Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CCNCC2)CC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (100 mg, 0.28 mmol), 2-cyanoacetic acid (43.3 mg, 0.51 mmol) in a mixture of DCM and DMF (20 mL/5 mL) were added HATU (241.9 mg, 0.64 mmol) and Et3N (85.8 mg, 0.85 mmol). After addition, the reaction mixture was stirred at rt overnight, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a beige solid (66.8 mg, 56%).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Cl:6][C:7]([C:13]([C:18]#N)=[CH:14][N:15](C)C)=[N:8][CH:9]=[N+:10]([CH3:12])[CH3:11].C1(C=CC=C(O)C=1O)[OH:21]>O.C(O)C>[Cl:6][C:7]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[C:13]([CH:18]=[O:21])[C:14]#[N:15]
Reactant: CN(C)C=C(C#N)C(Cl)=NC=[N+](C)C
Reactant: Oc1cccc(O)c1O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: CN(C)C=NC(Cl)=C(C#N)C=O
Temperature: 0 °C
Yield: 8968.5 %

Procedure:
31.4 g of N-(3-chloro-4-cyano-5-dimethylamino-2-aza-2,4-pentadienylidene)-N,N-dimethyl ammonium perchlorate and 0.1 g of pyrogallol are stirred in a mixture of 140 ml of water and 200 ml of ethanol for one hour at 25° to 30° C. Precipitaion of reaction products is completed by addition of 500 g of ice. Vacuum filtration is then carried out. This is followed by washing with cold water. Drying is effected at 20°C over P2O5. 13.2 g (71.2%) of 3-chloro-5-dimethylamino-2-formyl-4-aza-2,4-pentadienenitrile, with a melting point of 145° to 147°C (with decomposition), are thus obtained in the form of pale needles.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1-Boc-4-hydroxymethyl-piperidine in anhydrous CH2Cl2 (50 ml) and TEA (4.5 ml) and cooled to 0° C. Mesyl chloride (840 μl) was added and the mixture was stirred for 15 min then at RT for 45 min. The mixture was washed with brine/1N HCl and then brine, dried over Na2SO4, concentrated in vacuo and dried under high vacuum to provide 1-Boc-4-methylsulfonyloxymethyl-piperidine as a yellow orange thick oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:25])([C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH:13]=[CH2:14])=[CH2:12].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28]>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:26]([CH:27]1[CH2:28][CH2:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([F:25])([F:5])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[CH:13][CH2:14]1)=[O:29])[CH3:32]
Reactant: C=CC(=C)CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CC(=O)OCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=C(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a slurry of aluminum chloride (0.1 equi) in toluene (1 mL/mmole), ethyl acrylate (1 equi.) (1 equi.) was added at ice temperature. The reaction mixture was stirred at ice temperature for 10 min. Then a solution 2-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-buta-1,3-diene (40) (0.5M in THF) (1 equi.) was added at ice temperature over a period of 20 min. The reaction mixture was stirred at ice temperature for 10 h, water, extracted with hexane, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (hexanes) gave 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-cyclohex-3-enecarboxylic acid ethyl ester (41) as a colorless oil (88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:33])[NH:19][CH:20]([C:29]([O:31]C)=[O:30])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:33])[NH:19][CH:20]([C:29]([OH:31])=[O:30])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)NC(=O)C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NC(Cc1ccc(Cl)cc1)C(=O)O
Reaction time: 0.33 h
Yield: 83 %

