Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:27]=O)=[CH:22][CH:21]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:27]=[C:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[O:8]
Reactant: NC(=O)c1sc2ccc(C(F)(F)F)cc2c1O
Reactant: COc1ccc(C(C=O)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=CNC(=O)c2sc3ccc(C(F)(F)F)cc3c2O)c2ccc(OC)cc2)cc1
Yield: 78.9 %

Procedure:
To a solution of 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (300 mg, 1.15 mmol) in hot toluene (30 ml) were added 2,2-di-(4-methoxyphenyl)acetaldehyde (380 mg, 1.48 mmol) and p-toluenesulfonic acid monohydrate (20 mg). The reaction mixture was stirred at reflux temperature for one hour with azeotropic removal of water, cooled, and evaporated. Trituration of the residue with diethyl ether gave a yellow solid that was filtered, washed with ether, and dried in vacuo; to yield 453 mg (79%) of 3-hydroxy-N-[2,2-di(4-methoxyphenyl)ethenyl]-5-trifluoromethylbenzo[b]-thiophene-2-carboxamide, m.p. 178°-183° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][C:4]#[N:5].[N+:7]([CH3:10])([O-:9])=[O:8].C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:1][C:2]([CH3:6])([CH2:10][N+:7]([O-:9])=[O:8])[CH2:3][C:4]#[N:5]
Reactant: C[N+](=O)[O-]
Reactant: C=C(C)CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(CC#N)C[N+](=O)[O-]
Temperature: 103 °C
Yield: 93.6 %

Procedure:
In a one liter glass reactor equipped with a thermometer, a cooling apparatus and a stirrer, 3-methyl-3-butenenitrile (37.0 g, 0.456 mol) and nitromethane (557.0 g, 9.125 mol) were charged. Then, 1,8-diazabicyclo[5.4.0]-7-undecene (13.9 g, 0.091 mol) was dropwise added over a period of 5 minutes at room temperature while stirring. After the dropwise addition, the mixture was heated and refluxed at 103° C. for 13.5 hours. After cooling the mixture to room temperature, unreacted nitromethane was evaporated off under reduced pressure. To the residue, dichloromethane (300 g) and 5% sulfuric acid (300 g) were added and stirred. Thereafter, the mixture was phase separated to obtain a dichloromethane layer. To the aqueous layer, dichloromethane (300 g) was added and the mixture was phase separated to obtain a dichloromethane layer. Two dichloromethane layers were combined and washed with water (300 g). After drying the dichloromethane solution over anhydrous sodium sulfate, dichloromethane was evaporated off under reduced pressure to obtain brown crystal 3,3-dimethyl-4-nitrobutanenitrile (60.7 g), a purity of which was 92.0%. Its yield was 86.1% based on 3-methyl-3-butenenitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH2:29][CH2:30][CH3:31]>CS(C)=O.O>[CH2:28]([O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17])[CH2:29][CH2:30][CH3:31]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1

