Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25]C)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(=[O:10])=[O:9].B(Br)(Br)Br>>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([C:7]1[CH:6]=[CH:5][C:4]([C:18]2[C:19]([OH:25])=[CH:20][CH:21]=[C:22]([F:24])[CH:23]=2)=[CH:3][C:2]=1[F:1])(=[O:9])=[O:10]
Reactant: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2Cl)c(F)c1
Agent: BrB(Br)Br
Product: O=S(=O)(c1ccc(-c2cc(F)ccc2O)cc1F)c1ccccc1Cl

Procedure:
The subtitle compound was prepared by the method of example 2 step (iii) using the product of step (iii) and boron tribromide.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Br:1][C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[C:13]([C:9]1[S:8][CH:12]=[CH:11][CH:10]=1)=[O:14]
Reactant: O=C(Cl)c1cccs1
Reactant: Brc1cscc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1cccs1)c1scc(Br)c1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 30 g of 3,4-dibromothiophene and 13.5 mL of thiophene-2-carbonylchloride in 120 mL of carbon disulfide was added 16.5 g aluminum trichloride portionwise over 10 minutes. The mixture was stirred for 3 hours, poured into 900 g of ice-water and extracted with methylene chloride. The organic layer was washed with 1N NaOH (aq), water, and dried (MgSO4). Filtration and concentration of the filtrate, in vacuo, afforded an oil which crystallized upon trituration with n-chorobutane to yield 32 g of the subject compound as an off-white solid, m.p. 105°-109° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:22][CH:21]4[N:23](C)[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.ClC(OC(Cl)C)=O.C(N(C(C)C)CC)(C)C>ClCCCl>[CH:21]12[NH:23][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]([N:6]1[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][C:14]=3[S:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22]2
Reactant: CN1C2CCC1CC(N1c3ccccc3Sc3cc(Br)ccc31)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Brc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine, 3i (1.0 g, 2.49 mmol) in 1,2-dichloroethane (15 mL) were added 1-chloroethyl chloroformate (807 μL, 7.5 mmol) and N,N-diisopropyl-N-ethylamine (1.4 mL, 7.97 mmol). The mixture was heated to reflux for 2.5 h, allowed to cool to rt, and evaporated. The mixture was evaporated and the residue was dissolved dissolved in methanol (15 mL) and heated to reflux for 1 h. After work-up, the residue was purified via flash column chromatography (eluent gradient: 0 to 30% MeOH in EtOAc containing 1% triethylamine) to yield 150 mg of recovered starting material 3i and 382 mg (66%) of title compound 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i as a mixture of endo and exo isomers. MS m/z (MH+) 387.1/389.1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:21]([OH:28])[CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](=[O:28])[CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cnc2c(c1)cc(C(O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cnc2c(c1)cc(C(=O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a 250 mL round bottomed flask charged with 1-(-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanol (2.3 g, 5.75 mmol) was added a solution of Dess-Martin periodinane in dichloromethane (0.3 M, 30 mL, 9 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 1-(-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanone (2.28 g, 99%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C21H22N2O4S [M+H]+ 399.48, observed 399.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:6]=[N:5][C:4]2=[N:15][N:16]=[CH:17][C:3]=12.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH2:6][N:5]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4]2=[N:15][N:16]=[CH:17][C:3]=12
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(-n2cnc3nncc-3c2N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(N2CN(C(=O)c3ccccc3)C3=NN=CC3=C2N)cc1
Reaction time: 0.75 h
Yield: 47.7 %