Procedure:
3-[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: To a 0° C. solution of D-4-chlorophenylalanine methyl ester (23.8 g, 111.0 mmol), Boc-D-1,2,3,4-tetrahydroisoquinoline carboxylic acid (30.8 g,111.0) and 4-dimethylaminopyridine (75 mg, 0.61 mmol) in 200 mL of dichloromethane is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 30.8 g, 111.0 mmol) and the mixture stirred for 20 min. Remove ice bath and stir at room temperature for 4 hr. Wash 4 times with 200 mL each of water. The combined aqueous portions are extracted two times with 200 mL of dichloromethane. The combined organic portions are washed once with brine, dried (MgSO4), filtered and concentrated in vacuo. Chromatography (silica gel, 35% ethyl acetate/hexanes) of the residue affords 43.0 g (83%) of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH3:10])([CH3:9])[CH3:8].O1CCCC1.Cl[C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=1>[Cl-].[Na+].O>[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:30]2[CH:38]=[CH:37][C:33]([C:34](=[O:35])[NH2:36])=[CH:32][N:31]=2)=[CH:18][CH:17]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Add potassium tert-butoxide (4.28 g, 36.2 mmol) to a stirred solution of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (6.40 g, 27.0 mmol) and anhydrous tetrahydrofuran (120 mL). Stir for 30 minutes under nitrogen at room temperature. Add 6-chloronicotinamide (4.27 g, 27.2 mmol) and beat to reflux for 18 h under nitrogen. Cool to room temperature pour the reaction mixture into brine (150 mL), and extract with diethyl ether (3× 150 mL). Dry the diethyl ether extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform to yield 4.46 g (46%) of {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester: mass spectrum (ion spray): m/z=358.1 (M+1); 1H NMR (DMSO-d6): 8.58 (d, 1H), 8.22 (dd, 1H), 8.02 (br s, 1H), 7.46 (br s, 1H), 7.23 (d, 2H), 7.06-7.02 (m, 3H), 6.92-6.89 (m, 1H), 3.17-3.12 (m, 2H), 2.69 (t, 2H), 1.35 (s, 9H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15](C(O)(CCC2(C)OCC(C)(C)CO2)CO)[CH:16]=[CH:17][CH:18]=1.[CH3:34][C:35]([CH3:37])=[O:36]>>[C:35]([CH2:37][CH2:34][C:35]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH:14]=2)[CH2:37][O:12][C:13]([CH3:14])([CH3:18])[O:36]1)(=[O:36])[CH3:34]
Reactant: CC(C)=O
Reactant: CC1(C)COC(C)(CCC(O)(CO)c2cccc(OCc3ccc4ccccc4c3)c2)OC1
Product: CC(=O)CCC1(c2cccc(OCc3ccc4ccccc4c3)c2)COC(C)(C)O1
Yield: 45 %

Procedure:
Using the procedure described in Example 1, 2-[3-(naphth-2-ylmethoxy)phenyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)butane-1,2-diol (0.77 g) was reacted with acetone to give 4-(2-acetylethyl)-2,2-dimethyl-4-[3-(naphth-2-ylmethoxy)phenyl]-1,3-dioxolane (0.32 g, 45%), as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=2[F:20])=[O:9])[CH:7]=1.[BH4-].[K+]>Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=2[F:20])[OH:9])[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Product: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
(5-bromo-2-chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanone 3c (8.0 g, 21.3 mmol) was dissolved in 240 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of potassium borohydride (1.73 g, 32.0 mmol) in an ice bath. The reaction mixture was stirred for 16 hours at room temperature. Thereafter, 50 mL 1 M hydrochloric acid were added. The reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (100 mL×2). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanol 3d (8.0 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([F:22])[F:21])=[CH:16][CH:15]=2)[C:12]=1[CH3:13])=[O:7])C.Cl>C(O)C>[F:22][CH:20]([F:21])[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)F)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ccc(C(F)F)cc1
Reaction time: 12 h
Yield: 90.1 %

Procedure:
2N Aqueous solution of sodium hydroxide (32 ml) was added to a solution of 1-[4-(difluoromethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.8 g) in ethanol (32 ml) at room temperature and stirred at the same temperature for 12 hours. After completion of the reaction, 1N hydrochloric acid aqueous solution was added and the precipitated solid was filtered to give the titled compound (1.46 g) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([F:13])[CH2:10][C@:9]1([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:14][CH2:15][CH3:16])=O)(C)(C)C>Cl>[Cl:25][C:20]1[CH:19]=[C:18]([C:17]([C@@:9]2([CH2:14][CH2:15][CH3:16])[CH2:10][C@H:11]([F:13])[CH2:12][NH:8]2)=[O:26])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CCC[C@@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(F)CN1C(=O)OC(C)(C)C
Agent: Cl
Product: CCC[C@]1(C(=O)c2ccc(Cl)c(Cl)c2)C[C@H](F)CN1
Yield: 29 %

