Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][CH2:20]Br>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:15]#[N:16])[CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Into a round-bottom flask under argon fitted with an addition funnel and thermometer was added anhydrous dimethylsulfoxide and sodium hydride (1.17 g, 48.8 mmol, 95%). Then a solution of (4-chlorophenyl)acetonitrile (A) (2.70 mL, 22.2 mmol) and 1,3-dibromopropane (2.48 mL, 24.4 mmol) in diethyl ether (15 mL) was added slowly, while maintaining the reaction temperature at 20–30° C. The reaction mixture was maintained at room temperature for overnight. The reaction mixture was carefully quenched with water (50 mL) and then extracted with hexane (3×100 mL). The organic extracts were combined, washed with water (3×75 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2.9 g of 1-(4-chlorophenyl)-cyclobutanecarbonitrile, B, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 2.03–2.09 (m, 1H); 2.36–2.62 (m, 3H); 2.76–2.84 (m, 2H); 7.34 (s, 4H); 13C NMR (CDCl3, 75 MHz): δ 17.0, 34.6 (2C), 39.7, 123.9, 127.1, 129.1, 133.7, 138.3.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[N:19][CH:20]=[C:21]([NH:23][C:24]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([I:32])[CH:31]=3)=[O:25])[CH:22]=2)=[CH:13][C:12]=1[Cl:39])C1C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:25])[C:26]3[CH:31]=[C:30]([I:32])[CH:29]=[N:28][CH:27]=3)[CH:20]=[N:19][C:18]=2[O:33][CH2:34][C:35]([F:36])([F:37])[F:38])=[CH:13][C:12]=1[Cl:39]
Reactant: O=C(Nc1ccc(-c2cc(NC(=O)c3cncc(I)c3)cnc2OCC(F)(F)F)cc1Cl)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cc(NC(=O)c3cncc(I)c3)cnc2OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.7 %

Procedure:
{2-Chloro-4-[5-[(5-iodo-pyridine-3-carbonyl)-amino]-2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-phenyl}-carbamic acid benzyl ester (87 mg, 127 μmol) was, with cooling, combined with trifluoroacetic acid (3 mL) to give a brown solution. The reaction mixture was warmed to room temperature and stirred for 72 h. The crude reaction mixture was concentrated in vacuo, poured into 50 mL ethyl acetate and extracted with 1 M NaOH (1×25 mL). The aqueous layer was washed with ethyl acetate (1×50 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 40% EtOAc in heptane) to give the title compound (59 mg, 84%); LC-MS (UV peak area/ESI) 98.1%, 548.9795 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9](Br)=[CH:8]2)=[O:4].[Br-].[CH2:25]([Zn+])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2-c2ccccc2)c1O
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A mixture of 3-bromo-5-hydroxy-2-oxo-1-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (120 mg, 0.323 mmol), benzylzinc bromide solution (1.6 mL, 0.806 mmol, 0.5 M in THF), and Pd(PPh3)4 (37 mg, 0.0323 mmol) in THF (6 mL) was refluxed under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., saturated NH4Cl and EtOAc were added. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was dissolved in a mixture of EtOAc/EtOH (1:1). To the resulting mixture were added 50 mg of 10% Pd/C and 50 mg of sodium acetate. The mixture was placed under H2 atmosphere for 1 h, then filtered through a pad of Celite. The filtrate was concentrated, and the residue was chromatographed (0-50% EtOAc/hexanes+2% AcOH) to give 25 mg of the title compound. MS: (+) m/z 387.32 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]([CH:7]1[C:12](=[O:13])[CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][S:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([F:39])[CH:31]=1.CCCCCC.CCOC(C)=O>CC(C)=O>[CH2:1]([O:4][C:5]([C:7]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[C:12](=[O:13])[CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][S:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Reactant: C=CCOC(=O)C1CSCC(NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C=CCOC(=O)C1(Cc2ccc([N+](=O)[O-])c(F)c2)CSCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-tert-butoxycarbonylamino-4-oxo-tetrahydro-thiopyran-3-carboxylic acid allyl ester (2.55 g, 8.08 mmol) in acetone (150 mL) was added K2CO3 (3.38 g, 24.2 mmol) and 4-bromomethyl-2-fluoro-1-nitro-benzene (2.12 g, 8.9 mmol) and the reaction mixture was stirred at 25° C. for 16 h. After dilution with water the product is extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4 and evaporated. The product obtained as a light yellow solid was suitable for use in the next step: TLC (hexane-EtOAc 1:3) Rf=0.26; HPLC RtA=2.31 min; ESIMS [M+NH4]+=486.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.C=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]1([CH:13]=[CH:8][CH:7]=[CH:6][C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ccccc1
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: Clc1ccc(C=CC=Cc2ccccc2)cc1