Procedure:
To a stirred solution of 4-amino-5-(4'-methylphenyl)pyrazolo[3,4-d]pyrimidine (0.40 g, 1.77 mmol) in pyridine (9 mL) was added benzoyl chloride (0.25 g, 1.77 mmol) dropwise. After 45 minutes, the pyridine was removed in vacuo and the resulting solids were washed with water and EtOH to afford 0.28 g of the title compound; m.p. 297°-300° C. Anal. calcd. for C19H15N5.0.75 H2O: C, 66.55; H, 4.85; N, 20.42. Found: C, 6.43; H, 4.69; N, 19.77.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]([NH:17][C:18]([NH:20][C:21]#[N:22])=[NH:19])([CH3:16])[CH3:15].[OH-].[Na+]>O>[ClH:1].[ClH:1].[F:2][C:3]([F:12])([F:13])[C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][C:21]([NH:20][C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[NH:19])=[NH:22])=[CH:6][CH:5]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)NC(=N)NC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NC(=N)NC(=N)NCc1ccc(C(F)(F)F)cc1

Procedure:
A stirred mixture of 6.9 g (0.035 mole) of p-trifluoromethylbenzylamine hydrochloride and 4.3 (0.035 mole) of 1-i-propyl-3-cyanoguanidine is immersed in a 180° C oil bath for 1 hour. The melt is cooled and dissolved in 35 ml of hot water. The solution is cooled in an ice bath, made alkaline with 40% sodium hydroxide solution, and extracted with 150 ml of ether. The ether layer is dried over potassium carbonate, filtered and the ether solution made strongly acidic with a saturated ethereal hydrochloric acid solution. The precipitate is washed twice with 25 ml of anhydrous ether and recrystallized from a mixture of ethanol and heptane (3:5) to obtain 1-(p-trifluoromethylbenzyl)-5-i-propylbiguanide dihydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C:6]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23]O)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[OH:7].C([O-])([O-])=O.[K+].[K+].ClC1C=CC(Cl)=CC=1[N+]([O-])=O.O.O.[C:45]([OH:50])(=[O:49])[C:46]([OH:48])=[O:47]>CS(C)=O.CC(C)=O.O>[CH3:25][N:2]([CH2:3][CH2:4][CH2:5][C@@:6]1([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[O:7][CH2:23][C:16]2[CH:17]=[C:18]([C:19]#[N:20])[CH:21]=[CH:22][C:15]1=2)[CH3:1].[C:46]([OH:48])([C:45]([OH:50])=[O:49])=[O:47]
Reactant: CN(C)CCCC(O)(c1ccc(F)cc1)c1ccc(C#N)cc1CO
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 10 gm of (RS)-(±)4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile in 50 ml of dimethylsulfoxide (DMSO) at room temperature was added 12 gm of anhydrous K2CO3 and 6.73 gm of 2,5-dichloronitrobenzene was added to the above reaction mixture at room temperature and stirred at 100° C. for 15 hours. To the reaction mixture, 250 ml of water was added and extracted with toluene, the toluene layer was washed with water and 5% sodium hydroxide solution and after acid base treatment yielded an oily product. The oil was dissolved in 40 ml of acetone at 30° C. and 3.4 gm of oxalic acid dihydrate was added to it, stirred, cooled, filtered and dried at 60° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>>[F:9][C:10]([F:20])([F:21])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccsc1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1ccsc1

Procedure:
Prepared in a similar manner to example 4 using thiophene-3-carboxylic acid and 4-trifluoromethoxy-benzylamine. MS (M+H, 302.0).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17].CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][C:16]([O:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=C(O)CCCBr
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)CCCBr
Temperature: 0 °C
Reaction time: 18 h

Procedure:
N-Boc-ethanolamine (2.10 g; 13.0 mmol), 4-Bromobutyric acid (2.18 g; 13.0 mmol) and N,N-dimethylaminopyridine (0.318 g; 2.60 mmol) were dissolved in CH2Cl2 (35 mL) and the mixture was cooled to 0° C.; EDAC (3.75 g; 13.6 mmol) was added and the reaction was slowly warmed to room temperature and stirred for 18 hours. Then the mixture was diluted with CH2Cl2, washed with aqueous Na2HPO4 (5%, 2×50 ml) aqueous NaH2PO4, (5%, 2×50 ml) and brine (1×40 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C:26]([CH2:25][C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:34][CH:33]=3)([OH:32])[CH2:31][CH2:30]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(CC2(O)CCNCC2)cc1
Product: COc1ccc(CC2(O)CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1

