Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[O:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[O:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOC(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCOC(Cn2nc(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c3cc(OC(F)F)ccc32)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.8 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-((4-methylmorpholin-2-yl)methyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (63 mg, 97.9 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for 15 h the mixture was concentrated in vacuo then 25 mL Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added. After 1 h the mixture was concentrated and purified by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) to give 2-[5-difluoromethoxy-1-(4-methyl-morpholin-2-ylmethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (22 mg, 43%). MS (M+H)+=514; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.39 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.39 (dd, J=9.0, 2.3 Hz, 1H), 7.20 (s, 1H), 4.58-4.68 (m, 2H), 3.74 (d, J=11.9 Hz, 1H), 3.37-3.48 (m, 1H), 2.79 (d, J=11.3 Hz, 1H), 2.57 (br. s., 3H), 2.18 (s, 3H), 1.84-2.01 (m, 1H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
The solution of ethyl 2-(4-aminophenyl)acetate (500 mg, 2.79 mmol) and triethylamine (0.58 mL, 4.18 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (0.24 mL, 3.07 mmol) dropwise at room temperature and stirred overnight. The mixture was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound. LC-MS: m/z (M+H)=258.3
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([Br:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(OC)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC)c(F)c1
Temperature: 25 °C

Procedure:
The (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (5.16 g, 26.0 mmol) is dissolved in carbon tetrachloride (300 mL) along with NBS (5.56 g, 31.3 mmol) and benzoyl peroxide (0.63 g, 2.60 mmol) and refluxed for 2 h. The solution is then allowed to cool to room temperature and is filtered. The filtrate is evaporated and the residue purified via flash column chromatography (EtOAc/hexanes 5:95→EtOAc/hexanes 2:8) to give bromo-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester as a yellow oil. 1H NMR (CDCl3) δ 7.37 (d, J=12 Hz, 1H), 7.26-7.23 (m, 1H), 6.93 (t, J=8 Hz, 1H), 5.31 (s, 1H), 3.91 (s, 3H), 3.81 s, 3H).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)=[CH:7]2.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+].O1[CH2:43][CH2:42][CH2:41]C1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:11]2[C:2]([CH:41]3[CH2:42][CH2:43]3)=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:5]=[CH:4]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Reactant: C1CCOC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C2CC2)CC1
Temperature: 25 °C

Procedure:
(R)-4-[5-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.2047 g, 0.0004446 mol), cyclopropyl trifluoroborate potassium salt (0.0658 g, 0.000445 mol), [1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.03 g, 0.00004 mol) and cesium carbonate (0.434 g, 0.00133 mol) were added to a capped 40 mL vial equipped with a magnetic stir bar. The vial was degassed and purged with nitrogen. tetrahydrofuran (5.00 mL, 0.0616 mol) and water (0.50 mL, 0.028 mol) were added and the reaction mixture was stirred at reflux for 24 h under a nitrogen atmosphere. HPLC analysis showed that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethylacetate. The combined organic extracts were washed with 1N HCl (20 mL) and brine (20 mL) and then dried over magnesium sulfate. The solvent was removed under vacuum and the crude product was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give 109.3 mg of the title compound (58% yield).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[S:23][CH:24]=[C:25]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[N:26]=3)[CH:15]=2)=[O:12])[CH:5]=1.O1CCCC1.CO.O.[OH-].[Li+]>O>[CH:27]1([C:25]2[N:26]=[C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:31])=[O:2])[CH:19]=[CH:18][CH:17]=3)[S:23][CH:24]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1cccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1cccc(C(=O)O)c1)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A solution composed of 0.5 g of (E)-3-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester, 20 ml of tetrahydrofuran, 3 ml of methanol, 3 ml of water and 353 mg of lithium hydroxide monohydrate was allowed to stand at room temperature for 20 hr. The solvents were removed by rotary evaporation and the residual materials were taken up in 30 ml of water. Addition of excess acetic acid caused the precipitation of 0.49 g of (E)-3-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 208°-209° C. after recrystallization from 2-propanol.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[OH-].[NH4+]>C(O)C.[Ni]>[NH2:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[CH:21][CH:20]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C#N)cc3)cc12
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CN)cc3)cc12