Procedure:
A solution of (S)-2-(3,4-dichloro-benzoyl)-4-fluoro-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.220 g, 0.545 mmol) in 1N methanolic HCl (3 mL) was stirred at 20° C. under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo then purified by chromatography (silica, 0 to 20% MeOH in DCM) to yield (3,4-dichloro-phenyl)-((2R,4S)-4-fluoro-2-propyl-pyrrolidin-2-yl)-methanone (0.048 g, 0.158 mmol, 29%) as a first fraction (yellow oil) then (3,4-dichloro-phenyl)-((2S,4S)-4-fluoro-2-propyl-pyrrolidin-2-yl)-methanone (0.072 g, 0.238 mmol, 44%) as a second fraction (yellow oil), each as a monohydrochloride salt, MS=304 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][C:19]#[CH:20])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Cl-].[Cl:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:22][CH:23]=[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:9]([CH2:18][C:19]#[CH:20])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: C#CCC(C(=CCl)c1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-4-pentyn-1-one and chloromethyltriphenylphosphonium chloride there is obtained 3-[α-chloromethylene-2,4-dichloro-β-(2-propynyl)-phenethyl]-pyridine as an isomer-pure compound in the form of white crystals, m.p. 87-88° C.;
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].[Na+].Cl[C:23]1[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:27][CH:28]=1.Cl[C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1>[Zn].[Ni](Cl)Cl.C(Cl)(Cl)Cl.CN(C)C=O>[F:30][C:29]([F:32])([F:31])[C:25]1[CH:24]=[C:23]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: Cl[Ni]Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Reaction time: 6 h

Procedure:
33 g of zinc powder, 33 g of triphenylphosphine, 5 of sodium iodide, 2.2 g of nickel(II) chloride and 200 ml of dimethylformamide were mixed under a nitrogen atmosphere and the mixture was initially introduced into the reaction vessel. The mixture was kept at 50° to 60° C. for half an hour, after which a suspension coloured deep red-brown was present. A solution containing 20.2 g (0.11 mol) of 3-chloro-benzotrifluoride, 38.2 g (0.22 mol) of methyl 4-chloro-benzoate and 100 ml of dimethylformamide was added dropwise to this suspension in the course of half an hour. After 6 hours at 80° C., the reaction mixture was introduced into 500 ml of chloroform and filtered. The residue on the filter was boiled up in 400 ml of toluene and filtered off hot. After cooling, 15 g of dimethyl biphenyl-4,4'-dicarboxylate (50.5% of theory--based on the methyl 4-chloro-benzoate employed) of melting point 213° to 214° C. were obtained. The filtrate was extracted by shaking with dilute aqueous hydrochloric acid and with water and the organic phase was dried over sodium sulphate and concentrated. The resulting residue was distilled. 6.4 g of 3,3'-bis-(trifluoromethyl)-biphenyl (20% of theory--based on the 3-chloro-benzotrifluoride employed) and a total of 16 g of methyl 4-(3-trifluoromethylphenyl)-benzoate (52% of theory--based on the 3-chloro-benzotrifluoride employed) of boiling point 125° C. to 130° C. under 0.1 to 0.3 mbar were obtained in this manner.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH2:24]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:31]([CH2:24][C@H:10]1[C@H:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:30])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11]1)=[N+:32]=[N-:33]
Reactant: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN=[N+]=[N-]
Temperature: 60 °C
Yield: 94.5 %

