Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13]O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1
Reactant: CO
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C=Cc1ccc(N)cc1
Yield: 72 %

Procedure:
4-Aminocinnamic acid (15.0 g, 77.6 mmol) was added to a mixed solvent of methanol (250 ml) and chloroform (150 ml), and sulfuric acid (3 ml) was added, which was followed by refluxing under heating for 47 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made weak alkaline with a saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 7.84 g of methyl 4-aminocinnamate as a yellow solid (72%). This solid (7.80 g, 44.1 mmol) was dissolved in methanol (250 ml) and 10% palladium-carbon (780 mg) was added. The mixture was stirred at room temperature for 19 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite and low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to give 5.98 g of methyl 3-(4-aminophenyl)propionate as a colorless solid (76%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
To a solution of N-benzyl-O-benzyl-N2-Boc-D-serinamide (1 g) and dichloromethane (5 mL), aq. HCl (10%) (5 mL) was added. The solution was stirred for 2 hours at room temperature for completion of reaction. The solution was concentrated under vacuum to remove dichloromethane and subsequently water was added. The aqueous was basified to pH 8-10 with 5% sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine solution. Organic layer was concentrated under vacuum to obtain an oily residue 0.22 g of N-benzyl-O-benzyl-D-serinamide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:7][CH2:6][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=1[N+:11]([O-:13])=[O:12])(=[O:16])=[O:15]
Reactant: Cc1cccc(CCO)c1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C)c2[N+](=O)[O-])cc1
Yield: 100 %

Procedure:
3-Methyl-2-nitrophenethyl tosylate was prepared according to the general method as outlined in Preparation 1 starting from 3-methyl-2-nitrophenethyl alcohol (1.06 g, 5.86 mmol) and tosyl chloride (1.34 g, 7 mmol). 2 g product was taken crude to the next step. Yield 100%; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 2H), 7.29 (m, 3H), 7.17 (t, 2H), 4.23 (t, J=6 Hz, 2H), 2.89 (t, J=6 Hz, 2H), 2.42 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:34]=[C:10]3[C:11]([C:15]4[CH:33]=[CH:32][C:18]([O:19][C@@H:20]5[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]5)=[CH:17][CH:16]=4)=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[CH2:23][CH2:24][C@@H:20]([O:19][C:18]2[CH:17]=[CH:16][C:15]([C:11]3[C:10]4[N:9]([N:8]=[C:7]([NH:6][C:4]([CH:1]5[CH2:2][CH2:3]5)=[O:5])[CH:34]=4)[CH:14]=[CH:13][CH:12]=3)=[CH:33][CH:32]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-c3cccn4nc(NC(=O)C5CC5)cc34)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc2c(-c3ccc(O[C@@H]4CCNC4)cc3)cccn2n1)C1CC1

Procedure:
(R)-tert-Butyl 3-(4-(2-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyridin-4-yl)phenoxy)pyrrolidine-1-carboxylate (0.44 g, 0.95 mmol) was stirred in DCM (10 mL) and TFA (1 mL) at room temperature for 3 h. The reaction mixture was concentrated in vacuo and loaded onto an SCX column in DCM. MeOH (100 mL) was passed through the column and the compound was eluted with (7 N NH3 in MeOH in MeOH) (1:5) (200 mL). The filtrate was concentrated in vacuo to give (R)—N-(4-(4-(pyrrolidin-3-yloxy)phenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20].C1C=C(Cl)C=C(C(OO)=[O:29])C=1>ClCCl>[O:29]1[C@H:12]2[CH2:11][CH:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C:3](=[O:20])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of compound 2 (320 mg, 1.17 mmol) in anhydrous dichloromethane (25 mL) was added m-CPBA (316 mg, 1.41 mmol) at 0° C. under an atmosphere of argon. The solution was stirred at 0° C. for 3 h. The solution was then diluted with dichloromethane (50 mL) and washed with an aqueous sodium bicarbonate solution (10%). The organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash chromatography (Hexanes/EtOAc: 8:2) to yield compound 22 (260 mg, 78%). 1H NMR (CDCl3) δ: 0.79 (s, 18-CH3), 0.85 (s, 19-CH3), 0.60-2.11 (residual CH and CH2), 2.43 (dd, J1=18.8 Hz, J2=8.7 Hz, 16β-H), 3.12 (t, J=5.8 Hz, 2×CH of epoxide), 3.16 (broad, s, 2×CH of epoxide).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:24]=[N:25][N:26](C(C)(C4C=CC=CC=4)C)[N:27]=3)=[CH:13][CH:12]=2)[C:8](=[O:37])[C:7]2([CH2:41][CH2:40][CH2:39][CH2:38]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C1(C)C=CC=CC=1>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:24]=[N:25][NH:26][N:27]=3)=[CH:15][CH:16]=2)[C:8](=[O:37])[C:7]2([CH2:38][CH2:39][CH2:40][CH2:41]2)[N:6]=1
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 17.5 °C
Yield: 78.8 %