Procedure:
1.5 gm (5 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°-165° C., were stirred with 1.05 gm of potassium carbonate and 0.9 ml of n-butyl bromide in 15 ml of dimethyl sulfoxide for 60 hours. The mixture was subsequently diluted with water, and the reaction product was extracted with toluene. After washing, drying and evaporating the extract, the residue (1.7 gm) was recrystallized from cyclohexane. Yield: 1.2 gm (67% of theory); m.p.: 72°-74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:5].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>O1CCCC1>[N:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:1][C:21]2=[O:22])=[CH:12][CH:13]=1
Reactant: Nc1ccccc1C(=O)NCCCSc1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)n1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
Under nitrogen atmosphere, to a solution of 718 mg (2.5 mmol) of 4-[3-(2-aminobenzoylamino)propylthio]pyridine in 15 ml of tetrahydrofuran, 811 mg (5.0 mmol) of 1,1'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off and the residue was dissolved in chloroform. The solution was washed with water and dried. The solvent was distilled off and the residue was recrystallized from ethanol/chloroform/ether to give 514 mg of the desired product (65.7% yield, white crystals).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].Cl.[F:27][C:28]([F:37])([F:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]4[CH2:32][CH2:31][N:30]([CH2:29][C:28]([F:36])([F:37])[F:27])[CH2:35][CH2:34]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: FC(F)(F)CN1CCNCC1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN1CCN(CC(F)(F)F)CC1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 76.6 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and commercially available 1-(2,2,2-trifluorethyl)piperazine hydrochloride (CAS 13349-91-2) (87 mg, 0.422 mmol) in acetonitrile (1 ml) with diisopropylethyl amine (0.24 ml, 1.405 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (105 mg, 77%), MS (ISP) m/e=488.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([S:28][CH3:29])[N:22]=1.Cl>C1COCC1.O>[Cl:20][C:21]1[CH:26]=[C:25]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:2]([F:9])([F:8])[F:1])[N:24]=[C:23]([S:28][CH3:29])[N:22]=1
Reactant: FC(F)(F)[C@@H]1CCCN1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
(2S)-2-(Trifluoromethyl)pyrrolidine (858 mg, 6.17 mmol) was dissolved in THF (10 mL) in a 250 mL RB flask. The mixture was cooled in an ice bath. Then molecular sieves were added and let stir for 5 minutes. LiHMDS (6.78 mL, 6.78 mmol) was added slowly followed by addition of 4,6-dichloro-2-(methylthio)pyrimidine (1.444 g, 7.40 mmol), and the reaction was stirred at 0° C. for an additional 10 minutes. Then water (10 mL) was added followed by dropwise addition of 6N HCl until pH was acidic. The mixture was then extracted with EtOAc (3×30 mL) and the organic was combined, washed with saturated NaCl, filtered and concentrated. The crude oil was purified on Biotage 25 g SNAP column with a gradient of 0 to 35% EtOAc in Hexane over 25 minutes to afford the title compound (1.42 g) as a clear oil. LC-MS (ES) m/z=298 [M+H]+.
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([Br:15])[CH:14]=1)[CH2:10][OH:11].[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[C:29]([Si:16]([O:11][CH2:10][C:9]1[CH:8]=[C:7]([Br:6])[CH:14]=[C:13]([Br:15])[CH:12]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Br)cc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1cc(Br)cc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
With stirring, imidazole (1.1 g, 16.0 mmol) is added to a solution of 3,5-dibromobenzyl alcohol (2.8 g, 10.5 mmol) in absolute DMF (20 ml), and the mixture is cooled to 0° C. tert-Butyldiphenylsilyl chloride (3.3 ml, 17.8 mmol) is added dropwise to the reaction solution, which is then stirred at 0° C. for 2 h. The mixture is then warmed to RT and stirred for another 2 h. The reaction mixture is diluted with ethyl acetate (20 ml) and extracted with a semisaturated aqueous NH4Cl solution (20 ml). The organic phase is dried over MgSO4, filtered off and concentrated under reduced pressure. Further purification is carried out by chromatography [PE/EA (99:1)] on a silica gel column. This gives the title compound (5.0 g) as a colorless solid. TLC, silica gel (glass plates), [petroleum ether/ethyl acetate (99:1)], Rf=0.8.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH:6]([C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[N+:28]([O-])=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][N:8]=1)C.C(=O)([O-])O.[Na+].[NH4+]=S>C1(C)C=CC=CC=1.O>[OH:29][N:28]1[C:21]2[C:20](=[CH:25][C:24]([C:26]#[N:27])=[CH:23][CH:22]=2)[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)=[C:5]1[OH:4]
Reactant: CCOC(=O)C(c1ccc(CN2CCOCC2)cn1)c1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc2c(c1)c(-c1ccc(CN3CCOCC3)cn1)c(O)n2O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 76 %

Procedure:
(5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester HCl (8.0 g, 17.9 mmol was slurried in toluene (80 ml) at room temperature and sodium hydrogen carbonate (7.52 g, 89.5 μmol) dissolved in water (50 ml) was added and the reaction mixture stirred at room temperature for 25 min. The organic phase was separated and washed with water and then concentrated to dryness and then redissolved in ethanol (80 ml) and the solution added to a preheated solution of ammonium sulphide (26 ml, 21 w/w %, 107.4 mmol) in water at 50° C. over 20 mins. The resulting yellow slurry was stirred for 1 hr at 50° C. then cooled in an ice bath. The slurry was filtered and washed with water followed by isopropanol. After drying at 50° C. under vacuum gave a yellow powder, 6.67 g, (purity 94%), 76% yield of 1,2-Dihydroxy-3-(5-morpholin-4-ylmethyl-pyridin-2-yl)-1H-indole-5-carbonitrile. 1H NMR (400 MHz; d6-DMSO,): δ 14.36 (br s, 1H), 10.86 (br s, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.88 (br d, 1H), 7.87 (br d, 1H), 7.78 (br dd, 1H), 7.36 (dd, J=1.0, 8.0 Hz, 1H), 7.08 (d, H=8.1 Hz, 1H), 3.56 (t, J=4.0, 8.2 Hz, 4H), 3.37 (s, 2H), 2.27 (br s, 4H); 13C NMR: (100 MHz, d6-DMSO): δ 163.8, 148.8, 142.7, 136.7, 136.1, 123.1, 121.5, 120.4, 119.4, 119.1, 102.0, 81.9, 67.2, 66.6, 58.8, 53.3 ppm; MS (ESI) m/z [M+1]+ 351.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:40]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([NH2:40])=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)O)CC2)c2ncnn12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(N)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylic acid (0.5 g), 1-hydroxybenzotriazole ammonium salt (0.21 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 67%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.[NH2:17][C:18]([NH2:20])=[S:19].[H-].[Na+].O>O1CCOCC1>[CH:14]([C:6]1[C:5]([C:3]2[CH2:2][S:19][C:18](=[NH:17])[N:20]=2)=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: NC(N)=S
Reactant: CC(C)c1nn2ccccc2c1C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn2ccccc2c1C1=NC(=N)SC1
Yield: 61.4 %

