Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27]>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1
Reactant: COc1ccccc1S
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: COc1ccccc1SC1=C/C(=C2/C(=O)NN=C2C)Nc2ccccc21

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 2-methoxythiophenol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 3.68 (s, 3H) 6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H) 13.04 (bs, 1H); ESI-MS: m/z calc'd for C20H17N3O2S 363.10. found 364.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl)#[N:2].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21])#[N:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1cccc(CCl)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Yield: 76.4 %

Procedure:
A solution of 3-cyanobenzyl chloride (13.3 g) in N,N-dimethylformamide (30 ml) was added dropwise to a suspension of potassium phthalimide (15.9 g) in N,N-dimethylformamide (160 ml) at ambient temperature under stirring and the resultant mixture was stirred for 12 hours at ambient temperature. The reaction mixture was poured into water and the precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and tetrahydrofuran and the resultant solution was washed with brine and dried over magnesium sulfate. The solvent was concentrated in vacuo and the precipitate was collected by filtration to give N-(3-cyanobenzyl)phthalimide (17.1 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[C:11](Cl)=[C:10]([CH:17]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[C:11]2[S:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CS
Reactant: CC1(C)CN(Cc2ccccc2)CC(C=O)=C1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(s1)C(C)(C)CN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To a solution of 1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde (75 g, 0.28 mol) in DCM (1.2 L) was added ethyl 2-mercaptoacetate (67 g, 0.56 mol) and triethylamine (85 g, 0.84 mol) was added slowly at room temperature. Upon complete addition, the reaction mixture was heated at reflux overnight. Upon cooling to room temperature, the reaction was quenched with the addition of water. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (0-20% EtOAc/hexane) to afford the title compound (31.7 g, 27.5% over two steps).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:39]=[CH:38][C:13]2[N:14]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH:29]4[CH2:31][CH2:30]4)[C:19]3=[O:32])=[N:16][C:12]=2[CH:11]=1)C)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[CH:29]1([N:20]2[C:21](=[O:28])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]([CH2:17][C:15]3[N:14]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:13]4[CH:38]=[CH:39][C:10]([CH2:9][NH:7][CH3:6])=[CH:11][C:12]=4[N:16]=3)[C:19]2=[O:32])[CH2:31][CH2:30]1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CN(C)C(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(=O)Cl
Product: CNCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCC(C)C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-methyl-carbamic acid tert-butyl ester (39 mg, 0.071 mmol) and anisole (77 μL, 0.71 mmol) in DCM (3 mL) was added TFA (165 μL, 2.14 mmol). The solution was allowed to reach room temperature and after 1 h another amount of TFA (200 μL) was added. After 1 h the volatiles were removed in vacuo and the residue was stripped with DCM (2×) and methanol (1×). The TFA salt was dissolved in methanol followed by the addition of acetyl cloride (50 μL, 0.71 mmol) and concentrated. This procedure was repeated once. The product was triturated in diethyl ether to give 3-cyclopropyl-1-[5-methylaminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-1H-quinazoline-2,4-dione; HCl salt (31 mg, 91%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]([CH3:27])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[CH3:27]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49 e) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (D): 371.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:31])[C@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:14][O:15][C:16](=[O:31])[C@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=173-175° C.). The reaction was monitored by tlc (Rf=0.6 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [N:1]#[C:2][NH2:3].[H-].[Na+].[Cl:6][C:7]1[C:16](Cl)=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:19]([O-:21])=[O:20])=[C:12]([F:18])[CH:13]=2)[N:8]=1>CN(C=O)C>[Cl:6][C:7]1[C:16](=[N:3][C:2]#[N:1])[NH:15][C:14]2[C:9](=[CH:10][C:11]([N+:19]([O-:21])=[O:20])=[C:12]([F:18])[CH:13]=2)[N:8]=1
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1F
Reactant: N#CN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN=c1[nH]c2cc(F)c([N+](=O)[O-])cc2nc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a solution of cyanamide 2.31 g in DMF 100 mL, was added sodium hydride (60% suspension in oil) 4.40 g under ice-cooling. The mixture was stirred at room temperature for 30 min, to which 2,3-dichloro-6-fluoro-7-nitroquinoxaline 13.10 g was added under ice-cooling, followed by raising slowly to room temperature. The resulting mixture was stirred at room temperature for 20 min, then which was poured into ice water containing 1N HCl 110 mL under stirring. The precipitation was collected by filtration and washed with water and i-PrOH to give the title compound 12.80 g.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([CH2:9][CH:10]([CH3:21])[C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=[O:16])=[O:12])=[O:8])=[CH:4][CH:3]=1.[C:22]([O-:25])(=[S:24])[CH3:23].[Na+]>C(#N)C>[C:22]([S:24][CH:9]([C:7](=[O:8])[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:25])[CH3:23]
Reactant: CC(CC(=O)c1ccc(Cl)s1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)SC(C(=O)c1ccc(Cl)s1)C(C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Bromination of the [S]-1-[3-(5-chloro-2-thenoyl)-2-methylpropionyl]-L-proline and reaction of the brominated product with sodium thioacetate in acetonitrile gives a mixture of the [R-(R*,S*)] and [R-(R*,R*)] isomers of the product of the Example as a glass.
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.Cl.[CH2:13](O)[CH3:14]>>[CH2:13]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)[CH3:14]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(N)cc1

