Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:31])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:16]=[N:15][C:14]([CH:13]([F:31])[F:12])=[N:19][CH:18]=1)[CH2:23][C:24]1([C:27]([F:30])([F:28])[F:29])[CH2:26][CH2:25]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1)c1ccc(Cl)cc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,4-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=468.0, tR (minutes, Method F)=3.14. [α]D20=+32.40 (c=3.15 mg/mL,CHCl3)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CO)c(C)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cnc(C=O)c(C)c1

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-yl)-methanol (2.12 g, 15.45 mmol) (Weidmann, K. et al. J. Med. Chem. 1992, 35, 438-450) in CH2Cl2 (50 mL) was added MnO2 (9.41 g, 108.18 mmol) and the reaction mixture was refluxed overnight. Then it was cooled and the mixture was filtered through a layer of celite. The filtrate was concentrated to afford a brown/yellow oil. Purification by flash column chromatography on silica get using 30% EtOAc/hexane afforded 3,5-dimethyl-pyridine-2-carbaldehyde as a yellow oil (960 mg, 31% over 3 steps). 1H NMR (CDCl3) δ 2.39 (s, 3H), 2.62 (s, 3H), 7.41 (s, 1H), 8.47 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>O1CCCC1>[CH3:4][C:2]([C:5]1[C:10]([O:11][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:1])[CH3:3]
Reactant: COCCOCCl
Reactant: Cc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(C)nc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,6-Bis(1,1-dimethylethyl) 5 hydroxy-2-methyl pyrimidine (9.8 g, 44.1 mmoles) is dissolved in 100 mL of tetrahydrofuran and added dropwise to a suspension of sodium hydride (1.2 g, 48.5 mmoles) in THF (50 mL) at 0° C. The reaction mixture is warmed to room temperature over 15 minutes. 2-Methoxyethoxymethyl chloride (7.1 g, 57.3 mmoles) is added to the reaction mixture at room temperature. After being stirred at room temperature for 4 hours, the reaction is quenched by the addition of saturated ammonium chloride and the tetrahydrofuran is evaporated. The organics are extracted into 300 mL of ether. The ether is washed with 100 mL of brine and dried over magnesium sulfate. Evaporation of the solvent gives the crude product which is purified by flash chromatography (silica, 10% ether/hexane). Yield of 4,6 bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-methylpyrimidine=11.3 g (82%) as a clear oil.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:12][CH2:11]1)#[N:9].[C:24]1([C:30]2[CH:35]=[CH:34][C:33](N)=[C:32]([NH2:37])[CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(OCC)(=O)C>[C:20]([S:17]([NH:16][CH:13]1[CH2:12][CH2:11][N:10]([C:8]2[NH:37][C:32]3[CH:31]=[C:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:35]=[CH:34][C:33]=3[N:9]=2)[CH2:15][CH2:14]1)(=[O:19])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)S(=O)(=O)NC1CCN(C#N)CC1
Reactant: Nc1ccc(-c2ccccc2)cc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)(=O)NC1CCN(c2nc3ccc(-c4ccccc4)cc3[nH]2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
To the toluene solution (1 mL) containing 1-cyano-4-(tert-butylsulfonylamino)piperidine (22 mg) were added 4-phenyl-1,2-phenylenediamine (20 mg) and ytterbium triflate (20 mg), and the mixture was stirred in a sealed tube at 130° C. for 16 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and aqueous saturated sodium chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified on a collective thin-layer chromatograph (chloroform:methanol=15:1) to give the title compound (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.[C:14]([C:17]1[CH:18]=[CH:19][C:20](OS(C(F)(F)F)(=O)=O)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])(=[O:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>C(O)C.COCCOC.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>[C:14]([C:17]1[CH:26]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:20]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)c(OC)c1
