Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:16]([C:17]2[S:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=3)=[CH:20][CH:21]=2)=[CH:15][C:14]([CH2:32][C:33]#[N:34])=[N:13]1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:16]([C:17]2[S:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:23]=3)=[CH:20][CH:21]=2)=[CH:15][C:14]([C:32]2([C:33]#[N:34])[CH2:3][CH2:2]2)=[N:13]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CC#N)nn3-c3ccccc3Cl)s2)c1
Reactant: BrCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C4(C#N)CC4)nn3-c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
1,2-dibromoethane (40 μL, 0.46 mmol) was added to a stirred suspension of the [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]acetonitrile (68 mg, 0.15 mmol), benzyltriethylammonium chloride (20 mg, 0.088 mmol), and 50% aqueous NaOH (2 mL) at 0° C., the resulting mixture was stirred at rt overnight. After diluted with water, the mixture was extracted with ether. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-70% EtOAc/hexanes) to give the title compound as a white solid (59 mg, 82%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.84-7.82 (m, 1H), 7.74-7.71 (m, 1H), 7.58-7.43 (m, 5H), 7.21 (d, 1H), 6.79-6.77 (m, 2H), 3.07 9d, 3H), 1.73-1.68 (m, 4H). MS(ES): 480 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH2:9][O:10][C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH2:23][CH2:24][C:25]3=[O:30])[CH2:8][O:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1([CH2:9][O:10][C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH2:23][CH2:24][C:25]3=[O:30])[CH2:6][O:7][CH2:8]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN=[N+]=[N-])COC2)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-(2-((3-(azidomethyl)oxetan-3-yl)methoxy)-3,4-dimethoxyphenyl)-indan-1-one (3 g, 7.57 mmol) in in tetrahydrofuran (30 mL), were added triphenylphosphine (7.6 g, 29.28 mmol) and the reaction mixture was stirred at RT for 2 h. Water (3 mL) was added to the above reaction mixture and the resultant reaction mixture was heated to 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was acidified with 1N hydrochloric acid solution. Then extracted with ethyl acetate (3×) and the aq layer was basified with sodium bicarbonate solution and extracted with ethyl acetate and the combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound as a liquid.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17](=[O:21])[NH:18][CH2:19][CH3:20])[CH:14]=[C:13]([Cl:22])[C:12]=1[C:23](Cl)=[O:24]>>[Cl:10][C:11]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:22])[C:12]=1[C:23]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:24])[C:17]([NH:18][CH2:19][CH3:20])=[O:21]
Reactant: c1cc2cc[nH]c2cn1
Reactant: CCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Product: CCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3cnccc23)c(Cl)c1

Procedure:
3,5-Dichloro-N-ethyl-4-(1H-pyrrolo[2,3-c]pyridin-3-ylcarbonyl)benzamide was prepared from 1H-Pyrrolo[2,3-c]pyridine and 2,6-dichloro-4-(ethylcarbamoyl)benzene carbonyl chloride (Compound No. 2).
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1([OH:30])[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:30][C:17]1([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:31])=[O:8])=[O:16])[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Reaction time: 24 h

Procedure:
A mixture of 9-hydroxy-9-fluorenylcarbonyl-L-proline benzyl ester (3.8 g, 9.3 mmol) from step 1 above and 10% palladium on carbon (390 mg) in ethyl acetate (100 mL) was stirred under an atmosphere of hydrogen (balloon pressure) for 24 hours. The mixture was filtered through celite and concentrated in vacuo to give 9-hydroxy-9-fluorenylcarbonyl-L-proline. HPLC=90%, R.T.=2.97 min; M+1=324.1; 1H NMR (CD3OD, 400 MHz) δ 7.78–7.75 (m, 2H), 7.47–7.32 (m, 6H), 4.49–4.45 (q, 1H 2.42–2.30 (m, 2H), 2.01–1.94 (m, 1H), 1.78–1.71 (m, 1H), 1.58–1.41 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.C1C[O:20]CC1>>[CH3:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2](=[O:20])[NH:3][CH:4]=[CH:5]2
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: Cl
Product: Cc1ccc2c(=O)[nH]ccc2c1[N+](=O)[O-]
Temperature: 22 °C
Yield: 87 %

Procedure:
1-chloro-6-methyl-5-nitroisoquinoline (50 g, 225 mmol) was suspended in THF (500 mL, 10 mL/g) and treated with 5 N aq HCl (500 mL, 10 mL/g). The suspension was stirred vigorously in a 2 L Morton Flask under a reflux condenser and heated with a heating mantle to reflux overnight (14 h). The resulting suspension was allowed to cool to room temperature (22° C.). The solid was removed by suction filtration and the filtrate set aside. The solid was washed with water (100 mL), Et2O (2×100 mL) and hexane (100 mL), then air-dried to afford 40 g as a light yellow powder. The reserved filtrate was concentrated in vacuo to a volume of ˜500 mL to afford a second crop of product. The second crop was washed with water (100 mL), Et2O (2×100 mL) and hexane (100 mL), then air-dried to afford 4 g as an orange powder. A total of 44 g (87% yield) of the title compound were isolated in this fashion. MS (M+H)+ 205.