Procedure:
In 15% hydrogen chloride-ethanol, p-aminophenylacetic acid was refluxed. After removal of ethanol by distillation, the residue was extracted with ethyl acetate and the extract was washed successively with water, saturated sodium bicarbonate solution and water and dried. The ethyl acetate was then distilled off to give p-aminophenylacetic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([C:14](=[O:25])[NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]([NH:15][C:14]([C:11]2([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:25])[CH3:17])=[CH:19][CH:20]=1
Reactant: C[C@H](NC(=O)C1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)C1(c2ccc(F)cc2)CCNCC1)c1ccc(F)cc1
Reaction time: 12 h
Yield: 128 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-4-[(S)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (735 mg, 1.653 mmol) in dichloromethane (8 mL) at 0° C. was added slowly trifluoroacetic acid (1.78 mL, 23.148 mmol) and stirring continued for 12 h at room temperature. The solvent was removed under reduced pressure. Toluene was added to the residue and evaporated under reduced pressure which was repeated two times. The residue was dried under high vacuum to yield 970 mg 4-(4-fluoro-phenyl)-piperidine-4-carboxylic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide; compound with trifluoro-acetic acid. MS ISP (m/e): 345.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].O[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: OCCOc1ccncc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCOc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (193 mg, 0.6 mmol), (prepared as described in Example 49), 4-(2-hydroxyethoxy)pyridine (166 mg, 1.2 mmol), (J. Chem. Soc. Perkin II, 1987, 1867), in methylene chloride (5 ml) containing triphenylphosphine (330 mg, 1.26 mmol) and diisopropyl azodicarboxylate (255 mg, 1.26 mmol) was stirred at ambient temperature for 2 hours. The precipitate was filtered, triturated with ether followed by ethyl acetate, and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline (142 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][SH:5].C(#N)C.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13](F)[CH:12]=1.C(OCC)(=O)C>CCCCCC>[CH3:1][O:2][C:3]([C:4]1[S:5][C:13]2[CH:12]=[C:11]([Br:10])[CH:18]=[CH:17][C:14]=2[CH:15]=1)=[O:6]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: COC(=O)CS
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(Br)cc2s1
Temperature: 85 °C
Yield: 89.8 %

