Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([CH2:13][CH2:14][Cl:15])[CH2:7][N:6]([CH3:16])[C:5](=O)[C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([CH2:13][CH2:14][Cl:15])[CH2:7][N:6]([CH3:16])[C:5](=[S:27])[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=O
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=S
Reaction time: 2 h

Procedure:
7-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one, 6.0 g (0.022 mole) was suspended in 200 ml of toluene. To this suspension was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-dilsulfide. The mixture was heated to reflux with vigorous stirring for 2 hours. Because the reaction was not complete, an additional amount (3.0 g) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and the mixture stirred at reflux for 2 hr and left standing for 56 hr at room temperature. The toluene layer was decanted and washed with 50 ml of dilute aqueous sodium hydroxide and 50 ml of dilute hydrochloric acid. Toluene was removed by rotary evaporation (~80° C., water aspirator). The crude oil was recrystallized from isopropyl alcohol giving 3.5 g (54%) of pale yellow crystals, m.p. 125°-127° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:43](=[O:44])[C:42]2[CH:45]=[CH:46][C:47]3[N:48]=C[O:50][C:51]=3[C:41]=2[O:40][C:39]=1[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:43](=[O:44])[C:42]4[C:41](=[C:51]([OH:50])[C:47]([NH2:48])=[CH:46][CH:45]=4)[O:40][C:39]=3[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1ncoc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(O)c(N)ccc4c3=O)cc2)CCC1
Yield: 14 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-8-phenyl-chromeno[7,8-d]oxazol-6-one was reacted to give the title compound as a yellow oil (25 mg, 14%). LCMS (Method G): RT=3.75 min, [M+H]+=499.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@@H:7]([O:9]CC2C=CC=CC=2)[C@@H:6]([O:17]CC2C=CC=CC=2)[C@@:5]1([CH3:33])OCC1C=CC=CC=1)(=[O:3])[CH3:2].C([OH:36])C.Cl>[Pd].CO>[C:1]([N:4]1[CH2:8][C@@H:7]([OH:9])[C@H:6]([OH:17])[C@H:5]1[CH2:33][OH:36])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)OCc1ccccc1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)N1C[C@@H](O)[C@H](O)[C@H]1CO

Procedure:
The title compound was synthesized as described for compound 9 using (2R,3R,4R)-1-acetyl-3,4-dibenzyloxy-2-benzyloxy-methylpyrrolidine (Compound 12) (0.595 g, 1.3 mmol), ethanol (30 ml), methanol (10 ml), 10% Pd/C (0.10 g) and a catalytic amount of 1M hydrochloric acid. Purification of the product on silica gel (Eluent: Ethyl acetate/methanol (1:1)) afford-ed(2R,3R,4R)-1-acetyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine(0.2g,yield: 86%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[O:15][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCOCC1c1ccc(F)c(F)c1
Reactant: O=C=NC(=O)Cl
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)c(F)c1)COC2

Procedure:
3-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Y(2)) was reacted as described in Intermediate X(3) with carbonisocyanatidic chloride to give 8-(3,4-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate Y(3)). LC-MS (M+H)+=282.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.08-7.20 (m, 3H) 4.67 (d, J=15.26 Hz, 1H) 4.46 (dd, J=15.56, 2.14 Hz, 1H) 3.98-4.10 (m, 2H) 3.67 (br. s., 1H).