Reaction SMILES: [N:1]1([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3F)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=1.[H-].[Na+].[ClH:33]>O1CCCC1.CO>[ClH:33].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:28][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=2)=[CH:25][CH:24]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(N2CCOCC2)nc(-c2ccncc2OCc2ccc(F)cc2)cc1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
To a solution of 2-(morpholin-4-yl)-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.60 g, 2.07 mmol), and 4-fluorobenzyl alcohol (3.3 g, 26.2 mmol) in tetrahydrofuran (15 ml) was added sodium hydride (1.03 g, 2.58 mmol) at 0° C. After stirring at 60° C. for 5 hours, the resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish colorless oil. The methanol (10 ml) solution of resulting oil was treated with 4N hydrochloric acid (5 ml). The residue obtained by evaporation was washed by ethyl acetate to furnish 6-(3-(4-fluorobenzyloxy)pyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one hydrochloride (0.23 g, 0.53 mmol, 31%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([N:1]([C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:2]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccccc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
Reaction of ethyl 2-aminobenzoate with two molar equivalents of benzyl Chloride in acetone in the presence of potassium carbonate affords ethyl 2-(N,N-dibenzylamino)-benzoate which, on saponification in aqueous ethanolic potassium hydroxide and isolation of the product from a neutral medium, affords 2-(N,N-dibenzylamino)benzoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][N:8]=2)[C:4](=[O:21])[NH:3]1.[H-].[Na+].IC.[C:27]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:27][N:3]1[C:2]([CH3:22])([CH3:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:9][N:8]=2)[C:4]1=[O:21]
Reactant: CC1(C)CN(c2ccc(C#Cc3ccccc3)cn2)C(=O)N1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ccc(C#Cc3ccccc3)cn2)CC1(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
(110 mg, 378 μmol) 4,4-Dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one (Example 15, step 3) was dissolved in DMF (0.5 ml) and cooled to 0-5° C. NaH (55%) (19.8 mg, 453 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (35.3 μl, 566 μmol, 1.5 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one (93 mg, 81% yield) was obtained as a yellow solid, MS: m/e=306.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1cnc(Cl)c(N)c1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of 2-chloro-5-methyl-3-nitro-pyridine (20 g, 0.12 mol) in 300 mL of ethanol is added SnCl2 (132 g, 0.7 mol) slowly to keep internal temperature under 50° C. After addition completed, the reaction mixture is stirred for additional two hours at 50-55° C., then evaporated to dryness under reduced pressure. The residue is suspended in 400 mL of DCM, cooled with an ice bath, and neutralized carefully with 10N NaOH, The mixture is filtered through celite, washed the cake with DCM (100 mL×2). The filtrate is washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to give 16.5 g of 2-chloro-5-methyl-pyridin-3-ylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][Br:14])=[CH:11][CH:12]=1
Reactant: Cc1ccc(-c2ccccn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccn2)cc1

Procedure:
4-(2-Pyridyl)toluene, 2 mL (1.98 g, 11.7 mmol), N-bromosuccinimide (NBS), 2.5 g (14.0 mmol), and α,α′-azobis(isobutyronitrile) (AIBN), 23 mg (0.14 mmol) were suspended in 35 mL tetrachloromethane, and refluxed for 24 hours. The product was filtered, and the solvent removed from the filtrate by rotary evaporation. Equal amounts of chloroform and water were added and the product extracted. The chloroform layer was separated and dried, and the solvent removed. 4-(2-Pyridyl)benzyl bromide, 2 g, was obtained as a sticky yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=O)[CH:3]=1.O[C:11]1[CH:16]=[C:15](C)O[C:13](=O)[CH:12]=1.P(Cl)(Cl)(Cl)=O.FC(F)(F)C(O)=O.C(ON=O)CC(C)C.C(O)(=O)C1C(=CC=CC=1)N>COCCOC.CCCCCC.C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:13]2[C:4]([CH:3]=1)=[CH:15][CH:16]=[CH:11][CH:12]=2
