Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:3]2[CH:4]=[C:5]([CH2:6][NH2:7])[CH:8]=[CH:9][CH:10]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: NCc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: NCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A suspension of 3-bromobenzylamine hydrochloride 22 (1 g, 4.49 mmol) in DME (50 mL) was added with 4-trifluoromethyl phenyl boronic acid (1.2 mol eq, 1.0 g) and NaHCO3 (3 mol eq, 1.13 g) suspended in water (30 mL). The mixture was degassed under vacuum, then Tetrakispalladium was added (catalytic amount) and the reaction was stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (80 mL). The aqueous phase was extracted with EtOAc (3×40 mL) and the combined organic layer was washed with brine (50 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to afford 23A as a pale brown oil (1.5 g, quantitative yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([S:7]([C:10]1[CH:11]=[C:12]([C:20]([OH:22])=O)[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8])[CH3:6]>CN(C)C=O>[CH2:5]([S:7]([C:10]1[CH:11]=[C:12]([C:20]([Cl:3])=[O:22])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8])[CH3:6]
Reactant: CCS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Yield: 99.7 %

Procedure:
243 g of thionyl chloride, a few drops of dimethyl formamide and 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated and then the thionyl chloride in excess was distilled off under vacuum. 148 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 146°-147° C.; yield: 100%).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.I(O)(=O)(=O)=[O:15].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH:1]1([S:4]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=[N+]([O-])c1ccc(SC2CC2)cc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)C2CC2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
1-Cyclopropylsulphanyl-4-nitrobenzene in acetonitrile was admixed with iron(III) chloride and stirred at room temperature. Periodic acid was then added in portions. The mixture was stirred for 30 minutes and then added, with stirring, to a cooled, saturated sodium thiosulphate solution. Extraction was carried out with acetic ester (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified by means of chromatography (hexane/acetic ester 1:1) (yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:14](/[N+:11]([O-:13])=[O:12])\[CH3:15])=[C:4]([F:10])[CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1F
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C/C(=C\c1ccc(Cl)cc1F)[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.4 %

Procedure:
4-Chloro-2-fluorobenzaldehyde (10 g, 63.1 mmol), nitroethane (54.6 mL, 757 mmol) and piperidine (1.869 mL, 18.92 mmol) were dissolved in toluene (150 mL) and refluxed under Dean Stark conditions overnight. The reaction mixture was cooled to room temperature and the solvents were evaporated. The crude product was purified by column chromatography (silica, heptane/EtOAc 98:2) to give the desired product (10.4 g, 76%) as a yellow solid.
Reaction SMILES: [Br:1][C:2](=C)[CH2:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:5]([C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH:9]=C)=[O:6]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[Br:1][C:2]1[CH2:3][N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:5](=[O:6])[C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]=1
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)Br)Cc1ccc(OC)cc1OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COc1ccc(CN2CC(Br)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 15.8 %

Procedure:
[1,3-bis-(2,4,6-trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] (Grubbs second generation catalyst) (1.78 g, 2.05 mmol) was added to a solution of benzyl (1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl) amino]carbonyl}but-3-enylcarbamate (5.29 g, 10.2 mmol) in dichloromethane (1000 mL) and heated to 40° C. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (0.79 g). MS 489 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.36-7.35 (m, 4H), 7.33-7.30 (m, 1H), 7.17-7.15 (m, 1H), 6.46-6.43 (m, 2H), 6.13 (d, J=6.1 Hz, 1H), 6.04-6.03 (m, 1H), 5.13-5.07 (m, 2H), 4.93-4.88 (m, 1H), 4.75 (d, J=14.4 Hz, 1H), 4.64-4.60 (m, 1H), 4.47 (d, J=14.4 Hz, 1H), 3.86 (d, J=18.3 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.68-2.63 (m, 1H), 2.24-2.05 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19](O)=[O:20].[CH:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][C:33]=2[C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>C(Cl)Cl>[Cl:17][C:4]1[CH:5]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:18][C:19]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:28]2[CH2:27][CH2:26][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:30][CH2:29]2)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)=[O:20]
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3c(Cl)cc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 7 but using (2,6-dichloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (WO 03/099771). Title compound: ES-MS: 604.9/606.9 [M+H]+; tR=3.89 min (System 1); Rf=0.23 (CH2Cl2/(2N NH3 in MeOH), 95:5).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.CN(C)C=O.[CH3:15][S:16]([O-:18])=[O:17].[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(Br)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 4-bromobenzyl bromide (5 g, 20 mmol) and N,N-dimethylformamide (10.81 mL). Sodium methanesulfinate (3.06 g, 30 mmol) was added. The reaction mixture was stirred at 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with water. The resulting suspension was stirred for 10 minutes and filtered. The solid was rinsed with water and dried under vacuum to provide the title compound (4.75 g, 95% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=O)[C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[C:6]2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:22])[C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[C:6]2[O:5]1
Reactant: CN1CC(CCCl)Oc2cc3ccccc3nc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2cc3ccccc3nc2C1=S
Yield: 86.9 %