Procedure:
A mixture of 200 mg (0.63 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone, 100 mg of thiourea and 160 mg of sodium hydride were stirred in 2 ml of dioxane containing 120 μl of H2O at 60-70° C. for 30 minutes. 100 mg of 4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)thiazol-2(5H)-imine was obtained after workup. Compound 1087.
Reaction SMILES: [C:1]([CH:4]([NH:12][C:13]1[C:14]([Cl:24])=[CH:15][C:16]([Cl:23])=[C:17]([CH:22]=1)[C:18]([O:20]C)=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])(=[O:3])N.Cl.C(O)(=[O:28])C>>[C:18]([C:17]1[C:16]([Cl:23])=[CH:15][C:14]([Cl:24])=[C:13]([NH:12][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])[C:1]([OH:28])=[O:3])[CH:22]=1)([OH:20])=[O:19]
Reactant: COC(=O)c1cc(NC(C(N)=O)c2ccccc2Cl)c(Cl)cc1Cl
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1cc(NC(C(=O)O)c2ccccc2Cl)c(Cl)cc1Cl

Procedure:
A mixture of 43 parts of methyl 5-(α-carbamoyl-o-chlorobenzylamino)-2,4-dichlorobenzoate, 400 parts of a hydrochloric acid solution and 200 parts of glacial acetic acid is stirred and refluxed for 70 hours. The reaction mixture is cooled and the precipitated product is filtered off. It is washed on the filter with fresh water and then dissolved in ether. The ethereal solution is shaken with water and with alkaline water. The aqueous phase is separated, acidified with a hydrochloric acid solution and the product is extracted with ether. The latter is washed twice with water, dried, filtered and evaporated, yielding 34.1 parts of N-(5-carboxy-2,4-dichlorophenyl)-2-(o-chlorophenyl)glycine as a solid residue; mp. 210° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].N1C=CC=CC=1>C(OCC)C>[C:27](=[O:28])([O:29][CH2:30][CH3:31])[O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione and ethyl chloroformate with pyridine in diethyl ether there is obtained 2-[2-chloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenoxy]-ethyl ethyl carbonate, 1H-NMR (CDCl3, 400 MHz): 7.32 ppm (d,1H), 6.81 ppm (d,1H), 6.36 ppm (s,1H), 4.47°-4.54 ppm (m,2H), 4.16°-4.27 ppm (m,4H), 3.56 ppm (d,3H), 1.32 ppm (t,3H);
Reaction SMILES: [Br:1]Br.[C:3]([O:12][CH3:13])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6]>C(O)(=O)C>[Br:1][C:9]1[CH:8]=[CH:7][C:5]([OH:6])=[C:4]([CH:10]=1)[C:3]([O:12][CH3:13])=[O:11]
Reactant: BrBr
Reactant: COC(=O)c1ccccc1O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
Br2 (52 g) was slowly added to a stirred solution of methyl salicylate (50 g; 330 mmol) in 300 mL acetic acid. The reaction mixture was stirred at rt. for 10 h, poured on ice-water and the precipitate recrystallized from MeOH, giving the sub-title compound in a 83% yield.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[C:9]([CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[O:8][N:7]=1)=[O:5])C.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[CH:11]([C:9]1[O:8][N:7]=[C:6]([C:4](=[O:5])[NH:34][CH2:33][CH2:32][CH:29]3[CH2:28][CH2:27][N:26]([CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:31][CH2:30]3)[N:10]=1)[CH2:12]2
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)c1noc(C2CN3CCC2CC3)n1
Product: O=C(NCCC1CCN(Cc2ccccc2)CC1)c1noc(C2CN3CCC2CC3)n1
Temperature: 100 °C