Reactant: Cc1cc(Cl)cc(=O)o1
Reactant: Cc1cc(O)cc(=O)o1
Agent: CC(C)CCON=O
Agent: Nc1ccccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)cc2ccccc12
Yield: 55 %

Procedure:
A three-neck round-bottomed flask was equipped with a reflux condenser and two addition funnels. Dry DME(200 ml) was introduced into the flask and 4-chloro-6-methyl-2-pyrone(3.24 g, 22.4 mmol) prepared according to the procedure described in a literature (see: M. J. D. Van Dam et F. KOGL, Recueil 83, 39, 1964) from 4-hydroxy-6-methyl-2-pyrone and phosphorusoxychloride, and trifluoroacetic acid(0.1 ml) were added thereto. Isoamylnitrite(3.15 g, 26.9 mmol) and anthranilic acid(3.69 g, 26.9 mmol) each dissolved in DME(50 ml) were introduced into the respective funnels. The isoamylnitrite solution and anthranilic acid solution were added dropwise simultaneously while keeping the reflux condition. After confirming that the starting materials were completely used, addition was stopped and the reaction solution was cooled. The solvent was removed under reduced pressure and the residue was dissolved in methyene chloride(100 ml) and the organic layer was sequentially washed with 5% aqueous hydrochloric acid solution, 5% aqueous sodium hydroxide solution and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography(eluent: n-hexane/ethylacetate=9/1, v/v) to give 2.60 g(14.7 mmol, Yield 55%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([C:37]2[S:41][C:40]([NH2:42])=[N:39][N:38]=2)[CH:34]=[CH:35][CH:36]=1.CN(C=O)C>ClCCl.O>[Cl:30][C:31]1[CH:32]=[C:33]([C:37]2[S:41][C:40]([NH:42][C:16]([C:15]3[CH:14]=[CH:13][C:12]([O:11][C@@H:8]4[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]4)=[CH:20][CH:19]=3)=[O:18])=[N:39][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Reactant: Nc1nnc(-c2cccc(Cl)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(-c4cccc(Cl)c4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.351 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid (1.26 mmol, 1 eq.) is placed in 5 mL of dichloromethane at room temperature. 0.42 mL of diisopropylethylamine (2.52 mmol, 2 eq.), 0.705 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (1.51 mmol, 1.2 eq.) and 0.267 g of 3-chlorophenyl-1,3,4-thiadiazol-2-amine (1.26 mmol, 1 eq.) are added successively. 2 mL of DMF are added. The reaction mixture is stirred for 1 day at room temperature, diluted in dichloromethane, and water is added. Filtration of this medium gives 0.06 g of methyl cis-4-{4-[5-(3-chlorophenyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenoxy}cyclohexanecarboxylate. The organic phase is separated out by settling, washed with water, dried over sodium sulfate, filtered and evaporated. The residue is taken up in ethanol, filtered off by suction and washed with diethyl ether. 0.090 g of methyl cis-4-{4-[5-(3-chlorophenyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenoxy}cyclohexanecarboxylate is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11]C)[N:8]([CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:33])C(=O)C1>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:33])=[C:9]([CH3:11])[N:8]([CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cc2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1c(I)c2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of (S)-tert-butyl 2-((4-chloro-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate (1.0 g, 2.86 mmol, 1.0 eq) in DMF (20 mL), NIS (0.675 g, 3.00 mmol, 1.05 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. Solvent was removed and purified by column chromatography to afford (S)-tert-butyl 2-((4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate as white solid (1.0 g, 77% in yield) which was converted to the title compound as described in Example 30 above, LCMS m/z 519.