Procedure:
0.112 g (0.5 millimol) of palladium acetate, 10.05 g (50 millimols) of 4-chlorocinnamyl chloride, 6.5 g (62.5 millimols) of styrene and 9.27 g (50 millimols) of tri-n-butylamine in 50 ml of p-xylene are stirred for 23/4 hours at 120° C. The crude product is chromatographed on silica gel in methylene chloride and is recrystallised from n-hexane. 0.5 g (4% of theory) of the above compound are obtained in the form of white crystals of melting point 161.2° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:4][C:5]2[C:10]([C:11]=1I)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[Na+].[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.O>[F:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:4][C:5]2[C:10]([C:11]=1[NH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Fc1ccccc1-c1nc2ccccc2c(I)c1F
Reactant: Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccccc1-c1nc2ccccc2c(Nc2ccncc2)c1F
Temperature: 110 °C
Yield: 72 %

Procedure:
To a solution of 3-fluoro-2-(2-fluoro-phenyl)-4-iodo-quinoline (from Step F, 0.02 g, 0.05 mmol) in toluene (1 mL) was added S-BINAP (0.007 g, 0.01 mmol), sodium tert-butoxide (0.105 g, 1 mmol) and 4-aminopyridine (0.015 g, 0.05 mmol). The resulting mixture was degassed for 5 min., after which tris(dibenzylidineacetone) dipalladium(0) (0.0025 g, 0.0025 mmol) was added. The reaction mixture was heated to 110° C. for 48 h. and then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in rotary evaporator. The residue was purified using HPLC over a gradient of acetonitrile and water containing 0.1% trifluoroacetic acid to yield the desired compound (0.012 g, 65%). MS (ES) 334.1 (M+H)+.
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][O:29][CH2:28]1>O.ClCCl>[CH:1]([CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:31](=[O:32])[CH2:30][O:29][CH2:28][C:27]([OH:34])=[O:33])[CH2:18][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(=O)O1
Reactant: NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O
Product: O=C(O)COCC(=O)NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h

Procedure:
A 1.02 gram (2.10 millimoles) sample of sodium {2-[6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetate (prepared as described in Example XIII) and 7.3 milliliters of 5 N aqueous NaOH is heated under reflux temperature for 1.5 hours to obtain 6-(4-benzhydrylpiperidino)hexanamine and diglycolate in the reaction mixture; the mixture is then diluted with 25 milliliters of water and extracted with ether. The ether solution is washed with aqueous NaCl, dried with Na2SO4, and concentrated to obtain as residue, 6-(4-benzhydrylpiperidino)hexanamine. To a solution of 0.685 gram (1.96 millimoles) of the thus prepared 6-(4-benzhydrylpiperidino)hexanamine in 14 milliliters of dichloromethane is added drop by drop during about 10 minutes, a warm solution of 0.227 gram (1.95 millimole) of diglycolic anhydride in 26 milliliters of dichloromethane. After the addition, the mixture is stirred at a temperature range of 25°-30° C. for two hours to obtain the desired {2-[ 6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetic acid; the latter is isolated by volatilization of the solvent.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4]([CH3:15])([CH3:14])[CH:3]1[OH:16].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@@H:2]2[NH:1][S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([F:17])([F:29])[F:30])(=[O:27])=[O:26])#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2C(N)C1O
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NS(=O)(=O)c2ccccc2C(F)(F)F)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1 g of 4-amino-6-cyano-2,2-dimethyl-3-hydroxychroman and 1 g of 2-trifluoromethylbenzenesulfonyl chloride in 25 ml of pyridine is stirred at room temperature for 18 hours.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]#[N:23])=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC>C1COCC1.CCOCC.Cl>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]3[NH:46][N:45]=[N:44][N:23]=3)=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCC#N)cc2)ccc(C(C)=O)c1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(OCCCSc2ccc(C(=O)CCc3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The nitrile from Example 40, Step E, (1.0 g, 2.35 mmole) and tri-n-butyltin azide (1.0 g, 3.0 mmole) in dry THF (20 ml) were stirred at 70° for 48 hours, and then heated at reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with ether (20 ml) and concentrated HCl was added. After 1 hour, the solution was filtered, the solid was washed with ether and dried to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1>CN(C=O)C.C(OCC)(=O)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:22][C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O[C@H]2CCCNC2)cc1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(O[C@H]2CCCN(Cc3ccc4c(c3)OCO4)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To an ice water-cooled solution of (3S)-3-(4-aminophenoxy)piperidine (3.5 g) in DMF (20 mL) was added K2CO3 (7.5 g) and Nal (0.2 g), followed by the addition of 5-chloromethyl-1,3-benzodioxole (4.7 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL×3) and brine (100 mL), and dried (Na2SO4). The crude product was further purified by column chromatography (methanol:ethyl acetate1:10), to afford (3S)-3-(4-aminophenoxy)-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (4.4 g, 74% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([NH:30]C(OC(C)(C)C)=O)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]>CCOC(C)=O>[NH2:30][C@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH2:17][CH2:18]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
(2R)-2-Amino-3-(3,4-dichlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one was prepared according to the procedure for Preparation XVI using N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl](tert-butoxy)carboxamide (Step 1) (1.0 g, 1.8 mmol) and satd HCL in EtOAC. The resulting crude material was diluted with EtOAc and washed with satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo (700 mg). MS (ESI, pos. ion) m/z: 471 (M+H), (ESI, neg. ion) m/z: 469 (M−H). Calc'd for C20H24Cl2N4O3S: 470.09. Anal. Calc'd for C20H24Cl2N4O3S: C, 50.96; H, 5.13; N, 11.88; Cl, 15.04. Found C, 50.66; H, 5.14; N, 11.51; Cl, 15.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:33])([CH2:31][OH:32])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10]>C(O)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:33])([CH2:31][OH:32])[C@H:9]([N:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@](O)(CO)c1ccccc1F
Yield: 68.7 %