Procedure:
To 3.0 g (0.01 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]-quinolin-5(4H)-one in 30 ml of acetonitrile was added 1.3 g (0.006 mole) of phosphorus pentasulfide. The mixture was stirred vigorously at reflux for 2 hr. After cooling, the reaction mixture was diluted with 60 ml of toluene and filtered. The residue on the filter paper was washed with 50 ml of additional toluene/acetonitrile, 3/1, V/V. The filtrate was washed with 3×50 ml saturated sodium carbonate (caution: gas evolved), dried over anhydrous sodium sulfate, filtered, treated with activated charcoal, filtered again and concentrated by rotary evaporation (90° C., 30 mm). The residual syrup was crystallized from isopropyl alcohol, yielding 1.6 g (52%) of yellow crystals, m.p. 114°-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:24]2[CH2:25][CH2:26][CH:21]([C:19](=[O:20])[C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH2:22][CH2:23]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: Cl
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)cn2)CC1
Yield: 99.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 5-bromopyridine-2-carboxylic acid (1.2 g) and (4-chlorophenyl)piperidin-4-ylmethanone hydrochloride (1.6 g), the title compound (2.4 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][S:9]2)=[CH:4][CH:3]=1.[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:7]1[C:6](=[O:12])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9][CH2:8]1
Reactant: O=C1CCSc2cc(Cl)ccc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc(Cl)cc2SCC1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 7-chlorothiochroman-4-one (10 gms., 50.3 mmols) in chloroform (100 ml.) and cool the solution to 0°-5° C. Add bromine (2.60 ml., 50.3 mmols) dropwise over a 10-minute period. Stir the reaction mixture at room temperature for one hour, then add chloroform (100 ml.) and extract with 10% aqueous sodium sulfite (100 ml.) followed by water (200 ml.). Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo to a residue. Recrystallize the residue from cyclohexane to give 3-bromo-7-chlorothiochroman-4-one, m.p. 109°-110° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:33]([C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[CH3:25])(=[O:34])=[O:35])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F
Yield: 46 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (0.082 g, 0.239 mmol) and 2-methyl 5-fluorobenzenesulfonyl chloride (0.055 g, 0.263 mmol) the title compound was obtained (57 mg, 0.11 mmol, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 7.91 (d, J=5.3 Hz, 1H), 7.44 (dd, J=8.8, 2.6 Hz, 1H), 7.29-7.42 (m, 3H) 7.16-7.29 (m, 2H), 6.71 (s, 2H), 5.73 (d, J=5.1 Hz, 1H), 2.49 (s, 3H), 1.35 (s, 9H). MS (ES+): 516 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][O:25][C:24](=[O:27])[NH:23]2)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[Cl:14][C:4]1[N:3]=[C:2]([N:23]2[CH:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:26][O:25][C:24]2=[O:27])[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=1
Reactant: O=C1NC(c2ccc(F)cc2)CO1
Reactant: Cn1cc(-c2cc(Cl)nc(Cl)c2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Cl)nc(N3C(=O)OCC3c3ccc(F)cc3)c2)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
379 mg of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, 300 mg of 4-(4-fluorophenyl)oxazolidin-2-one, 192 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 705 mg of tripotassium phosphate and 172 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 10 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 212 mg of the objective compound as yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28].C1(C2OC3C=CC=CC=3C=2C(=O)C2C=CC(O)=CC=2)C=CC=CC=1.C(N(CC)CCCCl)C>>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([C:13]2[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[O:10][C:9]=2[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:22])=[CH:20][CH:19]=1)[CH3:28]
Reactant: Cc1cc(C)cc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)c1
Reactant: CCN(CC)CCCl
Agent: CCN(CC)CCCCl
Agent: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3cc(C)cc(C)c3)oc3ccccc23)cc1