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)benzonitrile (from the previous step) in ethanol and ammonium hydroxide (4:1, 0.2 M) stirred at room temperature was added raney nickel (10 eq). The reaction mixture was stirred under hydrogen atmosphere until the conversion was complete as shown by TLC. The reaction mixture was filtered through a short celite pad. The celite pad was washed with EtOAc. Combined organic extracts were concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 50-100% EtOAc in hexanes) to afford product 2-(4-(aminomethyl)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine. 1H NMR of the TFA salt: (methanol-d4): δ 8.81 (d, 1H), 8.79 (d, 1H), 8.38 (d, 1H), 7.51 (s, 1H), 7.44 (dd, 1H), 7.36 (dd, 4H), 4.07 (s, 2H), 3.29 (s, 2H), 3.20-3.14 (dd, 2H), 2.55 (s, 3H). LRMS [M+H]=343.2
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:33][C@@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1>O1CCOCC1>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:33][C@@H:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N[C@@H]1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCOC1

Procedure:
A solution of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (897 mg, 3.86 mmol) (Aldrich) and triethylamine (1.2 mL, 870 mg, 8.49 mmol) (Aldrich) in dioxane (20 mL) was treated with (R)-3-aminotetrahydrofuran p-toluene-sulfonic acid salt (1.0 g, 3.86 mmol) (Fluka). The mixture was stirred at reflux for 1 hour, then cooled and partitioned between brine and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography with a silica gel column using a 0–100% ethyl acetate in hexanes gradient to give (R)-2-methylsulfanyl-4-(tetrahydrofuran-3-ylamino)-pyrimidine-5-carboxylic acid ethyl ester as a colorless viscous oil. (Yield 1.0 g, 92%).
Reaction SMILES: ClC(OCC)=O.[N:7]1([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:16][N:17]1[C:26]2[C:25](=[O:27])[NH:24][C:23]3[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=3[NH:21][C:20]=2[C:19]([CH3:32])=[CH:18]1.[OH-].[Na+]>O1CCCC1>[CH3:16][N:17]1[C:26]2[C:25](=[O:27])[NH:24][C:23]3[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=3[N:21]([C:13](=[O:15])[CH2:12][N:7]3[CH2:8][CH2:9][CH2:10][CH2:11]3)[C:20]=2[C:19]([CH3:32])=[CH:18]1
Reactant: O=C(O)CN1CCCC1
Reactant: Cc1cn(C)c2c1Nc1ccccc1NC2=O
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cn(C)c2c1N(C(=O)CN1CCCC1)c1ccccc1NC2=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
1.1 g of ethyl chloroformate are added dropwise at 0° C. to a suspension of 1.29 g of pyrrolidin-1-ylacetic acid in 20 ml of tetrahydrofuran. 2.28 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one are added to the obtained suspension. The mixture is stirred 1 hour at 0° C. and a further 4 hours at room temperature. It is then poured onto 160 ml of 2 N sodium hydroxide solution and extracted with toluene. The organic phase is concentrated to dryness. The residue is chromatographed over a silica gel column by means of a mixture of dioxane/methanol (1:1) to yield 2.1 g of the title compound of m.p. 210° to 212° C. (from isopropanol).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:13].Br[CH2:34][CH2:35][CH2:36][CH2:37][Cl:38]>O1CCCC1>[Cl:38][CH2:37][CH2:36][CH2:35][CH2:34][O:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:13]
Reactant: ClCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)N1CCCCC1CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC(=O)N1CCCCC1CCOCCCCCl

Procedure:
Sodium hydride is added to tetrahydrofuran solution of octadecyl 2-(2-hydroxyethyl)piperidinecarboxylate and the mixture is reacted at 0° C. Then, 1-bromo-4-chlorobutane is added to the reaction mixture and reacted to obtain octadecyl 2-(4-chlorobutoxyethyl)piperidinecarboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].Br.Br[CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: CCN(CC)CCBr
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SCCN(CC)CC)=NC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), N-(2-bromoethyl)-N,N-diethylamine hydrobromide (64.5 mg, 0.25 mmol), N,N,N-tributyl-1-butanaminium iodide (7 mg, 0.03 mmol) and potassium carbonate (65.2 mg, 0.47 mmol) are dissolved in 3 ml acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: Br[C:2]1[N:11]2[C:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10]2)=[N:4][N:3]=1.[CH3:16][O-:17].[Na+].CO>CO>[CH3:16][O:17][C:2]1[N:11]2[C:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10]2)=[N:4][N:3]=1
Reactant: C[O-]
Reactant: Brc1nnc2n1C=Cc1ccccc1C2
Agent: [Na+]
Solvent: CO
Product: COc1nnc2n1C=Cc1ccccc1C2