Procedure:
A solution of 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.0 g) in acetic acid (15 ml) was hydrogenated over 10% palladium carbon (50% wet, 0.25 g) under ordinary pressure for 5 hours at room temperature and then 3 hours at 50° C. After cooling, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from diisopropyl ether to give 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone (0.69 g) as a colorless crystalline powder. The mother liquor was concentrated in vacuo and the residue was purified by chromatography on silica gel (eluent; hexane-ethyl acetate, 2:1) followed by crystallization from a mixture of diisopropyl ether and hexane to give the additional product (0.20 g).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.S1(CCCC1)(=O)=O>CN(C)C=O.ClCCCl.ClCCl.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O.CCOCC>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Product: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent (such as HOBt, EDCI, HATU, TBTU) at ambient temperature in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dichloromethane, 1,2-dichloroethane and N,N-dimethylformamide) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide is obtained after conventional workup.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(Cl)c(Cl)c1Cl
Product: O=C(Cl)c1cc(F)c(Cl)c(Cl)c1Cl

Procedure:
737 g (3.02 mols) of 2,3,4-trichloro-5-fluorobenzoic acid are introduced into 1.5 liters of thionyl chloride at room temperature, and the mixture is refluxed for 16 hours until the gas evolution ceases. Excess thionyl chloride is removed by distillation, and the residue is distilled.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:23])[CH:16]=[C:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH3:22])[CH:12]=[CH:13][CH:14]=1.O.C(OCC)C>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:23])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH3:22])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(C(=O)C=C2CCCN2C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CC2CCCN2C)c1

Procedure:
11.8 g of lithium aluminum hydride are added portionwise at 0° with stirring to 144.8 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyliden)ethanone dissolved in 1.4 liters of tetrahydrofuran. 30 minutes after completion of the addition, 300 ml of water are cautiously added dropwise, with cooling; then 800 ml of diethyl ether are added, and the organic phase is collected. The organic phase is dried over sodium sulfate, the solvent is removed by evaporation, and the oily residue is distilled under a vacuum to obtain 127 g (87% of theory) of the title compound:
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][CH2:9][CH2:10][NH:11][NH2:12].[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>C(O)C>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:11]([CH2:10][CH2:9][O:8][CH3:7])[N:12]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COCCNN
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: COCCn1nc(C(C)(C)C)cc1N
Temperature: 85 °C
Yield: 98.5 %

Procedure:
A stirred suspension of (2-methoxyethyl) hydrazine oxalic acid (0.50 g, 2.77 mmol) and 4,4-dimethyl-3-oxopentanenitrile (0.347 g, 2.77 mmol) in ethanol (6 mL) was heated at 85° C. for 4.5 h during which time all solids dissolved. The reaction mixture was allowed to cool overnight and then the solvent was evaporated. The residue was dissolved in dichloromethane (20 mL) and washed with saturated aqueous NaHCO3 (10 mL). The organic layer was separated using a phase separator cartridge and evaporated. The residual oil was dissolved in diethyl ether and evaporated to afford the title compound (0.538 g, 98%) as a solid. 1H NMR (300 MHz, CDCl3): 1.26 (9H, s), 3.33 (3H, s), 3.67 (2H, t, J 4.3 Hz), 3.95 (2H, br s), 4.13 (2H, t, J 4.6 Hz), 5.36 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:13]3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[CH:5][CH:4]=1)#[N:2].ClCCl.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:13]3[N:12]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)[C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(C(C)C)nc2N1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(C(C)C)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-(4-cyanophenyl)-5-methyl-2-(1-methylethyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (63 mg, 207 μmol) was stirred in abs. dichloromethane (50 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (118 mg, 621 μmol, 3 eq.), anhydrous copper(II) acetate (113 mg, 621 μmol, 3 eq.), abs. pyridine (1390 μl) and triethylamine (63 mg, 621 μmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (39 mg, 207 μmol, 1 eq.), anhydrous copper(II) acetate (38 mg, 207 μmol, 1 eq.) and abs. pyridine (500 μl) were then added, and the mixture was stirred at RT for a further 3 d. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and pyridine and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless solid (29.8 mg, 64% of theory).