Procedure:
Reaction of 2-(3,5-dimethylphenyl)-3-(4-hydroxybenzoyl)benzofuran with 2-diethylaminoethyl chloride by the procedure described in Example 1 for 2-phenyl-3-(4-hydroxybenzoyl)benzofuran and 3-diethylaminopropyl chloride gives 3-[4-(2-diethylaminoethoxy)benzoyl]-2-(3,5-dimethylphenyl)benzofuran.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:37]([C:35]1[CH:34]=[CH:33][C:32]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[C:31]([O:30][CH3:29])[CH:36]=1)#[N:38]
Reactant: COc1cc(C#N)ccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc(C#N)ccc1O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.5 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-methoxy-4-cyanophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.50 mg, 76.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.38 (s, 1H), 7.37 (d, 2H, J=2.4 Hz), 7.20 (m, 4H), 7.10 (d, 1H, J=2.4 Hz), 7.08 (s, 1H), 6.99 (apparent d, 1H, J=8.3 Hz), 6.76 (apparent d, 1H, J=8.3 Hz), 5.43 (apparent dd, 1H, J=5.1, 8.0 Hz), 3.91 (s, 3H), 3.34 (m, 2H), 2.63 (m, 2H), 2.63 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.7 Hz), 2.30–2.10 (m, 6H), 1.82 (m, 2H), 1.28 (d, 6H, J=6.8 Hz); ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15](Cl)=[N:14][CH:13]=[N:12]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH3:29])=[CH:23][CH:22]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15]([N:28]([CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[CH3:29])=[N:14][CH:13]=[N:12]2
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(Cl)ncnn12
Reactant: CNCc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(C)c2ncnn3c(C)nc(-c4cnn(C)c4Br)c23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-4-chloro-7-methylimidazo[5,1-f][1,2,4]triazine (9.80 g, 29.9 mmol) in dichloromethane (100 mL) was treated with 1-(4-methoxyphenyl)-N-methylmethanamine (4.52 g, 29.9 mmol). After stirring at room temperature for 10 minutes, the reaction was diluted with saturated aqueous sodium bicarbonate solution (100 mL) and stirred for an additional hour. The organic layer was then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the product as a solid. Yield: 12.9 g, 29.2 mmol, 98%. LCMS m/z 443.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.71 (s, 3H), 2.79 (s, 3H), 3.78 (s, 3H), 3.89 (s, 3H), 4.67 (br s, 2H), 6.82 (br d, J=8.7 Hz, 2H), 7.10 (br d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])=[CH2:2].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7])=[CH2:2]
Reactant: C=Cc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1cccc(C(=O)Cl)c1

Procedure:
To a mixture of 3-vinylbenzoic acid (1.0 g, 6.75 mmol) in CH2Cl2 (20 mL) is added oxalyl chloride (2.35 mL, 3.42 g, 26.9 mmol) and 1 drop of DMF. After 2 h the solvent is removed under reduced pressure and the residue is redissolved in CH2Cl2 and concentrated again (4×) to afford the title compound which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)[N:15]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH3:10].C(=O)([O-])[O-:28].[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)[N:15]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:10])=[O:28]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1SC
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1S(C)=O
Reaction time: 1 h

Procedure:
In 150 ml of chloroform-ethanol was suspended 3.40 g of 2-(3-methoxy-4-methylthiophenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole. Thereto was added, in small portions, 1.97 g of methachloroperbenzoic acid (80%) under ice-cooling. The mixture was stirred for 1 hour. Then, the mixture was returned to room temperature and stirred overnight. Thereto was added an aqueous sodium carbonate solution. The mixture was extracted with chloroform three times. The combined extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the resulting crystals were recrystallized from dimethylformamide to obtain 0.50 g of 2-(3-methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as light yellow acicular crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.ClC1C=C(Cl)C=C(Cl)C=1[O:24][C:25](=O)[CH:26]([CH3:39])[C:27](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:28].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:27]([OH:28])=[C:26]([CH3:39])[C:25](=[O:24])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CCCCCCCSc1nnc(N)s1
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: CCCCCCCSc1nn2c(=O)c(C)c(O)nc2s1
Reaction time: 0.75 h
Yield: 78 %

Procedure:
A mixture of 19.7 g of the thus obtained 2-amino-5-heptylthio-1,3,4-thiadiazole, 40.9 g of bis(2,4,6-trichlorophenyl)-2-methyl-malonate and 55 ml of chlorobenzene was stirred at 140°~144° C. for 45 minutes. After cooling, n-hexane was added thereto, the precipitate was collected by filtration. Further n-hexane was added to the filtrate, and the precipitate was collected The collected precipitates were combined. The combined precipitate was washed with n-hexane and thus 21.2 g of 2-heptylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo-[3,2-a] pyrimidin-5-one was obtained. m.p. 141°~143° C. Yield 78%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([C:45]([F:48])([F:47])[F:46])[CH2:42][C@H:41]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:52]([O:51][C:50]([NH:49][C@H:41]1[CH2:42][C@@H:43]([C:45]([F:48])([F:47])[F:46])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1)=[O:56])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxylic acid (0.014 g, 0.034 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.015 g, 0.041 mmol) and HATU (0.033 g, 0.086 mmol) in DMF (0.14 mL), DIPEA (0.018 mL, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the sub-title compound. LCMS calc. for C39H46F3N8O5 [M+H]+: m/z=763.4. found: 763.5.