Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[C:12]([O:23][CH3:24])=[N:13][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:15][CH:16]=1.[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[C:12]([O:23][CH3:24])=[N:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1nc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A mixture of ethyl 3-[N′-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetate (2.90 g, 7.10 mmol), 0.25 N NaOH (56.8 ml, 14.2 mmol), and THF (50 ml) was stirred for 5 h. The mixture was neutralized with 1 N HCl and the resulting precipitate was collected by filtration. The residue was recrystallized from CHCl3-MeOH-hexane to give 3-[N′-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetic acid (2.40 g, 89%) as a colorless crystalline powder. mp 195–197° C.; 1H-NMR (DMSO-d6) δ 3.59 (s, 2 H), 3.95 (s, 3 H), 6.88 (d, J=8.1 Hz, 1 H), 6.97–7.01 (m, 1 H), 7.33 (t, J=7.3 Hz, 1H), 7.61 (d, J=8.1 Hz, 1 H), 7.95–7.97 (m, 1 H), 8.29 (d, J=8.1 Hz, 1H), 8.81 (s, 1 H), 9.10 (s, 1 H), 12.35 (br s, 1 H); Anal. Calcd for C15H14BrN3O4: C, 47.39; H, 3.71; N, 11.05. Found: C, 47.27; H, 3.59; N, 10.86.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N+:4]([O-:8])=[C:5]([SH:7])[CH:6]=1.S([O-])([O-])(=O)=O.[Zn+2:14].[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Zn+2].C([O-])(=O)C>O>[CH:1]1[CH:2]=[CH:3][N:4]([O-:8])[C:5](=[S:7])[CH:6]=1.[CH:1]1[CH:2]=[CH:3][N:4]([O-:8])[C:5](=[S:7])[CH:6]=1.[Zn+2:14]
Reactant: [O-][n+]1ccccc1S
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: [O-]n1ccccc1=S

Procedure:
A method for producing submicron-sized particles of zinc pyrithione, comprising reacting a pyrithione or a water-soluble salt of pyrithione and a water-soluble zinc salt selected from the group consisting of zinc sulfate, zinc chloride, zinc acetate, and combinations thereof, in a turbulent flow reactor generating pulverizing forces, said turbulent flow reactor maintained at a pressure of from about 18,000 psi to about 23,000 psi and a temperature of from about 0° C. to about 23° C., said reaction producing submicron-sized particles of zinc pyrithione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:14][N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc(F)c(Cl)c1
Yield: 66.9 %

Procedure:
Using the same reaction procedure and workup as described in Example 1, 3-chloro-4-fluoro-benzaldehyde (2 g, 12.6135 mmol) in ethanol (63 mL) was reacted with nitro methane (0.68 mL, 12.6135 mmol), 10N NaOH solution (529.7 mL, 13.2441 mmol) at 0° C. for 1 hr to afford 1.7 g of the product (67.05% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:10](=[O:12])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:14])[CH3:13])[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionic acid (10 g) in tetrahydrofuran (20 mL) were added 1-(benzyloxycarbonyl)piperazine (16.3 g), 1-hydroxybenzotriazole (8.02 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.4 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in a mixed solvent of n-hexane and ethyl acetate (1/1) (40 mL) at 60° C. with heating, and the solution was stirred at room temperature overnight. To the mixture was added the same solvent (30 mL), and the mixture was further stirred overnight. The precipitated crystals were collected by filtration, and washed with the same solvent and dried under reduced pressure to give 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine (13.5 g). To a solution of the obtained 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine (5 g) in tetrahydrofuran (30 mL) was added hydrochloric acid (4 mol/L 1,4-dioxane solution, 40 mL), and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (3.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][NH:42][CH3:43])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:42]([CH2:41][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]4)=[CH:40][CH:39]=3)[CH3:43])=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine (35 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3. A portion of the fraction collected was further purified using prep method D to afford the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])[CH3:2]
Reactant: CCSc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCSc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a mixture of 2-ethylsulfanylbenzoic acid (9.11 g), chloroform (100 ml), and oxalyl chloride (9.72 g), DMF (2 drops) was added, and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give 10.03 g of 2-ethylsulfanylbenzoic acid chloride (Compound (1H)-241).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([CH:9]([CH:15]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)C(OCC)=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(OCC)C>CS(C)=O.O>[CH:27]1[C:28]2[CH:15]([CH2:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=3)=[O:8])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:22][C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C#N)cc1)C1c2ccccc2Sc2ccccc21
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(=O)CC2c3ccccc3Sc3ccccc32)cc1