Reaction SMILES: [CH3:1][O-].[Na+].CS([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)[CH2:14][CH2:13][N:12]1[CH3:30])(=O)=O>CO>[CH3:1][O:8][CH2:9][CH2:10][CH:11]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)[CH2:14][CH2:13][N:12]1[CH3:30]
Reactant: CC(C)Oc1cc(N2CCN(C)C(CCOS(C)(=O)=O)C2)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCC1CN(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
51.1 mg of sodium methoxide are added to a solution of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethyl methanesulfonate in 3 ml of methanol. The reaction medium is stirred for 10 minutes at ambient temperature and then 30 minutes at 90° C. in a microwave (CEM). The reaction medium is concentrated to dryness under reduced pressure, and taken up with water and ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a mixture of dichloromethane and methanol (100/0) to (80/20). 100 mg of 2-(2-methoxyethyl)-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazine are obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH3:5][C:6]1([CH3:13])[O:10][CH:9]([CH:11]=O)[CH2:8][O:7]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:13][C:6]1([CH3:5])[O:10][CH:9]([CH2:11][NH:4][CH2:1][CH2:2][CH3:3])[CH2:8][O:7]1
Reactant: CC1(C)OCC(C=O)O1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a solution of propylamine (0.72 mL, 7.7 mmol) and 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (1.0 g, 7.7 mmol) in 1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (2.28 g, 10.8 mmol). The mixture was stirred for 1.5 h at room temperature. The reaction mixture was then quenched with sat'd aq NaHCO3 and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (CH2Cl2 to 10% MeOH in CH2Cl2, gradient) to afford 1.26 g (73%) of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propan-1-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][C:27]([F:26])([F:39])[F:38])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-(trifluormethoxy)phenylboronic acid (CAS RN 175676-65-0). Off-white solid (34%). MS (ESI): m/z=509.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][C@@H:29]([C:31]([O-:33])=[O:32])[CH3:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][C@@H:29]([C:31]([OH:33])=[O:32])[CH3:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN[C@H](C)C(=O)[O-])cn(C)c34)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN[C@H](C)C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a stirred solution of N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-D-alaninate (D80) (110 mg) in THF (2 mL) was added aqueous NaOH (2 M, 2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was acidified with HCl (2 M) to pH 6-7. The resulting solid was separated and suspended in methanol (2 mL) with stirring, HCl (2M) was added until the solid dissolved completely. The solution was freeze dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-D-alanine (E59) (60 mg, HCl salt). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.48 (3H, d), 3.71 (3H, s), 3.86 (1H, q), 4.35 (2H, s), 4.89 (1H, m), 7.28 (1H, t), 7.45 (1H, d), 7.51 (1H, d), 7.60 (1H, s), 8.03 (1H, d), 8.13 (1H, d), 8.20 (1H, s). MS (ES): C24H26ClN4O4 requires 468; found 380.1 (M—C3H6NO2+).
Reaction SMILES: [C:1](#N)C.C1OCCOCCOCCOCCOCCOC1.CI.[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:37])[CH2:30][C:31]([CH3:36])([CH3:35])[O:32]2)=[C:27]([CH3:38])[CH:26]=1>[K]>[CH3:1][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:37])[CH2:30][C:31]([CH3:35])([CH3:36])[O:32]2)=[C:27]([CH3:38])[CH:26]=1
Reactant: CC#N
Reactant: Cc1cc(O)cc2c1C(=O)CC(C)(C)O2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CI
Product: COc1cc(C)c2c(c1)OC(C)(C)CC2=O
Yield: 85 %

Procedure:
In 50 ml of acetonitrile 4.9 g (20 millimoles) of the potassium salt of 7-hydroxy-2,2,5-trimethyl-4-chromanone are dissolved and the solution is stirred in the presence of 0.5 g (2 millimoles) of 18-Crown-6 at room temperature for 30 minutes. To the mixture 4.25 g (1.9 ml, 30 millimoles) of methyl iodide are added and the reaction mixture is stirred for a further hour. The inorganic salt is filtered off and the solvent is removed. The residue is taken up in chloroform, washed twice with 50 ml of water each, dried over sodium sulfate and evaporated. The product is crystallized from 90% ethanol. Thus 3.75 g of the desired compound are obtained, yield 85%. Mp.: 86°-88° C.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>C1C=CC=CC=1>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:27]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C1CCCN1Cc1ccccc1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: F[B-](F)(F)F
Solvent: c1ccccc1
Product: O=C(N=C1CCCN1Cc1ccccc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to free base (4.36 g.; 0.025 mole -- assuming 100% conversion) by adding 5 ml. of 50% NaOH to an aqueous slurry of the salt and benzene extraction. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 3.84 g. (0.025 mole) of m-chlorophenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred at room temperature for 2 hours and then taken to dryness in vacuo to give an oily residue which eventually crystallizes. Recrystallizations from acetonepetroleum ether affords a pure product, 1-(1-benzyl-2 -pyrrolidylidene)-3-(m-chlorophenyl)urea, m.p. = 91°-93° C.