Procedure:
The title compound, MS: m/e=448.5 (M+H+), was prepared from 1-(2-bromoethoxy)-4-(benzyloxy)-benzene and 4-(4-methoxy-benzyl)-piperidin-4-ol.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:21]12[CH2:28][O:27][C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[C:36][Si](C)(C)C)=[CH:31][CH:30]=3)([O:25][CH2:26]1)[O:23][CH2:22]2)[CH3:20]>O1CCCC1>[CH2:19]([C:21]12[CH2:26][O:25][C:24]([C:29]3[CH:30]=[CH:31][C:32]([C:35]#[CH:36])=[CH:33][CH:34]=3)([O:23][CH2:22]1)[O:27][CH2:28]2)[CH3:20]
Reactant: CCC12COC(c3ccc(C#C[Si](C)(C)C)cc3)(OC1)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C23OCC(CC)(CO2)CO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Tetrabutyl ammonium fluoride solution (3.3 ml, 1M in tetrahydrofaran) was added to a stirred solution of 4-ethyl-1-[4-(2-trimethylsilylethynyl)-phenyl]2,6,7-trioxabicyclo[2,2,2]octane (0.87 gms) in tetrahydrofuran (15 ml). The mixture was stirred for 30 minutes at room temperature when the solvent was removed under vacuum. The residue was taken up in ether and washed with water and brine. The ethereal solution was dried over anhydrous magnesium sulphate and evaporated in vacuo. Recrystallisation from hexane gave 4-ethyl-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2,2,2]octane as an off-white solid (0.66 gms).
Reaction SMILES: [C:1]([C:11]1[S:27][C:14]2[C:15]3[S:23][C:22]4[C:21]5[S:24][CH:25]=[CH:26][C:20]=5[S:19][C:18]=4[C:16]=3[S:17][C:13]=2[C:12]=1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pt].C(OCC)(=O)C>[CH2:1]([C:11]1[S:27][C:14]2[C:15]3[S:23][C:22]4[C:21]5[S:24][CH:25]=[CH:26][C:20]=5[S:19][C:18]=4[C:16]=3[S:17][C:13]=2[C:12]=1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1sc2c(sc3c2sc2c4sccc4sc23)c1CCCCCCCCCC
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCc1sc2c(sc3c2sc2c4sccc4sc23)c1CCCCCCCCCC
Reaction time: 24 h

Procedure:
2-dec-1-ynyl-3-decanyldithieno[2,3-d:2′,3′-d′]thieno[3,2-b:4,5-b′]dithiophene (107) (2.2 g, 4.15 mmol) was dissolved into ethyl acetate (30 mL). To this solution, 5% Pt/C (0.5 g) was added. The mixture was stirred under a H2 atmosphere (90 psi) for 24 hours. The solution was then filtered. After removal of the ethyl acetate, the residue was purified by chromatography on silica gel eluted with hexane to produce the target compound (2.00, 90.5%). Mp. 50.9-52.5° C. 1HNMR: solvent, CD2Cl2δ 7.41 (d, 1H), 7.33 (d, 1H), 2.83 (t, 2H), 2.50 (t, 2H), 1.73-1.26 (m, 32H), 0.87 (m, 6H). 13CNMR: 140.85, 140.40, 139.93, 133.38, 133.14, 132.22, 129.69, 121.17, 120.09, 98.92, 32.29, 32.25, 29.99, 29.94, 29.72, 29.63, 29.52, 29.33, 29.18, 29.06, 28.94, 23.05, 14.23.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](Br)=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30]([CH3:33])(=[NH:32])=[O:31].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([N:32]=[S:30]([CH3:33])([CH3:29])=[O:31])=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(C)(=N)=O
Reactant: Cc1cc(Br)cc2ncnc(Nc3ccc(F)cc3OCc3ccccc3)c12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1cc(N=S(C)(C)=O)cc2ncnc(Nc3ccc(F)cc3OCc3ccccc3)c12
Temperature: 25 °C