Procedure:
A solution of ethyl 2-(4-cyanobenzoyl)-2-(9H-thioxanthen-9-yl)acetate (5 g, 12.0 mmol) in dimethylsulphoxide (50 ml) and water (0.45 ml) was reacted as described in Example 1 (iv) and the product was isolated in a similar manner except the extraction used diethyl ether to give 4-[2-(9H-thioxanthen-9-yl)acetyl]benzonitrile as a yellow oil which solidified on standing.
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:17]([C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[CH3:18]>>[CH2:17]([C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:1](=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[CH3:18]
Reactant: CCc1ccccc1N
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Product: CCc1ccccc1NC(=O)c1ccccc1O

Procedure:
The 2′-ethyl-salicylanilide was prepared by condensing phenyl salicylate with 2-ethylaniline then purified as described in Example 2a. The ligand mixture was then prepared from 2′-ethyl-salicylanilide and 1,1′-bi-2-naphthol using the procedure described in Example 2a. 31P NMR (121.77 MHz): several peaks between 117.1-118.8 ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=[O:22].[CH2:27](N)[CH2:28][NH2:29].O.C(OCC)(=O)C>C1COCC1.CCCCCC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]2[NH:29][CH2:28][CH2:27][N:20]=2)[C:3]=1[S:21]([C:23]([F:25])([F:24])[F:26])=[O:22]
Reactant: NCCN
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1c(S(=O)C(F)(F)F)c(C2=NCCN2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinyl-pyrazole (0.81 g, 1.85 mmol) was dissolved in 8 ml of THF, and then ethylenediamine (0.40 ml, 5.98 mmol) was added. The mixture was stirred at room temperature for 1 hour, heated to 50° C. and then stirred for 24 hours. Then, ethylenediamine (0.40 ml, 5.98 mmol) and THF (3 ml) were further added, followed by stirring for 14 hours. After the completion of the reaction, 20 ml of water was added and THF was distilled off and, further, 10 ml of water and 20 ml of an aqueous saturated sodium chloride solution were added. The mixture was extracted twice with 40 ml of ethyl acetate and the ethyl acetate layer was washed twice with 30 ml of an aqueous saturated sodium chloride solution. The resultant was dried over anhydrous magnesium sulfate and then concentrated to obtain a yellow amorphous. The amorphous was subjected to silica gel column chromatography [eluent: mixed solvent of ethyl acetate and hexane (volume ratio=1:2)] to obtain 0.34 g (0.71 mmol) of the title compound as a pale yellow amorphous. Yield 38%.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([CH2:15][C:16](=O)[C:17](O)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[OH:18][C:17]1[C:16]([CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:7]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: CCO
Product: Oc1nc2ccccc2nc1Cc1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
The mixture of 1,2-phenylenediamine (8.64 g), phenylpyruvic acid (13.1 g), ethanol (100 ml) and 2N hydrochloric acid (100 ml) was stirred for 1.5 hours at 50° C. The reaction mixture was cooled to room temperature. The precipitated crystals were obtained by filtration. The crystals were washed with ethanol and dried to give the title compound (15.05 g) having the following physical data.
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[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH3:32])[CH:28]=3)[NH:23][C:22]2=[O:33])[CH2:17][CH2:16]1.[CH2:34](Br)[CH:35]=[CH2:36]>>[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[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH3:32])[CH:28]=3)[N:23]([CH2:36][CH:35]=[CH2:34])[C:22]2=[O:33])[CH2:19][CH2:20]1
Reactant: C=CCBr
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(C)cc5c4=O)CC3)c2cc1OC
Product: C=CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc(C)ccc21
Yield: 58 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.67 mmol) of Compound 22 was used in place of Compound 24 and allyl bromide was used in place of methyl iodide. As a result, 187.8 mg (yield: 58%) of Compound 53 was obtained as white crystals.
Reaction SMILES: COCCOC.Cl[C:8]1[S:12][N:11]=[C:10]([S:13][CH3:14])[N:9]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][S:13][C:10]1[N:9]=[C:8]([C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:15])[S:12][N:11]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CSc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nsc(-c2ccccc2Cl)n1
Yield: 50.8 %