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: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1cc(C(C)=O)ccc1-c1ccc(OC)cc1OC
Yield: 86.9 %

Procedure:
2,4-Dimethoxyphenylboronic acid (24 g, 134 mmol) was dissolved in ethanol (250 mL). The compound from Step A (21 g, 67 mmol) was dissolved in 1,2-dimethoxyethane (375 mL). The two solutions were mixed with tetrakis(triphenylphosphine)palladium (1 g, 0.9 mmol) and K2CO3 (8.9 g, 64 mmol). The resulting suspension was refluxed for 2 h and then poured into saturated NaHCO3 (1 L). The reaction mixture was extracted three times with CH2Cl2 (400 mL) and dried over Na2SO4. The solvent was removed to yield 35.6 g of crude product which was chromatographed on silica gel with hexane/ethyl acetate (2:1) followed by hexane/ethyl acetate (1:1) to yield 18.3 g (87%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 2.68 (3H, s, COCH3), 3.73 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.88 (3H, s, CO2CH3), 6.52 (1H, s ArH), 6.62 (1H, d, ArH), 7.23 (1H, d, ArH), 7.45 (1H, d, ArH), 8.13 (1H, d, ArH), 8.42 (1H, s, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Br)cc(F)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1c(Br)cc(F)cc1Br
Temperature: 10 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a solution of 101h (20 g, 71 mmol) in EtOH (500 mL) was added NaBH4 (10 g, 284 mmol). The mixture was stirred at room temperature (10° C.) for 4 h and TLC showed the start material disappeared. The reaction was quenched by aqueous HCl solution (150 mL, 1M) and evaporated in vacuo until most of EtOH was distilled. The residue was extracted by ethyl acetate (500 mL×3). The organic layers were combined, dried with Na2SO4, and evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 101i as a white solid (15 g, 75%). MS: [M−OH]+ 267. 1H NMR (500 MHz, DMSO-d6) δ 7.68 (d, J=8.5, 2H), 5.23 (s, 1H), 4.71 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[N:11]=[CH:12][N:13]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2c[nH]cn2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
To a cold (0° C.) solution of 4-(4-cyanophenyloxy)-imidazole (155 mg, 0.84 mmol) and triethylanine (0.129 mL, 0.92 mmol) in DMF (1 mL) was added trityl chloride (245 mg, 0.88 mmol). The resultant mixture was stirred at ambient temperature for 5 days. The product mixture was concentrated onto silica gel, chromatographed (Silica gel, 1:9 acetone in CHCl3) to afford the title compound as a white powder.
Reaction SMILES: [CH:1]1([C:7]2([CH:11]=O)[CH2:10][O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.CN.[C:21]([BH3-])#[N:22].[Na+].[OH-].[Na+]>CO>[CH:1]1([C:7]2([CH2:11][NH:22][CH3:21])[CH2:10][O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: O=CC1(C2CCCCC2)COC1
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: CO
Product: CNCC1(C2CCCCC2)COC1
Reaction time: 8 h

Procedure:
3-Cyclohexyl-3-formyloxetane (1.7 g) was dissolved in methanol (10 ml) at 25° C. In succession, anhydrous sodium acetate (3.3 g), methylamine hydrochloride (3.4 g) and sodium cyanoborohydride (630 mg) were added, followed by a further volume of methanol (30 ml). The mixture was stirred overnight and then basified with sodium hydroxide solution (1M, 22 ml) to pH9. Ether extraction, washing and drying, followed by evaporation gave 3-cyclohexyl-3-methylaminomethyloxetane as a colourless oil.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:33]([CH:34]=[O:35])=[C:32]([N:36]4[CH:48]=[CH:47][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[CH:46]=[C:38]5[C:37]4=[O:49])[N:31]=[CH:30][CH:29]=3)[CH:21]=2)=[N:17][CH:18]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:10][O:11][CH2:12]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:36]4[CH:48]=[CH:47][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[CH:46]=[C:38]5[C:37]4=[O:49])[C:33]=3[CH2:34][OH:35])[CH:21]=2)=[N:17][CH:18]=1)[CH3:2]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 165a (100 mg, 0.15 mmol) in methanol (10 mL) was added NaBH4 (34 mg, 0.90 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. Then the mixture was quenched with water (8 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 165 (35 mg, 35%) as light yellow solid. MS-ESI: [M+H]+ 663. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.51-7.48 (m, 2H), 7.35 (dd, J=2.0 Hz, 9.0 Hz, 1H), 7.27-7.23 (m, 2H), 6.83-6.81 (m, 2H), 4.97 (bs, 1H), 4.59-4.55 (m, 2H), 4.49-4.32 (m, 4H), 3.61 (s, 3H), 3.51-3.47 (m, 1H), 3.42-3.37 (m, 1H), 3.17-3.16 (m, 1H), 3.01-2.98 (m, 1H), 2.76-2.74 (m, 2H), 2.63-2.61 (m, 3H), 2.55-2.54 (m, 1H), 2.19-2.16 (m, 1H), 2.12-2.07 (m, 1H), 1.90-1.85 (m, 2H), 1.77-1.66 (m, 3H), 1.27-1.25 (m, 1H), 0.79 (t, J=7.0 Hz, 3H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11].O1CCOCC1.C([O-])([O-])=O.[K+].[K+].[C:34](Cl)(=[O:50])[O:35][CH2:36][CH:37]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2>O>[CH:48]1[C:49]2[CH:37]([CH2:36][O:35][C:34]([NH:8][C@@H:9]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[C:10]([OH:12])=[O:11])=[O:50])[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: Cc1cccc(OC[C@H](N)C(=O)O)c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1cccc(OC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask equipped with a stir bar and charged with the entirety of (S)-2-amino-3-(m-tolyloxy)propanoic acid TFA salt afforded in Step 3 (assumed 3.36 mmol) was added 1,4-Dioxane (4 mL) and water (16 mL), then K2CO3 (1.17 g, 8.49 mmol). The mixture was cooled to 0° C., then to the mixture was added (9H-fluoren-9-yl)methyl carbonochloridate (549 mg, 2.12 mmol). The mixture was allowed to warm to room temperature with stirring for 18 h. The mixture was diluted with water (10 mL) and then washed with diethyl ether (2×15 mL). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and then was extracted with CH2Cl2 (3×20 ml). The combined CH2Cl2 solutions were dried over MgSO4; filtered; then concentrated in vacuo to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyloxy)propanoic acid as a white solid, 430 mg (31% over two steps).
Reaction SMILES: Cl.[C:2]([N:9]1[CH2:13][C@@H:12]([S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:11]([N:19]([CH3:36])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:10]1)(OC(C)(C)C)=[O:3].C([N:39](CC)CC)C.[Si](N=C=O)(C)(C)C>C(OCC)(=O)C>[C:2]([N:9]1[CH2:13][C@@H:12]([S:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C@H:11]([N:19]([CH3:36])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:10]1)(=[O:3])[NH2:39]
Reactant: CCN(CC)CC
Reactant: CN([C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1SC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CN([C@@H]1CN(C(N)=O)C[C@H]1SC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
To a stirred solution of 1.5 M HCl in ethyl acetate (5 mL) was added (±)-N-Boc-trans-3-(N-methyl-4-phenoxybenzenesulfonamido)-4-tertbutylmercaptopyrrolidine (130 mg, 0.25 mmol) and stirring was continued at room temperature until no starting material was detected by TLC. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2. The solution was cooled to 0° C. and triethylamine (46 μL, 0.33 mmol) and TMSNCO (100 μL, 0.74 mmol) were added successively. The solution was stirred at room temperature overnight. The reaction mixture was extracted with water and saturated brine, and was dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (5% MeOH in ethyl acetate) to give (±)-N-carbamoyl-trans-3-(N-methyl-4-phenoxybenzenesulfonamido)-4-tert-butylmercaptopyrrolidine as a white powder (110 mg, 95%): 1H NMR (300 MHz, CD3OD) δ 7.85 (m, 2H), 7.42 (m, 2H), 7.22 (m, 1H), 7.10 (m, 4H), 4.24 (m, 1H), 3.96 (m, 1H), 3.42 (m, 2H), 3.08 (m, 2H), 2.87 (s, 3H), 1.28 (s, 9H); MS (ESI) m/e 463.2 (M+); HRMS (ESI) calcd for C22H29N3O4S2Na+ 486.1479. found 486.1481.
