an ice bath and then treated with 10.0 ml of bromodimethylborane with cooling and stirring. The starting material was consumed in less than 1 hour as determined by gas-liquid chromatography. The mixture was then diluted with 500 ml of ether and the resulting solution was extracted twice with water and then with water saturated with ammonium chloride, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 9.0 g (101 percent of theory) of the title compound as a brownish-black solid; m.p., 158°-160° C. This eluted as one clean peak in gas-liquid chromatography and had a proton NMR spectrum consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1.Cl.[C@H:37]12[CH2:43][C@H:40]([NH:41][CH2:42]1)[CH2:39][O:38]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:41]3[CH2:42][C@@H:37]4[CH2:43][C@H:40]3[CH2:39][O:38]4)=[O:30])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)N1C[C@@H]2C[C@H]1CO2
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a DCM (1.0 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol) was added CDI (51 mg, 0.32 mmol) at ambient temperature in one portion. After stirring 90 minutes, (1S,45)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.32 mmol) was added in one portion, followed by DIEA (0.083 mL, 0.48 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a pale-yellowish powder (60 mg, 86% yield). MS (apci) m/z=441.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([OH:3])=[O:2].C(N1C=CN=C1)(N1[CH:19]=[CH:18]N=C1)=O.CCO.[H-].[Na+]>C1COCC1>[CH2:18]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)=[O:3])[CH3:19]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]ccc2c1
Reaction time: 2 h
Yield: 127.7 %

Procedure:
Combine 5-carboxyindole (4.8 g, 29.8 mmol) in 150 mL THF and carbonyldiimidazole (9.7 g, 59.6 mmol) and stir overnight at ambient temperature. Treat the reaction mixture with 25 mL EtOH and 1.2 g (29.8 mmol) of a 60% oil dispersion of NaH and stir for 2 hours. Concentration under vacuum gives a residue. Partition the residue between 150 mL EtOAc and 100 mL brine. Separate the layers, dry the organic layer over MgSO4, filter, and concentrated to an oil. Chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give 7.2 g of an oil. Crystallize the oil from toluene gives the title compound: Analysis for C11H11NO2: calcd: C, 69.83; H, 5.86; N, 7.40; found: C, 69.82; H, 5.90; N, 7.38; ISMS 190 (M+1).
Reaction SMILES: [F-:1].[K+].[F:3][C:4]([F:15])([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([F:7])=O.S([O:21][CH3:22])(OC)(=O)=O>CN(C)C=O>[C:5]([O:21][CH3:22])([C:4]([C:8]([C:9]([F:12])([F:11])[F:10])([F:14])[F:13])([F:15])[F:3])([F:1])[F:7]
Reactant: [F-]
Reactant: COS(=O)(=O)OC
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 134.3 %

Procedure:
The reaction was carried out in the same equipment and in a similar manner to the procedure of Example 7 above, but using the following materials: spray-dried potassium fluoride (6 kg, 103.1 mole), anhydrous dimethyl formamide (25.1 kg), perfluorobutyryl fluoride (58% purity, 25.1 kg, 67.3 mole), and dimethyl sulfate (12.0 kg, 95.1 mole). 22.6 kg of product was obtained, which was 63.2% C4F9COH3 (b.=58-60° C.). The product identity was confirmed by GCMS and by 1H and 19F NMR.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])[N:13]=[C:12]([NH:22][CH3:23])[N:11]=2)[CH:7]=[C:6]([O:24][CH3:25])[C:3]=1[C:4]#[N:5].CCO.CCN(C(C)C)C(C)C.[NH2:38][NH2:39]>O>[CH3:23][NH:22][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:38][NH:39]3)=[C:6]([O:24][CH3:25])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH3:21])[N:13]=1
Reactant: NN
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCC[C@H]2C)n1
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2CCC[C@H]2C)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
Into a sealable tube, 2-fluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile (100 mg, 0.293 mmol), EtOH (5 mL), Hunig's base (0.05 mL, 0.29 mmol), and hydrazine anhydrous (0.055 mL, 1.76 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. After overnight, there was yellow suspension as well as some black colored solid formed. LCMS showed mainly product. The reaction was cooled to room temperature. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was purified further by flash column chromatography. The fractions with product were combined, and the solvent was removed under reduced pressure to afford the title compound (23.7 mg) as a white solid. LC-MS (ES) m/z=354 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 1.30 (d, J=6.3 Hz, 3H), 1.75-2.18 (m, 4H), 3.02 (s, 3H), 3.50-3.63 (m, 2H), 4.02 (s, 3H), 4.34 (m, 1H), 4.50 (m, 2H), 6.07 (s, 1H), 6.93 (s, 1H), 7.44 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[C:10]([Cu])#[N:11]>CN(C=O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)ccc1C#N
Yield: 60 %