Procedure:
TEA (1.29 g, 12.85 mmol) and mercapto-acetic acid methyl ester (1.14 g, 10.83 mmol) were added to acetonitrile (50 mL) previously purged with argon (10 minute). This was followed by the addition of 4-bromo-2-fluoro-benzaldehyde (2 g, 9.852 mmol) and the resulting mixture was heated to reflux at 85° C. overnight. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was cooled, concentrated, basified with 10% NaOH solution and extracted with ethyl acetate to afford the crude product. Purification by column chromatography on silica gel (5% ethyl acetate in hexane) afforded 2.4 g of the product (90% yield).
Reaction SMILES: [NH2:1][C:2]1([C:22]#[N:23])[CH2:7][CH2:6][CH:5]([NH:8][S:9](C2C=CC(OCC)=C(C)C=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[F:24][C:25]([F:44])([F:43])[C:26]1[CH:31]=[CH:30][C:29](S(NC2CCC(=O)CC2)(=O)=O)=[CH:28][CH:27]=1>>[NH2:1][C:2]1([C:22]#[N:23])[CH2:3][CH2:4][CH:5]([NH:8][S:9]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:44])([F:43])[F:24])=[CH:27][CH:28]=2)(=[O:11])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(N)(C#N)CC2)cc1C
Reactant: O=C1CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Product: N#CC1(N)CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Intermediate 125 was prepared by a method analogous to the method of preparing Intermediate 124 using 4-(trifluoromethyl)-N-(4-oxocyclohexyl)benzenesulfonamide (Intermediate 123) as the starting material.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[N:33][C:32](Br)=[CH:31][N:30]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[CH:19]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH:20]([CH3:22])[CH3:21].[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[CH:19]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH:20]([CH3:22])[CH3:21])[C:29]1[CH:34]=[N:33][C:32]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:31][N:30]=1
Reactant: CC(C)C(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Br)cn1)N1CCOCC1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCOCC2)cn1)N1CCOCC1
Temperature: 80 °C
Yield: 100 %

Procedure:
To a solution of (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrazin-2-yl)-[2-(2-methyl-1-morpholin-4-yl-propyl)-5-trifluoromethyl-benzyl]-amine (28 mg, 0.040 mmol) in toluene (0.5 mL) was added morpholine (0.01, 0.048 mmol), BINAP (5 mg, 0.004 mmol), sodium t-butoxide (6 mg, 0.056 mmol), and tris(dibenzylideneacetone)dipalladium (4 mg, 0.002 mmol). The mixture was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered over a pad of silica gel. Mother liquor is concentrated. The residue was purified by flash chromatography (silica gel) (eluting with 10-50% ethyl acetate in hexanes) to afford the title compound as a yellow orange gum (20 mg. 0.04 mmol).
Reaction SMILES: ClCl.ClC=C(Cl)C(Cl)=CCl.[Cl:11][CH:12]([Cl:22])[C:13](Cl)([Cl:20])[C:14](Cl)([Cl:18])[CH:15]([Cl:17])[Cl:16]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:11][C:12]([Cl:22])=[C:13]([Cl:20])[C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16]
Reactant: ClC(Cl)C(Cl)(Cl)C(Cl)(Cl)C(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClC=C(Cl)C(Cl)=CCl
Agent: ClCl
Product: ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl

Procedure:
The present invention is directed to a process for the preparation of of Z-1,1,1,4,4,4-hexafluoro-2-butene from 2,3-dichloro-1,3-butadiene. The process of the present invention includes the sequential steps initiating with initiating the reaction of chlorine with 2,3-dichloro-1,3-butadiene to obtain 1,2,2,3,3,4 hexachlorobutane followed by contacting the 1,2,2,3,3,4 hexachlorobutane with tetrabutyl ammonium chloride in a basic aqueous solution to produce 1,2,3,4-tetrachlorobuta-1,3-diene. Chlorine is added to the 1,2,3,4-tetrachlorobuta-1,3-diene to obtain 1,1,2,2,3,3,4,4 octachlorabutane followed by contacting the 1,1,2,2,3,3,4,4 octachlorobutane with tetrabutyl ammonium chloride in a basic aqueous solution to produce 1,1,2,3,4,4-hexachlorobuta-1,3-diene. Hydrogen fluoride is chlorinated and combined with the 1,1,2,3,4,4-hexachlorobuta-1,3-diene to provide E- or Z-1326mxz (1,1,1,4,4,4-hexafluoro-2-chloro-2-butene). Z-1,1,1,4,4,4-hexafluoro-2-chloro-2-butene is reacted with an aqueous solution of an alkali metal hydroxide and an alkali metal halide in the presence of a quaternary alkylammonium salt having alkyl groups of from four to twelve carbon atoms and mixtures thereof, to produce a mixture including hexafluoro-2-butyne. The final step is hydrogenating hexafluoro-2-butyne to 1,1,1,4,4,4 hexafluro-2-butene.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[O:12]1[CH2:15][CH:14]([NH2:16])[CH2:13]1>>[Cl:11][C:6]1[C:7]2[CH:8]=[CH:9][N:16]([CH:14]3[CH2:15][O:12][CH2:13]3)[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: NC1COC1
Product: Clc1ncnc2c1ccn2C1COC1

