Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].Br[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][Br:16].[CH2:17]([C:23]1[CH:24]=[C:25](B2OCC(C)(C)CO2)[S:26][CH:27]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Br:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:25]1[S:26][CH:27]=[C:23]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:24]=1
Reactant: CCCCCCc1csc(B2OCC(C)(C)CO2)c1
Reactant: BrCCCCc1ccsc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: COCCOC
Product: CCCCCCc1csc(-c2sccc2CCCCBr)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A mixture of a saturated solution of NaHCO3 (115 ml) and DME (230 ml) was sparged with argon for 45 minutes. 2-bromo-3-(4-bromobutyl)thiophene (10.4 g, 35 mmol) and 2-(4-hexylthiophen-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (9.9 g, 35 mmol) were added, followed by addition of Pd(PPh3)4. After warming up to 80° C., the mixture became first bright yellow, and then dark orange. After stirring at 80° C. for 18 h, a saturated solution of NH4Cl (aq, 210 ml) was added, and the mixture was extracted with ether. The organic phase was washed with water, a saturated solution of NaHCO3 and brine. After drying over magnesium sulfate and solvent removal, the dark orange oil was purified by column chromatography using hexanes as the eluent. The product (6.07 g, 45% yield) was isolated as a pale yellow oil and used without further purification. 1H-NMR (ppm, CDCl3): 0.87 (3H, t, J=6.96 Hz), 1.25-1.36 (6H, m), 1.61 (2H, m), 1.76 (2H, m), 1.88 (2H, m), 2.58 (2H, t, J=8.52 Hz), 2.76 (2H, t, J=7.56 Hz), 3.38 (2H, t, J=6.72 Hz), 6.86-6.93 (3H, m), 7.14 (1H, d, J=5.2 Hz); 13C-NMR (ppm, CDCl3): 14.1, 21.2, 22.3, 29.0, 29.2, 30.5, 30.7, 31.0, 31.1, 31.8, 121.2, 123.6, 128.1, 129.8, 132.0, 135.5, 137.1; ESI-MS (m/z) found: 385.06, [M+H], calculated: 385.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:20][S:21](O)(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:20][S:21]([O:12][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:23])=[O:22]
Reactant: COc1cccc(CC(C)O)c1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC(C)OS(C)(=O)=O)c1
Yield: 98.2 %

Procedure:
To a cold solution (5° C.) of 1-[3-(methyloxy)phenyl]-2-propanol (1) (75 g, 0.45 mol) in CH2Cl2 (500 mL) were added Et3N (100 mL, 0.72 mol) and DMAP (2.75 g, 22.5 mmol). Methanesulfonic acid (52 mL, 0.675 mol) was added slowly (drop-wise) to the above reaction mixture at that temperature over a period of 40 min. The resultant mixture was stirred between 5° C. and 10° C. for 8 h under N2. The reaction mixture was washed with H2O (3×150 mL), brine (1×100 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the crude product which was passed through a pad of silica to afford 108 g (98%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.24 and 7.20 (dd, J1=15.2 Hz, J2=3.8 Hz, 1H), 6.81-6.76 (m, 3H), 4.87 (sextet, J=6.00 Hz, 1H), 3.77 (s, 3H), 2.96 and 2.92 (dd, J1=14.0 Hz, J2=8.0 Hz, 1H), 2.87 and 2.84 (dd, J1=14.0 Hz, J2=5.6, Hz, 1H), 2.54 (s, 3H), 1.44 (d, J=6.4 Hz, 3H).
Reaction SMILES: C([NH:4][C:5]1[C:6]([F:26])=[CH:7][C:8]([Cl:25])=[C:9]([CH:24]=1)[O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)C>CO>[NH2:4][C:5]1[C:6]([F:26])=[CH:7][C:8]([Cl:25])=[C:9]([CH:24]=1)[O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Solvent: CO
Product: CCOC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl

Procedure:
Into a boron trifluoride methanol complex, methanol solution is added ethyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate, and the mixture is heated while stirring. Thereafter, the reaction solution is concentrated, the residue is dissolved in ethyl acetate, and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to obtain ethyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-23].
Reaction SMILES: [OH:1][CH2:2][C@:3]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:6](=[O:8])[N:5]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:4]1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[Cl-].[NH4+]>CN(C)C=O>[Si:29]([O:1][CH2:2][C@:3]1([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:7][C:6](=[O:8])[N:5]([C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:4]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](CO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a solution of tert-butyl(3S)-3-hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (8.23 g, 25.8 mmol) and imidazole (2.63 g, 38.7 mmol) in N,N-dimethylformamide (150 mL), tert-butyl dimethylsilyl chloride (4.66 g, 31.0 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, saturated aqueous solution of ammonium chloride (300 mL) was added in an ice bath, and the mixture was extracted with diethylether (300 mL×2). The organic layer was washed with water (300 mL×2) and saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 10:1→1:1) to obtain 7.98 g (71%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1>>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH:23][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Product: C[Si](C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1

Procedure:
[2-(3-trifluoromethyl-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine was prepared in analogy to example 1 from 4-trimethylsilanyl-benzaldehyde and 2-(3-trifluoromethyl-phenyl)-ethylamine. MS (ISP): 352.3 (M+H)+. 1HNMR (CDCl3, 300 MHz): δ 7.48 (m, 4H), 7.39 (m, 2H), 7.27 (d, 2H), 3.81 (s, 2H), 2.80-3.00 (m, 4H), 0.26 (s, 9H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH:43][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:28])=[O:29])[CH:31]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 25 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 15 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 601 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:39])[C:33]([CH3:38])([CH3:37])[CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][C:33]([C:32]1[N:39]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:31]=1)([CH3:38])[CH3:37]
Reactant: COCC(C)(C)C(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: COCC(C)(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
80 mg (0.188 mmol) of the compound from Example 100A and 41 mg (0.281 mmol) of N′-hydroxy-3-methoxy-2,2-dimethylpropanimidamide were reacted according to the General Method 2. Yield: 55 mg (56% of theory)
Reaction SMILES: C(OC([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([O:25]CC=C)=[O:24])[CH2:8]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:21][C@@H:19]([C@H:16]1[C:15](=[O:22])[N:14]2[C@@H:17]1[CH2:18][C:12]([CH:9]1[CH2:10][CH2:11][NH:7][CH2:8]1)=[C:13]2[C:23]([OH:25])=[O:24])[CH3:20]
Reactant: C=CCOC(=O)C1=C(C2CCN(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCNC3)C[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of allyl (5R,6S)-3-(1-allyloxycarbonylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.94 g) in a mixture of tetrahydrofuran (14 ml) and ethanol (2 ml) were added successively triphenylphosphine (130 mg), 5,5-dimethyl-1,3-cyclohexanedione (dimedone) (0.66 g) and tetrakis(triphenylphosphine)palladium(0) (280 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration and washed with tetrahydrofuran to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(pyrrolidin-3-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (480 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH2:9][C:8]2=[O:16])=O.[NH3:17].O>>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:7]([C:8](=[O:16])[CH2:9][CH2:10]2)=[CH:6][C:5]=1[C:3]([NH2:17])=[O:2]
Reactant: COC(=O)c1cc2c(cc1OC)CCC2=O
Reactant: N
Solvent: O
Product: COc1cc2c(cc1C(N)=O)C(=O)CC2
Temperature: 40 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
6-Methoxy-3-oxo-indan-5-carboxylic acid methyl ester (7 g, 31.82 mmol) was suspended in NH3.H2O (150 ml), and the mixture was heated to 40° C. and stirred for two hours, during this time the precipitate was formed. The precipitate was collected and dried to give product as white solid (5.2 g, 80% yield). LC-MS: m/e 206(MH+)
Reaction SMILES: [C:1](=[O:3])=O.Cl.[CH2:5]([O:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:10])[CH3:6].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl.C(OCC)C>[N-:10]=[C:1]=[O:3].[CH2:5]([O:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:10])[CH3:6]
Reactant: O=C=O
Agent: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: [N-]=C=O