Procedure:
A mixture of 3-ethoxycarbonyl-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.2 g) and 1-benzyl-4-(2-aminoethyl)piperidine (0.26 g) was stirred and heated at 100° C. for 2 hours. The cooled mixture was chromatographed on alumina eluting with chloroform to give 5-(quinuclidin-3-yl)-3-[{2-(1-benzylpiperidin-4-yl)ethyl}carbamoyl]-1,2,4-oxadiazole as an oil. The compound was treated with an ethanol solution of hydrogen chloride, the solution was evaporated in vacuo and the residue was powdered with ether to give 5-(quinuclidin-3-yl)-3-[{2-(1-benzylpiperidin-4-yl)ethyl}carbamoyl]-1,2,4-oxadiazole dihydrochloride (0.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8](=[O:17])[N:7]([CH2:18][C:19]([OH:21])=[O:20])[C:6]2=[O:22].[Cl:23][C:24]1[CH:25]=[N+:26]([O-:49])[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[N+:26]([O-:49])[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)[O:20][C:19](=[O:21])[CH2:18][N:7]1[C:6](=[O:22])[C:5]2[C:9](=[CH:10][C:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:17]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A mixture of 2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (0.183 g, 0.557 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.234 g, 0.557 mmol), EDC (0.321 g, 1.672 mmol) and DMAP (0.034 g, 0.279 mmol) in DCM (20 ml) was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with 1N HCl, 5% NaHCO3 and brine. The organic phase was dried over sodium sulfate, the solvent was removed, and the crude was purified by flash chromatography on silica gel cartridge (DCM:ethyl acetate from 1:1 to 4:1) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a pale orange solid (0.097 g, 0.133 mmol, 24% yield). MS/ESI+ 730.13 [MH]+; [αD]=−33.40, c=0.43, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.54 (br. s., 1H), 8.44 (s, 2H), 7.77 (s, 1H), 7.55 (s, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.39 (s, 2H), 4.04 (s, 3H), 3.93 (d, 2H), 3.39 (dd, 1H), 3.23 (dd, 1H), 3.15 (s, 3H), 1.01-1.37 (m, 1H), 0.50-0.72 (m, 2H), 0.25-0.45 (m, 2H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6]([CH3:12])([CH3:11])[C:5]1=[O:13].C(O[Cl:19])(C)(C)C>CO>[Cl:19][N:7]1[C:8](=[O:10])[CH2:9][N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:13])[C:6]1([CH3:11])[CH3:12]
Reactant: CC(C)(C)OCl
Reactant: CC1(C)NC(=O)CN(CCO)C1=O
Solvent: CO
Product: CC1(C)C(=O)N(CCO)CC(=O)N1Cl
Reaction time: 0.58 h
Yield: 79.5 %

Procedure:
A solution of 1-(2-hydroxyethyl)-3,3-dimethylpiperazine-2,5-dione (300 mg, 1.61 mmol) in methanol (3 ml) was cooled to 0° C. tert-Butylhypochlorite (272 ul, 2.4 mmol) was added. The resulting solution was stirred for 35 minutes, and then concentrated under reduced pressure. The crude material was purified by column chromatography, eluting the desired product from silica gel with a gradient of 1 to 10% methanol in dichloromethane to give the title compound as a white solid (284 mg, 1.28 mmol, 80%). 1H NMR (D2O, 400 MHz) δ 1.67 (s, 6H), 2.26-2.28 (t, J=5.0 Hz, 1H), 3.59-3.62 (t, J=5.0 Hz, 2H), 3.86-3.90 (q, J=5.0 Hz, 2H), 4.32 (s, 2H); LRMS (ESI/APCI) m/z 221 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([F:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=[O:22])[CH:12]([F:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C(F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.6 %

Procedure:
NaH (55-65%; 44 mg; 1.09 mmol; 1.2 eq.) was added to a solution of 3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (200 mg; 0.91 mmol; 1 eq.) in THF (15 mL) and the resulting mixture was stirred at room temperature for 15 minutes whereupon 2-fluoro-benzaldehyde (113 mg; 0.91 mmol; 1 eq.) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours then at 60° C. for a further 4 hours. NaH (44 mg; 1.09 mmol; 1.2 eq.) was added and the resulting mixture was stirred at 60° C. for 2 hours. The solution was diluted with brine extracted with EA (2×). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM then EtOAc) afforded the title compound (196 mg, 66%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:28]2[CH2:29][CH2:30][C:25]([F:31])([F:24])[CH2:26][CH2:27]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: FC1(F)CCNCC1
Product: CCOC(=O)c1c(N2CCC(F)(F)CC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 11 step C from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B) and 4,4-difluoro-piperidine. Pale yellow solid (110 mg, 44%). LC-MS: 431 (M+H)+.