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:35][C@@H:36]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>C(OCC)(=O)C>[OH:38][C@@H:37]([C@@H:36]([NH:35][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:45][CH:46]([CH3:47])[CH3:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)C[C@H](N)[C@H](O)c1ccccc1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](O)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid (696 mg, 4.78 mmol.) in ethyl acetate (15 mL) was added N-hydroxysuccinimide (550 mg, 4.78 mmol.) and then added N,N′-dicyclohexylcarbodiimide (986 mg, 4.78 mmol.) under chilling with ice. The resulting mixture was stirred at 5° C. for one hour, and to the mixture was added (1R,2S)-2-amino-4-methyl-1-phenyl-1-pentanol (1.01 g, 5.23 mmol.). The mixture was stirred overnight at room temperature for one hour. The resulting insoluble material was removed by filtration, and the filtrate was washed successively with 2N hydrochloric acid, water, an aqueous saturated sodium hydrogen carbonate solution, and an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by middle pressure silica gel column chromatography (n-hexane/ethyl acetate=1/1), to give the desired compound as a white crystalline product (1.29 g, yield: 89%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CCN(CC)CC.[F:36][C:37]([F:48])([F:47])[CH2:38]OS(C(Cl)(Cl)Cl)(=O)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CO.CS(C)=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([CH2:38][C:37]([F:48])([F:47])[F:36])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC(F)(F)F)C3)cc1
Temperature: 100 °C
Yield: 0.9 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (200 mg, 0.48 mmol) and Et3N (133 μL, 0.95 mmol). in toluene (1.5 mL) was added 2,2,2-trifluoroethyltrichloromethane sulfonate (91 μL, 0.95 mmol) and DMSO (0.5 mL). The reaction mixture was heated to 100° C. overnight. The reaction was cooled, diluted with methanol and adsorbed onto a mp-TsOH cartridge (2.5 g, 3 mmol/g). The cartridge was rinsed with MeOH (3 column volumes) and the product was eluted with 7M NH3 in MeOH. The basic fractions were concentrated in vacuo and purified by prep HPLC (low pH) to give the desired product (2.1 mg, 0.9% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][C:21](=O)C(F)(F)F)=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH3:21])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (0.59 mg, 1.3 mmol) in N,N-dimethylformamide (3 mL) was treated with potassium carbonate (0.28 g, 2.0 mmol) followed by methyl iodide (125 μL, 2 mmol) and stirred for 2 h. The reaction mixture was treated with additional methyl iodide (200 μL, 3.2 mmol) and stirred for 16 h. The reaction mixture was diluted with water (100 mL) and brine (25 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (3×100 mL) and brine (100 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue which was purified by silica gel to give the desired product (0.39 g, 81%).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:30][CH2:31][S:32](=[O:36])(=[O:35])[CH2:33][CH2:34]5)=[CH:25][CH:24]=4)=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 90.8 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 4-(4-aminophenyl)thiomorpholine 1,1-dioxide (0.158 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(4-(1,1-dioxidothiomorpholino)phenyl)acetamide as a white solid (0.31 g, 89.8% yield).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[F:16])([CH3:7])[CH3:6])C.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(C)Sc1cccc(F)c1F
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Sc1cccc(F)c1F)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
To a solution of 1.64 g (6.31 mmol) of 2-(2,3-difluoro-phenylsulfanyl)-2-methyl-propionic acid ethyl ester in THF (165 mL) at room temperature are added 1.62 g (12.6 mmol) of potassium trimethylsilanolate. The reaction is stirred at room temperature for 18 h. The solvent is removed under reduced pressure and the residue is partitioned between water and diethyl ether. The basic aqueous layer is separated, acidified using 1M aqueous HCl solution to pH 1 and extracted with DCM (3×100 mL). The organic phase is dried over MgSO4, filtered and the filtrate is concentrated under reduced pressure to give 1.32 g of 2-(2,3-difluoro-phenylsulfanyl)-2-methyl-propionic acid as a pale yellow solid. Yield: 90%, ES-MS: m/z 231 [M−H].