Procedure:
124 g (0.228 moles) of 2-butyl-3-{2′-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-1,3-diaza-spiro[4.4]non-1-en-4-one are dissolved in 500 ml of toluene and 900 ml of 37% aqueous hydrochloric acid are added thereto under stirring at a temperature of 15-20° C. The mixture is stirred for a further 4 h, then the aqueous phase is separated and washed twice with 250 ml of toluene. The aqueous phase is poured into a solution of 125 g of sodium acetate in water, the formed precipitate is filtered, thoroughly washed with water and dried under vacuum at 70° C., thereby obtaining 77 g of irbesartan.
Reaction SMILES: [C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10](Br)=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C[C:17]([N:19](C)C)=O>C(OCC)(=O)C.O.[Zn].[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:17]#[N:19])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CSc1nc(NC23CC(C2)C3)ncc1Br
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nc(NC23CC(C2)C3)ncc1C#N
Temperature: 90 °C
Yield: 55.8 %

Procedure:
N-(Bicyclo[1.1.1]pentan-1-yl)-5-bromo-4-(methylthio)pyrimidin-2-amine (1250 mg, 4.37 mmol), zinc dust (71.4 mg, 1.092 mmol), zinc cyanide (333 mg, 2.84 mmol), 1,1′-bis-(diphenylphosphino)-ferrocene (196 mg, 0.349 mmol), tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.218 mmol), and DMA (8.35 mL) were combined and heated overnight at 90° C. under a nitrogen atmosphere. The reaction mixture was diluted with 125 mL ethyl acetate and 50 mL water and filtered through a pad of Celite. The layers of the filtrate were separated and the aqueous layer was extracted with 75 mL ethyl acetate. The combined ethyl acetate layers were washed with 2×50 mL brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The crude oil was purified by silica gel chromatography (0%-30% ethyl acetate in hexanes). The product containing fractions were combined and concentrated to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carbonitrile (566 mg, 2.436 mmol, 55.8% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81-9.08 (m, 1H), 8.31-8.57 (m, 1H), 2.55-2.63 (m, 3H), 2.11 (s, 7H). MS (ESI) m/z 233.3 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=O)[CH2:4][CH2:3]1.[C:21]([C:25]1[CH:26]=[C:27]([NH2:32])[C:28]([NH2:31])=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]2[NH:31][C:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:14]=3)=[N:32][C:27]=2[CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CN1CCN(CCCCOc2cccc(C=O)c2)CC1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CN1CCN(CCCCOc2cccc(-c3nc4cc(C(C)(C)C)ccc4[nH]3)c2)CC1
Yield: 93.9 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzaldehyde (53 mg, 0.19 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (32 mg, 0.19 mmol, 1.0 equiv), and Na2S2O5 (48 mg, 0.25 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 75 mg (92%) of the title compound. MS (electrospray): mass calculated for C26H36N4O, 420.29; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.68-7.56 (m, 3H), 7.54 (br d, J=8.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.02 (dd, J=8.2, 2.2 Hz, 1H), 4.07 (t, J=6.1 Hz, 2H), 3.00-2.26 (m, 10H), 2.26 (s, 3H), 1.85-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](/[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:10]\NC(OC(C)(C)C)=O)=[C:4]([F:25])[CH:3]=1.Cl.NO.C([O-])(=[O:31])C.[Na+]>C(O)C.O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:10][OH:31])=[C:4]([F:25])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N/N=C(/c1ccncc1)c1cc(F)c(Br)cc1F
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccncc1)c1cc(F)c(Br)cc1F
Yield: 114.1 %