Procedure:
To 25 ml of 1,2-dimethoxyethane were added 2.0 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 2.25 g of 3-chlorophenylboronic acid, 694 mg of tetrakistriphenylphosphine palladium and about 25 ml of a 2 M aqueous sodium carbonate solution, and the mixture was heated under reflux for 3 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into water, and the mixture was extracted with t-butyl methyl ether. The organic layer was dried with anhydrous sodium sulfate, and the residue obtained by concentration was subjected to silica gel column chromatography to obtain 1.48 g of 3-methylthio-5-(2-chlorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: C(O)C.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].[Br:24][C:25]1[CH:30]=[C:29]([F:31])[C:28](I)=[C:27]([F:33])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CCOCC.O.C1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([C:18]2[CH:17]=[CH:16][C:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)=[CH:20][CH:19]=2)=[C:27]([F:33])[CH:26]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
Reactant: Fc1cc(Br)cc(F)c1I
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: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3c(F)cc(Br)cc3F)cc2)CC1

Procedure:
First, 50 ml of ethanol containing 5.61 g of 4-(trans-4-pentylcyclohexyl)phenylboronic acid dissolved therein, 50 ml of benzene containing 5.0 g of 4-bromo-2,6-difluoro-1-iodobenzene dissolved therein, 15.7 ml of a sodium carbonate aqueous solution with a concentration of 2.0 mol/l, and 0.45 g of tetrakis(triphenylphosphine)palladium(0) were put in an argon-replaced 200 ml flask, and stirred under reflux for 48 hours. After the reaction, water and ether were added to the reaction solution for extraction. The resultant ether layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:hexane) and recrystallized from acetone, to obtain 2.58 g (Y: 39.1%) of 4-bromo-2,6-difluoro-4′-(trans-4-pentylcyclohexyl)biphenyl. The purity of the resultant compound was 100.0% as measured by GC. (5-b) Synthesis of polymerizable compound 2,6-difluoro-4′-(trans-4-pentylcyclohexyl)-4-vinylbiphenyl represented by formula (E) above
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([F:35])[CH:31]=2)[N:26]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:17]([CH:18]3[CH2:23][CH2:22][N:21]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([F:35])[CH:31]=5)[N:26]=4)[CH2:20][CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CNC(=O)c1ccc(-c2nccnc2C2CCN(c3ccc4cc(F)ccc4n3)CC2)cc1F
Temperature: 100 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
To a solution of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide (155 mg, 0.493 mmol, prepared according to Step 2 of Example 1), 2-chloro-6-fluoroquinoline (108 mg, 0.595 mmol, Combi-blocks), and DMSO (2 mL) was added potassium carbonate (240 mg, 1.737 mmol). The solution was stirred at 100° C. After 72 h, the reaction was allowed to cool to room temperature and diluted with water (50 mL). After stirring for 30 min, the solution was filtered and the filtered solid adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0-80% EtOAc in hexane, to provide a light yellow solid, which contained residual DMSO as measure by NMR. The solids were redissolved in diethyl ether and washed with water, brine, and concentrated in vacuo to give 2-fluoro-4-(3-(1-(6-fluoroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-N-methylbenzamide (90 mg, 0.196 mmol, 39.7% yield), as a light yellow solid. m/z=460 (M+1). 1H NMR (300 MHz, CDCl3) δ ppm 8.55 (d, J=2.48 Hz, 1H), 8.49 (d, J=2.48 Hz, 1H), 8.26 (t, J=8.04 Hz, 1H), 7.82 (d, J=9.21 Hz, 1H), 7.65 (dd, J=5.26, 9.06 Hz, 1H), 7.44 (dd, J=1.61, 8.04 Hz, 1H), 7.36 (dd, J=1.61, 12.42 Hz, 1H), 7.28-7.32 (m, 1H), 7.22 (dd, J=2.92, 8.92 Hz, 1H), 7.04 (d, J=9.21 Hz, 1H), 6.77 (br. s., 1H), 4.64 (d, J=13.45 Hz, 2H), 3.14-3.31 (m, 1H), 3.03-3.14 (m, 3H), 2.81-3.02 (m, 2H), 2.05-2.21 (m, 2H), 1.82 (d, J=11.69 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]([N:10]([CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[N:29]#[C:30]Br>C(O)C>[NH2:29][C:30]1[N:5]([CH2:6][CH2:7][C:8]([N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:17])=[O:9])[CH2:4][C:3]2[C:2](=[CH:21][CH:20]=[C:19]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=2)[N:1]=1
Reactant: N#CBr
Reactant: CN(C(=O)CCNCc1cc(Oc2ccccc2)ccc1N)c1ccccc1
Solvent: CCO
Product: CN(C(=O)CCN1Cc2cc(Oc3ccccc3)ccc2N=C1N)C1CCCCC1
Reaction time: 3 h