Reaction SMILES: BrBr.Cl[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[CH2:10]([SH:13])[CH2:11][CH3:12].[OH-].[K+]>C(Cl)Cl.CO>[C:7]([C:6]1([S:13][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5]1)(=[O:9])[CH3:8]
Reactant: CCCS
Reactant: CC(=O)CCCCl
Agent: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCSC1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A solution of 134 g (0.83 mol) of bromine in 130 ml of methylene chloride is added dropwise at 10° C. with stirring to a solution of 100 g (0.83 mol) of 5-chloropentan-2-one in 400 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour, then washed with water and dilute, aqueous sodium carbonate solution and dried over sodium sulphate. The mixture is concentrated by removing the solvent under reduced pressure, and the residue is taken up in 200 ml of methanol and 63 g (0.83 mol) of n-propylmercaptan are added at 5° C. with stirring. A mixture of 93 g of potassium hydroxide powder in 500 ml of methanol are then added dropwise. The reaction mixture is first stirred at room temperature for 2 hours and then at 40° C. for 4 hours. The mixture is subsequently concentrated by removing the solvent under reduced pressure and the residue which remains is taken up in methylene chloride. The organic solution is washed successively with water, dilute aqueous sodium hydroxide solution and again with water, then concentrated under reduced pressure and then subjected to a vacuum distillation. In this manner, 42 g (32% of theory) of 1-acetyl-1-propylmercapto-cyclopropane of boiling point 107° C./20 mbar are obtained.
Reaction SMILES: C(O)=O.OS([O-])(=O)=O.[K+].[Cl:10][C:11]1[CH:12]=[C:13]2[N:36](COCC[Si](C)(C)C)[C:35]([O:45][C@H:46]3[C@H:50]4[O:51][CH2:52][C@@H:53]([OH:54])[C@H:49]4[O:48][CH2:47]3)=[N:34][C:14]2=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.[OH-].[Na+]>O.C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]2[NH:36][C:35]([O:45][C@H:46]3[C@H:50]4[O:51][CH2:52][C@@H:53]([OH:54])[C@H:49]4[O:48][CH2:47]3)=[N:34][C:14]2=[N:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccc(-n5cccn5)cc4)cc3)c(Cl)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=CO
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccc(-n5cccn5)cc4)cc3)c(Cl)cc2[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Combined formic acid (3 mL, 78 mmol), saturated aqueous KHSO4 (0.33 mL, 0.289 mmol), and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(4-pyrazol-1-ylphenyl)phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo-[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (187 mg, 0.289 mmol). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to 0° C. in an ice bath. The pH of the reaction mixture was adjusted to >11 by the addition of NaOH (3120 mg, 78 mmol) in water (5 mL). THF (5 mL) was added to the reaction mixture, then the reaction was removed from the ice bath and allowed to warm to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to 6 through the addition of concentrated HCl. The reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (1×50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative HPLC reverse phase (C-18), using a 19×100 mm Sunfire™ column and eluting with a 10%-90% acetonitrile/water+0.05% TFA gradient followed by a 90% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from acetonitrile and water to give the title compound as a white solid. LC-MS: calculated for C27H22ClN5O4 515.14 observed m/e: 515.92 (M+H)+(Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 8.30 (d, J=2.5 Hz, 1H), 7.87 (m, 4H), 7.85 (s, 1H), 7.79 (m, 4H), 7.77 (d, J=1.5 Hz, 1H), 6.58 (t, J=2 Hz, 1H), 5.56 (qt, J=5 Hz, 11H), 4.99 (t, J=5.3 Hz, 1H), 4.49 (t, J=5.3 Hz, 1H), 4.28-4.31 (m, 1H), 4.19 (dd, J=5.5 Hz, 10.5 Hz, 1H), 4.12 (dd, J=4.5 Hz, 10 Hz, 1H), 3.92 (t, J=7.5 Hz, 1H), 3.62 (t, J=8.8 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH:10]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:9]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCc1ccc(C(CCCC(=O)O)c2cccnc2)cc1
Product: O=C(O)CCCC(c1ccc(CCNS(=O)(=O)c2ccc(F)cc2)cc1)c1cccnc1

Procedure:
Prepared analogously to Example 10e from 5-(4-(2-aminoethyl)phenyl)-5-(3-pyridyl)pentanoic acid and 4-fluorobenzenesulphonic acid chloride.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCl>[Cl:17][S:18]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:7][CH:6]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(Cc2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A solution of 4-benzyl-nitrobenzene (4.26 g, 70 mmol) dissolved in dichloromethane (25 mL) was added dropwise to a solution of chlorosulfonic acid (6 mL) in dichloromethane (25 mL) at−30° C. The mixture was stirred for 10 minutes at 0° C., then poured onto ice and shaken. The organic phase was separated and solvents were evaporated. The residue was recrystallized from dichloromethane/hexanes to yield 4-(4-chlorosulfonylbenzyl)-nitrobenzene (5.52 g, 78%) as dichloromethane hemisolvate crystals.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Br:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Br:12][CH2:13][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: BrCBr
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(C#N)(CBr)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
3.2 g of 2-(3,3,3-trifluoropropyl)malononitrile, 7.0 g of dibromomethane and 5.5 g of potassium carbonate were added to 40 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 18 hours. Thereafter, the reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.4 g of 2-bromomethyl-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (52)).