Procedure:
To a solution of 0.262 g of 3-bromo-11H-s-triazolo [3,4-b][3]benzazepine in 2 ml of methanol was added 1.0 ml of 2 N-sodium methoxide/methanol and the mixture was refluxed for one hour. The solvent was evaporated off and, following the addition of water, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over Na2SO4. The solvent was then evaporated off and the residue was treated with isopropyl ether. By the above procedure was obtained 3-methoxy-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethyl acetate-n-hexane yielded colorless prisms, melting point: 161°-162° C. The infrared absorption spectrum of this product was identical with that of the compound obtained in Example 34.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:30]C(=O)OC(C)(C)C)[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[N:25][CH:24]=[CH:23]4)[CH:19]=2)=[CH:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:30])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[N:25][CH:24]=[CH:23]4)[CH:19]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc3cnccc3c2)c1)Cc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](COc1cncc(-c2ccc3cnccc3c2)c1)Cc1c[nH]c2ccccc12
Reaction time: 1 h

Procedure:
A solution of Example 27B (0.125 g, 0.25 mmol) in dichloromethane (3 mL) at room temperature was treated with TFA (400 μL), stirred for 1 hour, and concentrated. The concentrate was azeotropically distilled with diethyl ether two times and the residue was purified by reverse phase HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide the desired product as the di-trifluoroacetate salt (0.110 g, 70%). MS (ESI) m/e 395 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 11.02 (br s, 1H), 9.52 (s, 1H), 8.76 (d, J=3 Hz, 1H), 8.62 (d, J=8 Hz, 1H), 8.44-8.46 (m, 2H), 8.38 (d, J=9 Hz, 1H), 8.11-8.20 (m, 3H), 8.04-8.08 (m, 1H), 7.83-7.86 (m, 1H), 7.62 (d, J=9 Hz, 1H), 7.37-7.40 (m, 1H), 7.31 (d, J=3 Hz, 1H), 7.08-7.12 (m, 1H), 6.99-7.03 (m, 1H), 4.37-4.41 (m, 1H), 4.18-4.23 (m, 1H), 3.86-3.91 (m, 1H), 3.16-3.20 (m, 2H); Anal. Calcd for C25H22N4O.2TFA.H2O: C, 49.35; H, 3.61; N, 7.43; F, 22.67. Found: C, 49.04; H, 3.55; N, 7.42; F, 22.28.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[CH3:26])(=[O:18])=[O:17])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH3:26][C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[S:16]([N:11]1[CH:10]2[CH:13]([CH2:14][CH2:15][NH:8][CH2:9]2)[CH2:12]1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2CC3CCNCC32)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8-(2,4-dimethyl-benzenesulfonyl)-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester in dioxane (8 mL) was added trifluoro acetic acid (3 mL), the reaction mixture was stirred for 16 h at room temperature. The solvent and the excess of trifluoro acetic acid were removed under reduced pressure. The resulting trifluoro acetic acid salt of the title compound was used crude without further purification (150.0 mg, 49%). MS (ESI) mass calcd. for C14H20N2O4S, 280.39; m/z found, 281.2 [M+H]+.
Reaction SMILES: C1(N(C2CCCCC2)C)CCCCC1.[CH:15]([S:17]([N:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)(=[O:19])=[O:18])=[CH2:16].Br[C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1[CH3:40].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[O:27]1[C:23]2([CH2:22][CH2:21][N:20]([S:17](/[CH:15]=[CH:16]/[C:31]3[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=3[CH3:40])(=[O:18])=[O:19])[CH2:29][CH2:28]2)[O:24][CH2:25][CH2:26]1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: C=CS(=O)(=O)N1CCC2(CC1)OCCO2
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Dicyclohexyl-methyl-amine (34.2 ml, 162.8 mmol) was added to a solution of 8-ethenesulfonyl-1,4-dioxa-8-aza-spiro[4.5]decane (17.3 g, 74.01 mmol), 4-bromo-3-methyl-benzoic acid (19.1 g, 88.82 mmol), Pd(dba)2 (4.26 g, 7.40 mmol) and tri-t-butylphosphonium tetrafluoroborate (2.15 g, 7.40 mmol) in NMP (70.0 ml), and the mixture was stirred at 100° C. for one hour in a nitrogen atmosphere. The reaction solution was cooled to room temperature and then diluted with ethyl acetate, and the organic layer was washed with a 1 M aqueous hydrochloric acid solution and saline. The organic layer was allowed to stand for a while, and the precipitated solid was filtered off. The resulting solid was washed with ethyl acetate to give 4-[(E)-2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-vinyl]-3-methyl-benzoic acid as a gray solid (25.6 g, 94.1%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)(=O)C>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[NH:11][C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[N:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc3ccsc23)c(C)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 19.8 %