Procedure:
A mixture of 2-bromo-5-fluorotoluene (2) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 3 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=1.[O-:13][CH2:14]C.[Na+]>C1COCC1>[Cl:12][C:4]1[CH:3]=[C:2]([O:13][CH3:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a mixture of 500 mg of methyl 4,6-dichloronicotinate and 5.0 mL of THF was added dropwise 157 mg of sodium ethoxide (28 wt % of methanol solution) under cooling in an ice bath. It was warmed to room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography to obtain 162 mg of methyl 6-chloro-4-methoxynicotinate as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:3].[Br:18][CH2:19][CH2:20][CH2:21][Cl:22].CO>COC(C)(C)C>[Br-:18].[Cl:22][CH2:21][CH2:20][CH2:19][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:1])[CH3:3]
Reactant: CCCCCCCCCCCCCCN(C)C
Reactant: ClCCCBr
Solvent: COC(C)(C)C
Solvent: CO
Product: CCCCCCCCCCCCCC[N+](C)(C)CCCCl
Product: [Br-]
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A one-liter, 3-necked, round-bottomed flask equipped with air condensers and a magnetic stirring plate was charged with N,N-dimethyltetradecylamine (311.59 grams, 1.29 moles), 1-bromo-3-chloropropane (203.09 grams, 1.29 moles) and methanol (250 mL). Reaction was maintained at 65° C. for 24 hours. Methanol was removed by rotary evaporation under reduced pressure to yield a sludge. To the sludge was added methyl-tert-butylether (500 mL) causing a white solid to slowly form The mixture was stirred for one-half hour and white, paste-like particulate was collected by vacuum filtration. The solid was placed in a vacuum oven at 35° C. for 24 hours. Yield 420 grams (1.05 molest 82%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)O[C:4]=2[CH:3]=1.[ClH:17].C([O:22][C:23]([N:25]1CCC(N)C1)=O)(C)(C)C>>[Cl:17][C:16]1[CH:15]=[C:5]2[C:4]([C:23](=[O:22])[NH:25][C:7]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)=[N:6]2)=[CH:3][CH:2]=1
Reactant: Clc1ccc2nc(NC3CCNC3)oc2c1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Product: O=c1[nH]c(NC2CCNC2)nc2cc(Cl)ccc12

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride (example 1, step 1) the title compound was prepared from 2,7-Dichloro-4(3H)-quinazoline (Bioorganic & Medicinal Chemistry 2003, 11, 2439-2444) and 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available) and subsequent cleavage of the tert-butyl oxy carbonyl protecting group under acidic conditions. (MH+) 265.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:11]N1C(=O)CCC1=O.O.C(Cl)Cl>C(O)(=O)C>[Br:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)ccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(Cl)cc1Cl
Yield: 99.5 %

Procedure:
1 g of 5-bromo 2-chloro anisole and 0.66 g of N-chloro succinimide in 10 ml of acetic acid is heated at 90° C. for 20 hours. The reaction medium is poured into water, extraction is carried out with methylene chloride. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulphate and evaporated under reduced pressure. 1.15 g of sought product is obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[C:5]#[N:6].[C:11]([N:18]1C=CN=C1)(N1C=CN=C1)=[O:12].C1C[O:26]CC1>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[NH:18][C:11](=[O:12])[O:26][C:2]=2[CH:3]=1)#[N:6]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: N#Cc1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-amino-4-hydroxybenzonitrile (8.2 g, 61 mmol) in THF (200 mL) was added 1,1′-carbonyldiimidazole (11.6 g, 72 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The reaction was then quenched with 1N HCl (50 mL), and the mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated to give 6-cyanobenzoxazolinone (9.8 g, 100%). 1H NMR (CDCl3) δ 7.49 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.15 (d, J=0.9 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=1[OH:44]>C1(C)C=CC=CC=1.CN(C=O)C>[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][C:23]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=2[OH:44])=[O:25])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)NC(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a solution of aminodiphenylmethane (200 mg, 1.09 mmol) in toluene, triethylamine (0.18 ml, 1.11 mmol) and triphosgene (129.4 mg, 0.44 were added. The reaction mixture was stirred at 80° C. for 3 hours. It was cooled to room temperature and all solvent was evaporated. Then 2-amino5-nitrophenol (168 mg, 1.09 mmol) in DMF (2 mL) was added. The reaction mixture was stirred at 80° C. for 16 hours, then cooled to room temperature. Chromatography of the resulting liquid on silica gel (hexane:ethyl acetate; 1:1) gave product (210 mg, 53%). m.p: 237.4-237.9° C.; EI-MS m/z 364 (M+H)+.