Procedure:
3.1 g (7 mmol) of N-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine, 0.8 g (8.8 mmol) dimethylsulphoximine (V.1), 0.4 g (1.4 mmol) 2-(di-t-butylphosphino) biphenyl, 0.5 g (0.5 mmol) Pd2dba3 and 1.0 g (10.2 mmol) sodium tert-butoxide in dioxane are heated to 80° C. for 4.5 h. After cooling to RT the reaction mixture is filtered, diluted with water and extracted with EtOAc. The organic layers are pooled dried and evaporated. The residue is purified by FC giving rise to N-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-5-methyl-quinazolin-4-amine.
Reaction SMILES: C([Si:5](C)([C:12]1([CH2:18][CH:19]([CH3:21])[CH3:20])SCCCS1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CC=C.[OH2:23]>CC#N.Cl[Hg]Cl>[CH2:11]([CH2:10][C:6]1([SiH2:5][C:12](=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)[CH2:6][CH:7]=[CH2:8]
Reactant: O
Reactant: C=CCC[Si](C)(c1ccccc1)C1(CC(C)C)SCCCS1
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: C=CCCCC1([SiH2]C(=O)CC(C)C)C=CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 44 (6.19 g, 17.7 mmol) in CH3CN (200 mL) was added water (10 mL) and HgCl2 (24 g, 88 mmol). After stirring overnight at rt, the mixture was concentrated and partitioned between water (100 mL) and hexane (200 mL). The organic layer was isolated and the aqueous layer extracted twice with 50 mL portions of hexane. The combined organic extracts were washed with saturated aqueous NaCl and dried over Na2SO4. Concennation to dryness in vacuo at rt gave quantitatively crude ketone 45 as a yellow oil. This ketone was used in the next reaction without further purification: Rf 0.75 (1/19 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.41-7.35 (m, 3H), 5.91-5.78 (m, 1H), 4.99 (dd, J=17.0, 1.7 Hz, 1H), 4.90 (dd, J=10.0, 1.7 Hz, 1H), 2.44 (d, J=6.7 Hz, 2H), 2.16-2.06 (m, 3H), 1.16-1.07 (m, 2H), 0.78 (pd, J=6.7 Hz, 6H), 0.51 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([F:15])[F:14])[CH3:10].C(OCC)(=O)C>CN(C=O)C>[CH2:9]([O:11][C:12](=[O:17])[C:13]([F:15])([F:14])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: Fc1ccc(I)cc1
Reactant: CCOC(=O)C(F)(F)Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-Fluoro-4-iodobenzene (30 g, 135 mmol) and 2-bromo2,2-difluoroacetic acid ethyl ester (29 g, 142.9 mmol) were dissolved in DMF (100 ml) and Cu (21.5 g, 71.2 mmol) was added. The reaction mixture was heated at 90° C. for 18 h. Ethyl acetate (100 ml) was added and the reaction mixture was quenched with a solution of potassium dihydrogen phosphate (20 g) in water (200 ml). The resultant solution was stirred for 30 min, filtered and was washed with ethyl acetate. The organic layer was separated, washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give 2,2-difluoro-2-(4-fluorophenyl)acetic acid ethyl ester (26.5 g) as a yellow liquid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(=[O:7])=[O:6]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCOCC
Product: O=S(=O)(CCCCl)NC1CCN(Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
3-Chloropropanesulfonyl chloride (0.26 mL) was added to the ether solution (10 mL) containing 4-amino-1-benzylpiperidine (400 mg) at 0° C., followed by stirring for 3 hrs. The reaction mixture was concentrated under reduced pressure to give the title compound (678 mg).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=[CH:3]1.NN>CO>[NH2:10][CH2:9][CH2:8][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1nc(-c2ccccc2)ccc1=O
Agent: NN
Solvent: CO
Product: NCCn1nc(-c2ccccc2)ccc1=O
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2-(6-oxo-3-phenylpyridazin-1(6H)-yl)ethyl)isoindoline-1,3-dione (2.1 g, 6.1 mmol) and hydrazine (10 mL, 10.0 mmol) (THF) in MeOH (40 mL) was heated to 75° C. A clear solution was formed. After overnight (18 h), the slurry was cooled to room temperature and was filtered and washed with MeOH. The filtrate was concentrated and washed with 20% MeOH/CH2Cl2 to give a yellow solid (LCMS indicated the presence of product). The filtrate was concentrated under vacuum and was carried to next step.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]([F:30])([F:29])[C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[CH2:19][N:20]1[CH:24]=[N:23][C:22]([NH2:25])=[N:21]1>>[CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:25][C:22]3[N:23]=[CH:24][N:20]([CH2:19][C:18]4[CH:26]=[CH:27][CH:28]=[C:16]([C:15]([F:30])([F:14])[F:29])[CH:17]=4)[N:21]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1
Reactant: Nc1ncn(Cc2cccc(C(F)(F)F)c2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cccc(C(F)(F)F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-trifluoromethyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(O)[O-].[Na+].[N+:15]([CH2:18][CH2:19][CH3:20])([O-:17])=[O:16].[OH-].[Na+]>C(O)C.O>[N+:15]([CH:18]([CH2:19][CH3:20])[CH:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[OH:8])([O-:17])=[O:16]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCC[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C(O)c1ccc(C)cc1)[N+](=O)[O-]