Procedure:
A mixture of crude methanesulfonic acid trans-4-(benzyl-methyl-amino)-1-[2-(4-fluorophenyl)-ethyl]-piperidin-3-ylmethyl ester (139 mg, 294 μmol) and sodium azide (58 mg, 882 μmol) in N,N-dimethylformamide (2 mL) was heated at 60° C. for 20 hours, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed three times with water, dried over sodium sulfate, and concentrated under vacuum to provide a gum (106 mg, 95%) which was used without purification. 1H NMR (300 MHz, CDCl3) δ7.33 (m, 5H), 7.16 (m, 2H), 6.99 (t, J=9 Hz, 2H), 3.70 (m, 2H), 3.52 (d, J=13 Hz, 1H), 3.41 (m, 1H), 3.20 (m, 2H), 2.83 (m, 2H), 2.61 (m, 2H), 2.42 (m, 1H), 2.3-1.8 (m, 4H), 2.19 (s, 3H), 1.75 (m, 1H).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1.O>[F:27][C:26]([F:29])([F:28])[CH2:25][O:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc(Sc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Sc2ccccc2)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
A solution was obtained by combining 20.2 g of 4-hydroxyphenyl phenyl sulfide which had been synthesized according to the well-known formulation, 15.3 g of 2,2,2-trifluoroethyl p-toluenesulfonate, 12.4 g of potassium carbonate, and 80 g of DMF. The solution was aged at 100° C. for 16 hours. The aged solution was cooled to room temperature, to which 50 g of water was added to quench the reaction. To the solution, 200 g of toluene was added for extraction. The organic layer was separated, and washed with 100 g of 5 wt % sodium hydroxide aqueous solution and water in sequence. On subsequent concentration in vacuum, 16.4 g of the target compound, phenyl 4-(2,2,2-trifluoroethoxy)phenyl sulfide was obtained as oily matter. Yield 96%.
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[C:4]([CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=1)#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: COc1cccc(N)c1
Product: C#CC(Nc1cccc(OC)c1)c1ccccc1
Reaction time: 12 h
Yield: 82.6 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and m-anisidine (0.150 g, 1.22 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 97/3. The mixture was purified by flash column chromatography on silica gel (4% ethyl acetate in hexanes) to give the title compound (0.192 g, 82%). [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.50-7.40 (m, 4H), 7.36 (tt, J=6.8, 2.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.37 (dd, J=8.0, 2.4 Hz, 1H), 6.32 (dd, J=8.4, 2.0 Hz, 1H), 6.12 (ddd, J=16.8, 10.0, 6.0 Hz, 1H), 5.37 (dt, J=16.8, 1.4 Hz, 1H), 5.32 (dt, J=10.4, 1.4 Hz, 1H), 5.03 (br s, 1H), 4.18 (br s, 1H), 3.79 (s, 3H). 13C NMR (100.59 MHz, CDCl3) δ 160.50, 148.47, 141.68, 138.84, 129.71, 128.63, 127.35, 127.02, 115.98, 106.53, 102.62, 99.46, 60.71, 54.85. Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.17; H, 7.24; N, 5.78.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCOc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCOc1ccncc1
Temperature: 90 °C
Yield: 56.5 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 4-(3-chloropropoxy)pyridine hydrochloride (206 mg, 1.0 mmol) and potassium carbonate (303 mg, 2.2 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)quinazoline (257 mg, 56%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=[NH:62])(C1C=CC=CC=1)C1C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O.COCCOC>[NH2:62][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1S(C)(=O)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(N)cc1S(C)(=O)=O

Procedure:
To 4-bromo-2-methanesulfonylbenzoic acid (5 g) were added methanol (45 mL) and concentrated sulfuric acid (1.8 mL), and the mixture was stirred with heating under reflux. After completion of the reaction, the solvent was evaporated, and the residue was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give methyl 4-bromo-2-methanesulfonylbenzoate (3.34 g). To a mixture of the obtained methyl 4-bromo-2-methanesulfonylbenzoate (3.34 g), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (295 mg), 2-(dicyclohexylphosphino)biphenyl (399 mg), tripotassium phosphate (3.39 g) and benzophenonimine (2.5 mL) was added 1,2-dimethoxyethane (25 mL), and the mixture was stirred with heating under reflux. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in tetrahydrofuran (26 mL), 1N hydrochloric acid (100 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give methyl 4-amino-2-methanesulfonylbenzoate (1.46 g). Using the obtained methyl 4-amino-2-methanesulfonylbenzoate (1.46 g) and 3-chloropropane-1-sulfonyl chloride (1.03 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (0.53 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:15]=1[NH:16][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1O
Yield: 3.6 %

Procedure:
Using 5-chlorosalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.