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde (Preparation 208) and oxetan-3-amine to afford the title compound as a yellow solid in 67% yield, 2.81 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1
Reactant: CNS(=O)(=O)c1ccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)c1ccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc1
Yield: 21.8 %

Procedure:
To a round bottom flask, a mixture of methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (190 mg, 0.49 mmol) in methanol (20 mL), and water (2 mL) was treated with a solution of sodium hydroxide (332 mg, 8.3 mmol) in water (3 mL). The resultant mixture was heated for reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to afford 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (40 mg, yield: 21.9%). MS (ES+APCI) M+1=375.1.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.CO.N1CCCC[CH2:28]1>C(Cl)CCl>[CH3:28][O:10][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=2)[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=[O:15])[O:14]1
Reactant: C1CCNCC1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Solvent: ClCCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2ccccc21

Procedure:
Following a procedure similar to that described in Example 1 above, 4.5 g of 2-(4-dimethylaminophenyl)carbonylbenzoic acid, 1.2 ml of thionyl chloride and 5.0 ml of methyl alcohol were interacted in 30.0 ml of ethylene dichloride in the presence of 1.3 ml of piperidine at ambient temperature for approximately ten minutes to obtain 4.0 g of 3-methoxy-3-(4-dimethylaminophenyl)phthalide (Formula II: R0 =R=R1 =R2 =R5 =H; R4 =R4' =R5Y=CH3 ; X=O), a pale peach-colored solid which melted at 112.5° to 114.5° C. A significant infrared maximum appeared at 1773 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was consistent with the assigned structure. Analysis by mass spectrum showed m/e peaks at 283 (M+) and 252 (M+ -OCH3). A toluene solution of the product spotted on an acidic clay-coated paper developed a yellow-colored image.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:28]=1.C[Si](C#C)(C)C>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:27]([C:2]1[CH:3]=[C:4]([CH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[CH:28]
Reactant: CC(C)(CC(=O)O)Cc1ccc(OCCCNc2ccccn2)c(Br)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Product: C#Cc1cc(CC(C)(C)CC(=O)O)ccc1OCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 161.9 %

Procedure:
The final product of EXAMPLE 13, STEP 4 (500 mg) was dissolved in Et3N (10 ml) was treated with Cul (40 mg), triphenylphosphine (80 mg), Pd(Ph3P)2Cl2 (40 mg) and (trimethylsilyl) acetylene (1 ml). The reaction mixture was heated to 120 C. in a sealed tube for 20 hours under nitrogen atmosphere. The mixture was cooled to room temperature and was filtered through celite under vacuum. The filtrate was concentrated. The residue was dissolved in ethyl acetate and was washed with a saturated solution of ammonium chloride and dried over Na2SO4. The solid was removed by filtration and the filtrate was concentrated. The cude product was purified by flash chromatography on silica gel (EtOAc/Hexane/NH4OH: 80/19.5/0.5) to give 181 mg of desired compound as oily gum. NMR spectrum was consistent for the proposed structure.