Procedure:
A solution of 3-(2-amino-5-phenoxy-benzylamino)-N-methyl-N-phenyl-propionamide (diamine) (1.4 g, 0.0037 mol) and cyanogen bromide (0.58 g, 0.0055 mol) in 70 mL of ethanol was refluxed for 3 h. The solvent was evaporated to yield a residue, which was crystallized from EtOAc (100 mL). The resulting precipitate was dissolved in ethanol and stirred for 3 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried to yield the title product, pure 3-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]=[CH:9][CH2:10][CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1>CO>[CH:1]1([CH2:7][CH:8]=[CH:9][CH2:10][C@H:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(CC=CCC1CCCCC1)C(=O)O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CO
Product: CC(C)[C@@H](CC=CCC1CCCCC1)C(=O)O

Procedure:
154.65 g (0.65 mol) of racemic 6-cyclohexyl-2-isopropyl-4-hexenoic acid and 210.5 g (0.65 mol) of anhydrous quinine are dissolved in 1 liter of methanol. The mixture is concentrated by evaporation and the residue is recrystallised from ether/hexane. The crystallisate is filtered with suction and thoroughly washed with cold hexane. The salt is treated with 1N HCl and the acid is extracted with ether. Concentration by evaporation yields 6-cyclohexyl-2(R)-isopropyl-4-hexenoic acid of 90% ee. If the quinine salt is recrystallised a second time from ether/hexane before the treatment with HCl, the (R)-acid obtainable therefrom has a purity of more than 95% ee.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)(C)C>[C:1]1([C:7]2[N:16]=[C:15]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH2:25][CH2:26]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Solvent: CC(C)O
Product: c1ccc(-c2nc(N3CCN(c4ccccn4)CC3)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 9.6 g (0.04 mole) of 2-phenyl-4-chloroquinazoline, 6.4 g. (0.04 mole) of 1-(2-pyridyl) piperazine and 250 ml of isopropanol was refluxed for 4 hrs. The resulting reaction mixture was filtered after cooling to room temperature. The crystalline solid was dissolved in 400 ml of 3 N hydrochloric acid and the aqueous acidic liquid was washed with ether. The aqueous layer was adjusted to pH=7.5 which precipitated crystalline solid. This acidification and basification were repeated once. Yield of product was 6.8 g, m.p. 164°-166° C. (air dried).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].Cl.Cl[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1>C(Cl)Cl>[CH2:1]([NH:4][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=1)[C:2]#[CH:3]
Reactant: C#CCN
Reactant: FC(F)(F)c1cccc(NCCCl)c1
Agent: Cl
Solvent: ClCCl
Product: C#CCNCCNc1cccc(C(F)(F)F)c1

Procedure:
16.5 g of (0.3 mol) of propargylamine were dissolved in 100 ml of absolute methylene chloride, and the solution was admixed at room temperature in portions with the N-(2-chloro-ethyl)-3-(trifluoromethyl)-aniline hydrochloride obtained in step 3.1. While monitoring by chromatography, the mixture was heated until the reaction had gone to completion. After the reaction had ended, the reaction solution were extracted with the calculated quantity of sodium carbonate solution. After drying with sodium sulfate, the organic phase was evaporated under reduced pressure. The oily base thus obtained was used as such in the next step. (If this product contains significant impurities, it is advisable to recrystallize as its dihydrochloride).