Procedure:
The procedure of Example 1 was followed for the reaction of 120 g of p-tolualdehyde and 114 g of sodium bisulfite with 178 g of 1-nitropropane and 80 g of sodium hydroxide. Water and ethanol were the solvents. The product obtained was a clear, yellow liquid weighing 100 g; ir (film) 2.8 (s), 3.4 (m), 6.5 (s), 7.3 (m), 9.7 (m), 12.2 (s) microns.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[CH2:20]([O:19][P:18]([CH2:2][C:3]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOC(=O)c1cc(CBr)nc2ccccc12
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)c1cc(CP(=O)(OCC)OCC)nc2ccccc12
Temperature: 100 °C

Procedure:
Ethyl 2-(bromomethyl)quinoline-4-carboxylate (1.0 g, 3.4 mmol, as prepared above) was treated with triethyl phosphite (11.3 g, 68.0 mmol) and the resultant slurry was heated to 100° C. overnight. The reaction was concentrated under reduced pressure, diluted with DCM (50 mL), washed with sodium bicarbonate, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0:100-1:1 EtOAc/heptane) to afford compound 45a. Mass spectrum (LCMS, ESI pos.) Calcd. For C17H22NO5P: 352.1 (M+H). found 352.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28][C@@H:29]([OH:32])[C:30]#[CH:31]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:31]#[C:30][C@H:29]([OH:32])[CH3:28])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: C#C[C@@H](C)O
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 23.2 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (70 mg, 0.142 mmol), palladiumbisdichlorobistriphenylphosphine (9.96 mg, 0.014 mmol), copper(I) iodide (1.351 mg, 7.09 μmol) and TEA (0.099 ml, 0.710 mmol) in THF (6 ml) was added (2R)-3-butyn-2-ol (24.85 mg, 0.355 mmol) and the reaction mixture was irradiated in a personal microwave reaction for 10 minutes at 120° C. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(3R)-3-hydroxy-1-butyn-1-yl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (16 mg, 0.033 mmol, 23% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.24-7.45 (m, 3H), 7.11 (s, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 4.47-4.70 (m, 3H), 1.41 (d, 3H). LC-MS (ES+) m/z 482.03, [M+H].