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (40 mL) solution containing phenylalanine ethyl ester hydrochloride salt (0.02 mol, 4.6 g), N-cyclohexyl-N',N',N",N"-tetraethylguanidine (0.02 mol, 5.1 g) and triethylamine (0.06 mol, 6.0 g) at -10° C. (ice and salt bath) for 40 min at a pressure of 0 psig. The reaction mixture was transferred rapidly via cannula under carbon dioxide to the precooled solution of phosphorus oxychloride (0.02 mol, 3.1 g) in 40 mL dichloromethane. After stirring for 20 min at -10° C. diethylether (50 mL) was added to the reaction mixture. A white ppt formed and was filtered off. The filtrate was concentrated in vacuo and the residue was extracted with 3×25 mL diethylether. The ether layers were concentrated and the residue was distilled under vacuum (ca. 0.1-0.3 torr) collecting product, phenylalanine ethyl ester isocyanate, at 96°-106° C. (2.85 g, 64.5 %) of 99% purity as judged by GC. IR (neat) 2261, 1742 cm-1. 1H NMR (CDCl3) δ 7.34-7.18 (m, 5H), 4.24 (q, 2H, J=14.1), 4.23 (d, 1H, J=7.8), 3.141 (dd, 1H, Jgem =13.7, Jvic =4.8), 3.02 (dd, 1H, Jgem =13.8, Jvic =7.7), 1.28 (t, 3H, J=7.1) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][O:23][C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1
Yield: 62.6 %

Procedure:
By the same procedure as in Example 26-B), while using (2S)-1-(tert-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (2.00 g) and 4-fluorophenol (2.21 g), there was obtained 1.91 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[CH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH:23]=[N:24][OH:25])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([O:25][N:24]=[C:23]([C:22]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][CH:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:21]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(C=NO)cc1OC1CCCC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=NOC3(CCN(C(=O)OC(C)(C)C)C3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The compound obtained from step c above (170 mg, 0.0010 mole) and 3-cyclopentyloxy-4-methoxy-benzaldehyde oxime (236 mg, 0.0010 mole) were taken in dichloromethane (20%) in chloroform followed by the addition of pyridine (2 drops). The reaction mixture was stirred at room temperature for 10 minutes followed by the addition of sodium hypochlorite (2 mL) dropwise. The resulting reaction mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was evaporated under reduced pressure followed by diluting it with water. The compound was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 200 mg.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].O[N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13]>CN(C=O)C>[CH2:10]1[C:11](=[O:12])[N:7]([O:4][C:3]([CH2:2][Br:1])=[O:5])[C:8](=[O:13])[CH2:9]1.[Br:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C1CCC(=O)N1O
Agent: O=C(O)CBr
Solvent: CN(C)C=O
Product: O=C(CBr)ON1C(=O)CCC1=O
Reaction time: 2 h

Procedure:
The NHS (N-hydroxy succinimide) ester of bromoacetic acid was prepared as follows: 100 mmoles of (13.9 g) of bromoacetic acid were dissolved in 50 ml of anhydrous DMF, to this solution 100 mmoles (20.6 g) of N—N-Dicyclohexylcarbodiimide were added with stirring followed by 100 mmoles of N-hydroxysuccinimide (11.9 g adjusted for 100% purity), and the mixture was stirred for 6 hours at 37° C. The mixture was then placed for 2 hours at −20° C. to accelerate the precipitation of hydroxyurea, which was removed by filtration. In the filtrate the DMF was removed under reduced pressure at 45° C. and the active ester was recrystallized from 2-propanal.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:3]1
Reactant: Fc1ccccn1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(Oc2ccccn2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (prepared by reaction of 1-methyl-4-piperidone with phenyl lithium; 3.83 g, 20 mM) in dry DMSO (50 ml) was treated with sodium hydride (960 mg of 50% dispersion in oil, 20 mM), stirred for 1 hour then treated with 2-fluoro-pyridine (1.94 g, 20 mM). After 48 hours the reaction was poured on to water (200 ml) and extracted with ether (3×200 ml). The organic extract was washed with brine, dried and the solvent removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave the title compound (2.0 g,) m.p. 95°-6° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13]([C:39]2[CH:38]=[C:37]([C:36]([F:51])([F:50])[F:35])[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(F)cc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 91 %

Procedure:
The title compound was prepared in 91% yield from 2-(3′-fluoro-5-trifluoromethanesulfonyloxy-5′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Intermediate B) and 3,5-bis-trifluoromethylphenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC(CCN)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)C1
Temperature: 120 °C
Yield: 28.6 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (74 mg, 0.249 mmol) was dissolved in dry DMF (1 mL) nitrogen atmosphere. tert-Butyl 3-(2-aminoethyl)azetidine-1-carboxylate (50 mg, 0.249 mmol) was added followed by TEA (25 mg, 0.247 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (33 mg, 28.8%). 1H NMR (500 MHz, CDCl3): δ 1.43 (s, 9H), 1.62 (q, 2H), 1.73 (s, 9H), 2.19-2.27 (m, 1H), 2.83 (q, 2H), 3.23-3.26 (m, 2H), 3.84 (t, 2H), 5.25 (t, 1H), 7.42-7.51 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 26.24, 27.82, 28.61, 34.35, 41.72, 54.06, 61.82, 79.63, 107.55, 125.15, 128.93, 130.09, 131.79, 135.04, 156.38, 159.81; Mass Spectrum: M−H+ 462.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1([C:23]2[C:24]([CH3:31])=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:14](=[O:16])[NH:30][C:25]2[CH:24]=[CH:31][C:28]([CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:27][C:26]=2[NH2:29])=[N:11][NH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Reactant: Cc1c(N2CCOCC2)ccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Reaction time: 20 h
Yield: 88.6 %

Procedure:
4-tert-Butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (0.750 Kg, 3.30 mol, 1.0 wt), 4-morpholin-4-yl-methyl-benzene-1,2-diamine (0.752 Kg, 3.63 mol, 1.0 wt) and N,N′-dimethylformamide (11.25 L, 15.0 vol) were charged under nitrogen to a flange flask equipped with a mechanical stirrer and thermometer. 1-Hydroxybenzotriazole (HOBT, 0.540 Kg, 3.96 mol, 0.72 wt) was added at 15 to 25° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 0.759 Kg, 3.96 mol, 1.01 wt) was added at 15 to 25° C. and the mixture was stirred at this temperature for 16 to 24 hours. Reaction completion was determined by 1H NMR analysis. The reaction mixture was concentrated under vacuum at 35 to 45° C. The residue was partitioned between ethyl acetate (7.50 L, 10.0 vol) and sat. aq. sodium hydrogen carbonate solution (8.03 L, 10.7 vol) and the layers were separated. The organic phase was washed with brine (3.75 L, 5.0 vol), dried over magnesium sulfate (1.00 Kg, 1.33 wt) and filtered. The filter-cake was washed with ethyl acetate (1.50 L, 2.0 vol). The combined filtrate and wash were concentrated under vacuum at 35 to 45° C. to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (1.217 Kg, 88.6%) as a dark brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:39]1([N:43]2[CH2:49][CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40]1>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[CH:39]1([N:43]2[CH2:49][CH2:48][CH2:47][N:46]([C:15]([CH:13]3[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:14]3)=[O:17])[CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40]1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a stirred solution of 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (500 mg, 2.13 mmol) in DMF/DCM (1:10) (11 ml) was added HOBt (287 mg, 2.13 mmol) and EDCI (490 mg, 2.56 mmol). The resulting suspension was stirred at RT for 10 mins before dropwise addition of 1-cyclobutyl-1,4-diazepane (328 mg, 2.13 mmol) in DCM (3 ml). After stirring for 16 h at RT the reaction was shown to be complete by TLC and the solvent was evaporated at reduced pressure. The residue was treated with saturated aqueous NaHCO3 (10 ml) and the resulting aqueous extracted with EtOAc (3×7.5 ml). The combined organic phases were dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 99:1 to 97:3 gradient of DCM/2M NH3 in MeOH) provided the title compound (475 mg, 60% yield) as a yellow oil.