Procedure:
A solution of Z/E 1-(4-bromo-2,5-difluorophenyl)-1-(4-pyridinyl)methanimine (Intermediate 1, 150 mg) in ethanol (2 ml) was treated with a solution of hydroxylamine hydrochloride (44 mg) and sodium acetate (50 mg) in water (0.4 ml) then stirred at reflux for 2 h. The ethanol was removed under vacuum and the residue was partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under vacuum. The residue was purified on an SPE cartridge (silica, 2 g) eluting with cyclohexane/ethyl acetate (4:1 to 1:1) to give the title compound as a white foam (130 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[CH2:57][CH2:56][O:55][CH:54]1[C:58]1[CH:59]=[C:60]([C:64](=[N:66]O)[NH2:65])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C.CCOC(C)=O.N1C=CC=CC=1.C1(C)C=CC=CC=1>[O:53]1[CH2:57][CH2:56][O:55][CH:54]1[C:58]1[CH:59]=[C:60]([C:64]2[N:65]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:66]=2)[CH:61]=[CH:62][CH:63]=1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: NC(=NO)c1cccc(C2OCCO2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1cc(-c2nc(-c3cccc(C4OCCO4)c3)no2)ccc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 28 (2 973 mg; 11.60 mmol) and DIEA (3.94 mL; 23.2 mmol) in anhydrous DMF (10 mL) at 0° C. was added HATU (4 410 mg; 11.60 mmol). The reaction mixture was stirred at 0° C. for 10 min. Intermediate 68 (2 300 mg; 11.05 mmol) was added at once. The reaction mixture was stirred at 0° C. for 15 min and RT for 2 h. EtOAc was added and the organic layer was washed with water and brine (50 mL), dried (MgSO4) and the solvents were removed under reduced pressure to give an oil. The oil was taken up with toluene (70 mL) and pyridine (10 mL). The resulting mixture was heated at 110° C. overnight. EtOAc was added and the organic layer was washed with water and brine (50 mL), dried (MgSO4) and the solvents were removed under reduced pressure to give a yellow oil. The crude material was purified by flash chromatography (EtOAc/cHex) to afford the title compound as an oil. 1H NMR: (DMSO-d6, 300 MHz) δ 8.33 (m, 1H), 8.17 (m, 3H), 7.76 (m, 2H), 7.43 (d, J=7.9 Hz, 1H), 7.38-7.25 (m, 3H), 7.16 (m, 1H), 5.90 (s, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 4.15-3.98 (m, 4H), 3.25 (s, 3H), 2.31 (t, J=7.40 Hz, 2H), 2.04 (s, 3H). LC/MS (Method B): 429.2 (M+H)+ no (M−H)−. HPLC (Method A) Rt: 5.53 min (purity: 89.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]([CH2:18][CH3:19])[S:16][C:15](=[O:20])[NH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][F:11].Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][N:14]2[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][F:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:17]([CH2:18][CH3:19])[S:16][C:15]2=[O:20])[CH2:25][CH2:26]1
Reactant: CCC1SC(=O)NN=C1c1ccc(OCF)c(OC)c1
Reactant: ClCCN1CCOCC1
Product: CCC1SC(=O)N(CCN2CCOCC2)N=C1c1ccc(OCF)c(OC)c1