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:41])[C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[CH:25][C:24]=2[O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[O:39][CH3:40])=[CH:17][C:16]1=[O:42])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].CC(O)=O>CC#N.O>[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:41])[C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[CH:25][C:24]=2[O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[O:39][CH3:40])=[CH:17][C:16]1=[O:42])=[O:2]
Reactant: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)Nc1ccn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)c1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Yield: 54.6 %

Procedure:
A solution of di-tert-butyl [4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (40 mg, 0.06197 mmol) in CH3CN (800.0 μL), water (800.0 μL) and AcOH (800 μL, 14.07 mmol) was heated at 90° C. for 15 min then evaporated and co-evaporated with CH3CN (3×). The material was triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (1) (19 mg, 0.03385 mmol, 54.6%) as a white solid. ESI-MS m/z calc. 532.00055, found 533.3 (M+1)+; Retention time: 1.5 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.91 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.27 (dd, J=8.9, 5.8 Hz, 1H), 7.13 (dd, J=10.7, 3.0 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.86 (s, 1H), 6.86-6.81 (m, 1H), 6.44 (dd, J=7.6, 2.4 Hz, 1H), 5.52 (d, J=9.7 Hz, 2H), 3.76 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −2.12 (t, J=9.4 Hz) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH2:20])=O)=[CH:11][CH:10]=1.O.[OH-].[Na+]>C(OCC)C.C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:20])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCCC(N)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
(Ali, F. E.; Dandridge, P. A.; Gleason, J. G.; Krell, R. D.; Kruse, C. H.; Lavanchy, P. G; Snader, K. M. J. Med Chem., 1982, 25, 947). To a stirred suspension of lithium aluminum hydride (4.40 g, 116 mmol) in 120 mL diethyl ether was added dropwise a solution of 36b (5.60 g, 29.0 mmol) in 10 mL THF, and stirred at rt for 1 h. To the reaction mixture was added 7.5 mL water, 7.5 mL 5 N NaOH(aq), and 20 mL water. The organics were removed from the emulsion which was dissolved in water and extracted with ether. The organic portions were dried over Na2SO4(s), and condensed to give 37b (5.10 g, 98%) as an oil. UV λmax 223 (9410, 95% EtOH). (400 MHz, CDCl3) δ 7.10 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 3.79 (s, 3H), 2.71 (t, J=7 Hz, 2H), 2.58 (t, J=7 Hz, 2H), 1.63 (m, 2H), 1.48 (m, 2H); IR (liq.) 2933 (s), 2856, 2145 (w), 2059 (w), 1996 (w), 1612 (s), 1584, 1513 (s), 1461, 1442, 1246 (s), 1178, 1034 (s), 827, 822, cm−1. 1HRMS (FAB) calcd for C11H17NO+H1 180.1388, found 180.1387.
Reaction SMILES: C(OC(=O)C([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:26])[NH:24][CH3:25])[CH:18]=2)=[O:15])=[N:10][CH:9]=1)C)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=[C:46]([CH2:48][C:49]([OH:51])=[O:50])N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(NC)=O)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[CH:28]1([CH2:27][N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:26])[NH:24][CH3:25])[CH:18]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:46][CH2:48][C:49]([OH:51])=[O:50])=[CH:9][N:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)NC)c2)s1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: CNC(=O)c1cccc(NCC2CCCC2)c1
Product: CNC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N-methyl-benzamide and (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester