Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][Cl:34])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.415 mmol) in N,N-dimethylacetamide (3.0 mL) was added chloroacetyl chloride (52.8 μL, 0.664 mmol), and the mixture was stirred at room temperature for 4 hr. Chloroacetyl chloride (26.4 μL, 0.332 mmol) was further added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (15 mL), 5% aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[4-chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide as an oily residue.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[K+]>C(Cl)Cl>[CH:2]([CH:3]1[CH2:4][C:8]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])=[CH2:1]
Reactant: ClC/C=C/CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
The following experiment demonstrates the in situ preparation of the onium compound in the process. In a reaction flask were added 137.5 g (1.1 mol) trans 1,4-dichlorobutene-2, 160.0 g (1.0 mol) diethyl malonate, 600 cc methylene chloride and 6.8 g (5 mol % based on diethyl malonate) N,N-dimethylbenzylamine. The mixture was stirred at ambient temperature for 20 minutes and 124.8 g (2.0 mol) flaked 90% potassium hydroxide then added in small portions over a one-hour period while maintaining the reaction temperature at 25° C. with external cooling. The reaction was then stirred at ambient temperature for four hours. Diethyl 2-vinylcyclopropane-1,1-dicarboxylate (126.6 g; 59.8% yield) was obtained. In a similar manner, 5 mol % tri-n-butylphosphine was employed in the reaction and 69.6% yield diethyl 2-vinylcyclopropane-1,1-dicarboxylate obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:9][CH2:10][CH2:11][C:12]1=[O:13]
Reactant: O=C1CCCO1
Reactant: Nc1ccccc1Cl
Product: O=C1CCCN1c1ccccc1Cl
Yield: 25.4 %

Procedure:
Following example 19, 12.57 g (0.1 M) of 2-chloroaniline and 9.5 g (0.11 M) of γ-butyrolactone were heated for 48 hours. The excess starging materials were removed at 50°-80°/0.3 mm. Distillation of the residue gave 4.9 g (25%) of product (45% based on recovered 2-chloroaniline); b.p. 150°-155°/0.3-0.4 mm.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:4]([C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[O:1][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CC(C)(C)OC(=O)n1ncc2c(CCl)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2cccc3c2cnn3C(=O)OC(C)(C)C)c(C=O)c1
Temperature: 80 °C
Yield: 76.7 %

Procedure:
A mixture of 2-hydroxy-5-methoxybenzaldehyde (46 mg, 0.3 mmol), tert-butyl 4-(chloromethyl)-1H-indazole-1-carboxylate (80 mg, 0.3 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (1.0 mL) was heated at 80° C. for 2 h. The mixture was filtered and the solid was washed with DCM. The filtrate was concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give tert-butyl 4-((2-formyl-4-methoxyphenoxy)methyl)-1H-indazole-1-carboxylate (88 mg, 77%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:32])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:41]([O:45][C:46](=[O:49])[CH2:47]Br)([CH3:44])([CH3:43])[CH3:42].O>C(#N)C>[C:41]([O:45][C:46](=[O:49])[CH2:47][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]2=[O:32])=[CH:33][CH:34]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(4-hydroxybenzyl)-3-tritylthiazolidin-2,4-dione (20.0 g) in acetonitrile (200 ml) was added cesium carbonate (21.0 g), followed by bromoacetic acid t-butyl ester (7.4 ml) and the mixture was stirred at 25° C. for 3 hours. To the reaction mixture was added water and the organic layer was separated and concentrated in vacuo. The residue was extracted with toluene and the extract was washed with diluted hydrochloric acid and water and concentrated in vacuo to give the desired compound (24.9 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[C:31]([CH3:39])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[C:31]([CH3:39])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1ccc(C(F)(F)F)c2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(F)(F)F)c2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 51.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methyl-7-trifluoromethylbenzothiazole (116 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 94 mg (52%) of the title compound as an amorphous foam. mp 50°-54°. FDMS: m/e=476.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: COc1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-methoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.CC(C)[O-].[Al+3:24].CC(C)[O-].CC(C)[O-].O>C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.[Al+3:24].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O
Solvent: CC(C)O
Product: CC(C(=O)[O-])c1ccc2c(c1)Cc1cccnc1O2

Procedure:
2.5 G of 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid is dissolved in 80 ml of isopropyl alcohol. A solution of 2.1 g of aluminum isopropoxide in 25 ml of isopropyl alcohol is added dropwise to the solution with stirring, white crystals being immediately yielded. After refluxing the mixture for 1 hour, 3 ml of water is added, and then the whole mixture is further refluxed for 1 hour. After cooling, the crystals are filtered off, washed with isopropyl alcohol, and dried to give aluminum 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate as white crystals melting at above 250°C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:11][CH2:12][CH2:13][CH:14]1[O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH:2]=[O:1]
Reactant: O=Cc1cccc(CO)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=Cc1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
This alcohol (0.44 mole) was dissolved in CH2Cl2 (500 mL). DHP (50 g, 59 mole) and PTSA (1 g, 5 mmol) were added and the mixture was stirred overnight at r.t. After concentration in vacuo, the residue was purified by flash chromatography (5%→15% EtOAc in toluene) to give 85 g of the title compound.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]([F:37])([F:36])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=3)=[N:19]2)=[CH:14][CH:13]=1>CS(C)=O>[F:37][C:10]([F:9])([F:36])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:4][CH:30]4[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To an oven-dried round bottomed flask was added sodium hydride (60% oil immersion, 0.380 g, 9.50 mmol) and anhydrous dimethyl sulfoxide (30 mL). Gas evolution occurred, and the solution was stirred at room temperature for 15 minutes. Trimethylsulfoxonium iodide (2.10 g, 9.54 mmol) was added, the flask neck was rinsed with anhydrous dimethyl sulfoxide (5 mL), and the reaction was stirred for 15 minutes. To the reaction was added (E)-ethyl 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (C17) (3.22 g, 7.98 mmol) as a solid. The reaction was stirred at room temperature for 30 minutes, and then quenched with water and extracted with 1:1 ethyl acetate/hexanes (2×). The combined organic layers were washed with water (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as a yellow oil (1.50 g, 41%): 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.39 (dd, J=6.6, 5.9 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 4.19 (dt, J=14.0, 7.0 Hz, 2H), 2.64-2.52 (m, 2H), 1.97 (ddd, J=8.5, 5.3, 4.2 Hz, 1H), 1.71-1.61 (m, 1H), 1.42-1.32 (m, 1H), 1.29 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 418 ([M+H]+).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12]C)=O)=[O:7])(C)(C)C.Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CCCCCCC.CCOC(C)=O>[Si:26]([O:25][CH2:24][CH2:23][O:21][C:18]1[CH:17]=[CH:16][C:15]([C@@H:14]2[O:7][C:6](=[O:5])[NH:8][C@H:9]2[CH2:10][O:12][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:20][CH:19]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for intermediate 11 starting with (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate and (2-bromoethoxy)(tert-butyl)dimethylsilane. TLC (heptane/EtOAc 1:1) Rf=0.51; tR=1.764 min (UPLC 1); LC-MS: [M+H] 482; Rt 1.57 min; (LCMS method 1); 1H NMR (400 MHz, CDCl3): 7.31 (d, 2H), 6.96 (d, 2H), 5.26 (br s, 1H), 5.22 (d, 1H), 4.13 (m, 2H), 4.00 (m, 2H), 3.79 (m, 1H), 3.67 (m, 2H), 0.93 (s, 9H), 0.92 (s, 9H), 0.11 (m, 12H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH:12]([OH:14])[CH3:13])=[CH:10][N:11]=1>ClCCl.[O-2].[Mn+4].[O-2]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([C:12](=[O:14])[CH3:13])=[CH:10][N:11]=1
Reactant: CC(O)c1cnc(-c2ccccn2)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1cnc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
The compound prepared in Example 357 (2.5 g) was dissolved in 80 mL of dichloromethane and manganese (IV) oxide (21 g) was added stirred overnight at room temperature. The reaction mixture was filtered through a plug of Celite (trade mark), washed with dichloromethane, and concentrated under reduced pressure to afford the title compound (2.35 g) having the following physical data. 1H NMR (CDCl3): δ 8.64 (d, J=4.5 Hz, 1H), 8.39 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.83 (m, 1H), 7.39 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3OC(=O)[S:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:17]([C:27]#[N:28])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[N:28]=[C:27]([S:17]([C:20]4[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[S:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: O=c1oc(C2(c3ccc(Cl)cc3)CC2)ns1
Solvent: Clc1ccccc1Cl
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)c2nc(C3(c4ccc(Cl)cc4)CC3)ns2)cc1
Yield: 83.5 %

Procedure:
5.00 g (19.71 mmol) of 5-[1-(4-chlorophenyl)cyclopropyl]-1,3,4-oxathiazol-2-one and 3.75 g (20.69 mmol) of tosyl cyanide are stirred in 14 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled, 10 ml of pentane are added and the precipitate is filtered off and dried under vacuum. 6.43 g of product are obtained (86.7% purity, 72.3% yield; log P (pH2.3)=4.97).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)=[O:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[C:19]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[N:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[C:19]([CH:29]=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:18]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: N[C@H]1CC[C@@H](CNC(=O)C(F)(F)F)CC1
Reactant: COc1ccc2nc(C=Cc3ccccn3)nc(Cl)c2c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(C=Cc3ccccn3)nc(N[C@H]3CC[C@@H](CNC(=O)C(F)(F)F)CC3)c2c1

Procedure:
A solution of 140 mg of cis-4-trifluoroacetylaminomethylcyclohexylamine in 15 mL of toluene was combined with 180 mg of 4-chloro-6-methoxy-2-[2-(2-pyridyl)ethenyl]quinazoline, 500 mg of triethylamine and 20 mg of 4-dimethylaminopyridine, and heated under reflux for 15 hours. After the reaction solution was distilled off, the residue was combined with water, and extracted with chloroform. After drying over magnesium sulfate and concentrating, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 140 mg of the desirable compound.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:14]#[N:15])([CH2:12][CH3:13])[CH2:9]1)=O)(C)(C)C.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[C:14]([C:10]1([CH2:12][CH3:13])[CH2:11][NH:8][CH2:9]1)#[N:15]
Reactant: CCC1(C#N)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(C#N)CNC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, 3-cyano-3-ethyl-azetidine-1-carboxylic acid tert-butyl ester (0.40 g, 1.9 mmol) was dissolved in dichloromethane (12 mL). The light yellow solution was cooled to 0° C. and trifluoroacetic acid (4.4 mL) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to afford 3-cyano-3-ethyl-azetidine trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)([CH3:4])[CH3:3].[ClH:16].O1CCOCC1>C(Cl)Cl>[ClH:16].[NH:7]1[CH2:8][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(C(C)(C)O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(O)C1CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of tert-butyl 3-(2-hydroxypropan-2-yl)azetidine-1-carboxylate (0.87 g, 4.04 mmol) in DCM (15 mL) at 0° C. was added 4 M HCl in dioxane (8.08 mL, 16.16 mmol) dropwise. The reaction was stirred overnight at RT. The reaction mixture was concentrated and dried in vacuo to generate 2-(azetidin-3-yl)propan-2-ol hydrochloride as a brown solid (0.44 g, 71.8% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12](=O)[CH3:13].[NH2:15][C:16]([NH2:18])=[S:17]>>[NH2:18][C:16]1[S:17][CH:13]=[C:12]([C:3]2[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([F:10])[C:4]=2[F:11])[N:15]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1c(F)c(F)c(F)c(F)c1F
Product: Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)cs1
Yield: 86.7 %

Procedure:
Using 2′,3′,4′,5′,6′-pentafluoroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(Br)cc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of 2.17 g (10.0 mmol) of 5-bromo-2-methoxybenzyl alcohol in 10 mL of N,N-dimethylformamide was added 1.36 g (20.0 mmol) of imidazole, then 2.26 g (15.0 mmol) of tert-butyldimethylsilyl chloride. The reaction was stirred at ambient temperature for 30 min, and poured into 100 mL of water. The aqueous suspension was extracted with diethyl ether (3×15 mL), then the combined ether layers were back extracted with 1 M HCl (2×15 mL), saturated NaHCO3(aq.) (2×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 95:5 hexanes:ethyl acetate to give 2.91 g (88%) of the titled compound as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[CH:10][N:9]=[C:8]([NH2:13])[N:7]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:18][C:14](=[O:17])/[CH:15]=[CH:16]/[C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:13])=[N:9][CH:10]=1
Reactant: C=CC(=O)OC
Reactant: Nc1ncc(I)c(-c2ccco2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cnc(N)nc1-c1ccco1

Procedure:
From 4-furan-2-yl-5-iodo-pyrimidin-2-ylamine, methyl acrylate, bis(triphenylphosphine)palladium(II) chloride and cesium carbonate in dioxane. EI-MS m/e (%): 245 (M+, 54), 228 ([M—NH3]+, 100), 186 ([M—CO2Me]+, 56), 158 (52).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:10][C:11]([OH:13])=O)[N:4]=1)[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[CH3:33][N:34]([C@H:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][CH2:50][CH2:49]1)[C:35]([C:37]1[N:38]=[C:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[S:40][CH:41]=1)=[O:36].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:10][C:11]([N:45]2[CH2:46][CH2:47][CH:42]([C:39]3[S:40][CH:41]=[C:37]([C:35]([N:34]([CH3:33])[C@H:48]4[C:57]5[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=5)[CH2:51][CH2:50][CH2:49]4)=[O:36])[N:38]=3)[CH2:43][CH2:44]2)=[O:13])[N:4]=1)[CH3:2]
Reactant: CCc1cc(CC)n(CC(=O)O)n1
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(CC)n(CC(=O)N2CCC(c3nc(C(=O)N(C)[C@@H]4CCCc5ccccc54)cs3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-diethyl-1H-pyrazol-1-acetic acid (135 mg, 0.74 mmol) (i.e. the product of Example 15, Step C) in ethyl acetate (5.0 mL) was treated with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.0 mL, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6, Step C) (210 mg, 0.53 mmol), triethylamine (0.5 mL, 3.75 mmol) in ethyl acetate (5 mL). The reaction mixture was then stirred at room temperature for 12 h. The resulting suspension was concentrated in vacuo and purified by MPLC on silica gel using ethyl acetate/hexanes as eluant to give 60 mg of the title product, a compound of the present invention as an oil.