Procedure:
In analogy to Example 4, by reacting 5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-2-morpholinoethane, 2-morpholinoethyl-5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH2:4][CH2:3]1
Reactant: O=S1(=O)CCCO1
Reactant: CC1CCC(N)CC1
Solvent: C1CCOC1
Product: CC1CCC(NCCCS(=O)(=O)O)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-methylcyclohexylamine (97% cis and trans isomers, 11.0 g, 97.4 mmol) in tetrahydrofuran (70 mL) was slowly added a solution of 1,3-propane sultone (11.5 g, 92.8 mmol) in THF (20 mL). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with THF (50 mL) and acetone (50 mL). The solid was suspended EtOH. The suspension was stirred at room temperature for 5 minutes. The solid product was collected by filtration, washed with EtOH (50 mL), and dried in a vacuum oven (50° C.), to afford compound DR (16.1 g, 75%). 1H NMR (D2O, 500 MHz) δ ppm 3.08 (m, 2.5H), 2.93 (m, 0.5H), 2.87 (m, 2H), 1.99 (m, 4H), 1.64 (m, 3H), 1.47 (m, 1H), 1.24 (m, 2H), 0.88 (m, 1H), 0.78 (m, 3H). 13C NMR (D2O, 125 MHz) δ ppm 57.35, 56.52, 48.16, 18.05, 43.73, 43.30, 32.45, 31.13, 28.92, 28.69, 27.77, 24.55, 21.65, 21.53, 21.20, 18.38. ES-MS 236 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH3:17])[C:14]=3[CH3:16])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.Br[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([CH3:29])=[N:27][N:28]=2)[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH3:17])[C:14]=3[CH3:16])[C:10](=[O:18])[N:9]2[C:20]2[CH:21]=[CH:22][C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: Cc1nnc2ccc(Br)cn12
Reactant: Cc1c2c(nn1C)C(=O)NC2c1ccc(Cl)cc1
Product: Cc1c2c(nn1C)C(=O)N(c1ccc3nnc(C)n3c1)C2c1ccc(Cl)cc1
Reaction time: 0.02 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 24 using 4-(4-chlorophenyl)-2,3-dimethyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (Step 25.6) and 6-bromo-3-methyl[1,2,4]triazolo-[4,3-a]pyridine. After purification by silica gel column chromatography, the resulting residue was purified by SFC (Thar 100; column: PFP, 25 cm, Ø 3 cm, 5 μm, 60 Å; gradient: 10% B for 1 min, 10-15% B in 6 min, 15-50% B in 1 min, 50% B for 1.5 min, 50%-10% B in 1 min, 10% B for 0.5 min; A: scCO2, B: MeOH; flow: 100 mL/min). The residue was triturated in Et2O. tR: 3.26 min (HPLC 1); tR: 0.77 min (LC-MS 2); ESI-MS: 393 [M+H]+ (LC-MS 2); Rf=0.37 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H) 2.64 (s, 3H) 3.88 (s, 3H) 6.49 (s, 1H) 7.35 (s, 4H) 7.47-7.52 (m, 1H) 7.65-7.70 (m, 1H) 8.64 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20]([CH:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])[CH3:24])=[O:21]
Reactant: COC(=O)C(C)Br
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccccc1S(N)(=O)=O
Yield: 80.7 %