Procedure:
To a solution of 2-Chloro-N-mesitylthieno[3,2-d]pyrimidin-4-amine (51.4 mg, 0.17 mmol), TFA (0.11 mL, 1.36 mmol) in TFE (1 mL) was added 4-aminobenzonitrile (80.2 mg, 0.68 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC to afford the product as a white solid (13 mg, 20%): 1H NMR (DMSO, 300 MHz) δ 2.09 (s, 6H), 2.31 (s, 3H), 7.00 (s, 2H), 7.28 (d, J=5.7 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 8.06-8.08 (m, 3H), 9.60 (bs, 1H), 9.72 (bs, 1H).
Reaction SMILES: [S:1]1[N:5]=[C:4]([CH2:6][CH:7]([P:16]([O:21]CC)(=[O:20])[O:17]CC)[P:8]([O:13]CC)(=[O:12])[O:9]CC)[CH:3]=[N:2]1.C[Si](C)(C)Br.O>>[S:1]1[N:5]=[C:4]([CH2:6][CH:7]([P:16]([OH:21])(=[O:17])[OH:20])[P:8]([OH:13])(=[O:9])[OH:12])[CH:3]=[N:2]1
Reactant: CCOP(=O)(OCC)C(Cc1cnsn1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Product: O=P(O)(O)C(Cc1cnsn1)P(=O)(O)O
Reaction time: 24 h

Procedure:
1.18 g. of the tetraethyl 2-(1,2,5-thiadiazol-4-yl)-ethane-1,1-diphosphonate described in Example 3 is mixed with 3.3 ml. trimethylbromosilane under an atmosphere of nitrogen. The reaction mixture is left to stand for 24 hours at ambient temperature and the solution is then evaporated, the residue is mixed with water, the solution is adjusted to a pH of 5 with sodium hydroxide and mixed with methanol. The precipitate obtained is filtered off with suction. There is thus obtained 0.56 g. (53% of theory)of the desired diphosphonic acid in the form of the disodium salt with 1 mole of water of crystallisation; m.p.>300° C.; Mrel =0.9.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH:14](=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH:14]([OH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Fc1ccccc1F
Reactant: CCCCCCCCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1cccc(F)c1F

Procedure:
Butyllithium (2.5 M in hexanes 52.5 ml, 0.131 mol) was added dropwise to a stirred, cooled (−78° C.) solution of difluorobenzene (12.0 g, 0.105 mol) in dry THF (400 ml) under a stream of dry nitrogen. The reaction mixture was maintained under these conditions for 2.5 h and a solution of nonanal (14.9 g, 0.105 mol) in dry THF (50 ml) was added dropwise at −78° C. The mixture was allowed to slowly reach room temperature overnight. Ammonium chloride solution (2M, 200 ml) was added and the product was extracted into ether (2×150 ml), the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo and the residue was distilled under reduced pressure to give a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCl)CC)C.[CH2:30]([N:32]([CH2:35][CH2:36][CH2:37]Cl)[CH2:33][CH3:34])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:37][CH2:36][CH2:35][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CCCCl
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1Cl
Agent: CCN(CC)CCCl
Product: CCN(CC)CCCN1CCN(Cc2ccc(Cl)c(Cl)c2)C(c2ccccc2)C1

Procedure:
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3b, is alkylated by following the procedure described in Example 3c whereby, in place of diethylamino ethylchloride, the equimolecular amount of diethylamino propylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 210° C./0.04 mm. Hg.