Procedure:
34.6 g of 2-hydroxybenzenesulfonamide and 55.3 g of potassium carbonate are added to 800 ml of acetonitrile. With efficient stirring, 33.4 g of methyl 2-bromopropionate are added dropwise over 10 minutes and the suspension is then heated for 5 hours to 45° C. After the reaction mixture has cooled, the precipitated salts are isolated and the filtrate is concentrated in vacuo. The residue is recrystallised from ethanol, affording 41.8 g of 2-(1-methoxycarbonylethoxy)benzenesulfonamide with a melting point of 140°-142° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][P:16]([CH2:28][C:29]([OH:31])=O)([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[CH3:14].Cl.[CH3:33][O:34][C:35](=[O:46])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[NH2:37]>C(#N)C.CO.C(N(CC)CC)C>[CH2:13]([O:15][P:16]([CH2:28][C:29]([NH:37][C@H:36]([C:35]([O:34][CH3:33])=[O:46])[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=1)=[O:31])([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:17])[CH3:14]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
1,1'-Carbonyldiimidazole (0.56 g) was added portionwise to a cooled (0° C.) solution of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid (0.98 g) in 70 ml of acetonitrile. This reaction mixture was stirred under argon at 0° C. for 1.5 hours. The HCl salt of L-tyrosine methyl ester (0.8 g) was dissolved in methanol and neutralized with triethylamine (0.35 g). This solution was concentrated in vacuo, dissolved in 10 ml of warm acetonitrile and added dropwise to the above solution of activated phosphinic acid ester sidechain. The reaction was stirred overnight under argon and then concentrated in vacuo. A solution of the pot residue in dichloromethane was washed (H2O, aqueous NaHCO3, brine), dried (MgSO4) and filtered to yield 1.4 g of N-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine, methyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([C:31]2[N:39]3[C:34]([CH:35]=[N:36][C:37](O)=[N:38]3)=[CH:33][CH:32]=2)[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]>>[N:15]1[CH:16]=[C:17]([NH:20][C:37]2[N:36]=[CH:35][C:34]3=[CH:33][CH:32]=[C:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=4)[N:39]3[N:38]=2)[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCNCC5)nc4)nn23)c1

Procedure:
This example was prepared by using 5-Amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (WO2006/047277) and 7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c followed by deprotection as described in Example 1223. 1H-NMR (DMSO) δ 9.9 (s, 1H), 9.1 (s, 1H), 8.8 (s, 1H), 8.7 (s, 1H), 8.6 (brs, 1H), 8.4 (d, J=7.9 Hz, 2H), 8.2 (d, J=8.9 Hz, 1H), 8 (d, J=7.9 Hz, 1H), 7.8 (t, 1H), 7.3 (m, 2H), 7 (d, J=4.4 Hz, 1H), 3.4 (m, 2H), 3.36 (s, 3H), 3.0 (m, 3H), 2.0 (m, 2H), 1.85 (m, 2H); LC/MS (ESI+): 449 (M+H).
Reaction SMILES: [NH2:1][C@@:2]12[CH2:7][C@H:6]1[CH2:5][O:4][C:3]2=[O:8].[F:9][C:10]([F:16])([F:15])[CH2:11][C:12](O)=[O:13].OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[F:9][C:10]([F:16])([F:15])[CH2:11][C:12]([NH:1][C@@:2]12[CH2:7][C@H:6]1[CH2:5][O:4][C:3]2=[O:8])=[O:13]
Reactant: N[C@@]12C[C@H]1COC2=O
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC(F)(F)F)N[C@@]12C[C@H]1COC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
(±)-Trans-1-amino-3-oxabicyclo[3.1.0]hexan-2-one (128 mg, 1.13 mmol) was mixed with 3,3,3-trifluoropropionic acid in 2.3 mL of N,N-dimethylformamide. Hydroxybenzotriazole (17.4 mg, 0.11 mmol) was added followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (282 mg, 1.47 mmol). The pH of the reaction mixture was adjusted to 8.5 with triethylamine and the mixture was allowed to stir at ambient temperature for 2 hours. Water was then added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, then dried (sodium sulfate) and concentrated to give the crude product. This was purified by silica gel chromatography to afford 120 mg (45%) of 3,3,3-trifluoro-N-[(±)-trans-2-oxo-3-oxabicyclo[3.1.0]hex-1-yl]-propanamide.