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:37])=[N-].C(O)(=O)C>O1CCCC1.C(OCC)C>[CH3:37][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=[N+]=[N-]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O

Procedure:
To a suspension of 14 g (29 mmoles) of 1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one (prepared as described in Example 5 B) in 100 ml of tetrahydrofuran a solution of 35 mmoles of diazomethane in diethyl ether was added. The clear solution was treated with acetic acid to remove excess diazomethane and evaporated to dryness. After addition of 100 ml of benzene the solution was filtered, concentrated and chromatographed on a column containing 500 g of silica gel using a 4:1 (v/v) mixture of toluene and ethyl acetate as an eluent. There was obtained 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.N.[OH:29]O>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:29])=[CH:22][CH:21]=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: OO
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccc(C#N)cc4)s3)n2)c1
Agent: N
Solvent: CCO
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccc(C(N)=O)cc4)s3)n2)c1
Temperature: 40 °C
Reaction time: 60 h

Procedure:
4-(5-(6-(4-methylpyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)benzonitrile (Example 51, 40 mg, 0.11 mmol) was suspended in EtOH (8 ml). Aqueous ammonia (28-30%, 4 ml) was added followed by H2O2 (35%, 1 ml). The reaction mixture was stirred at 40° C. for 2.5 days. Aqueous ammonia (2 ml) and H2O2 (0.250 ml) were added and the reaction mixture was stirred a further 24 hours at 40° C. The reaction was partitioned between H2O (30 ml) and EtOAc (70 ml). After separation, the aqueous phase was extracted again with EtOAc (70 ml). After evaporation, and purification of the crude product by dry flash chromatography over SiO2 eluting with EtOAc/MeOH (5%-10%)/NEt3 (0.5%), 4-(5-(6-(4-methylpyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)benzamide was obtained as a yellow solid (46 mg, 74%). 1H NMR (300 MHz, DMSO-d6) δ 9.72 (br s, 1H), 8.59 (br s, 1H), 8.20-7.98 (m, 6H), 7.95 (d, J=8.6 Hz, 1H), 7.78-7.70 (m, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.57-7.45 (m, 3H), 2.25 (s, 3H). (APCI+) m/z 388 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:8])[CH2:4][C:5]([OH:7])=[O:6].[C:9]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O1CCCC1.Cl>[OH-].[Na+]>[CH2:9]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([NH:1][CH2:2][CH:3]([OH:8])[CH2:4][C:5]([OH:7])=[O:6])=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC(=O)c1ccccc1
Reactant: NCC(O)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCC(O)CC(=O)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18.1 g of 4-amino-3-hydroxy-butyric acid are dissolved in 176 ml of 2 N sodium hydroxide. To this there are added within 2 minutes 14.0 g of 3-benzoyloxy-4-methoxybenzoylchloride and subsequently 30 ml of tetrahydrofuran. The mixture is stirred intensively at room temperature for 2 hours, then treated with ice and acidified with concentrated hydrochloric acid. The separated solid is filtered off and washed with water. After drying, the filter cake is boiled in ethyl acetate and the insoluble portion is recrystallised from tetrahydrofuran/n-hexane (3.6:1). There is obtained 4-[(3-benzyloxy-4-methoxybenzoyl)amino]-3-hydroxy-butyric acid of melting point 158°-160° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH2:39][CH2:40][NH2:41])[CH:36]=[CH:37][CH:38]=1>>[CH2:15]([N:14]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:41][CH2:40][CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:16]
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCCc1cccc(C(F)(F)F)c1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3cccc(C(F)(F)F)c3)n2)c1)C1CCNCC1

Procedure:
Intermediate 84 was coupled with 2-(3-trifluoromethyl-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 485. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.24 (m, 3H), 7.77 (t, 1H), 7.67 (t, 1H), 7.55 (m, 2H), 7.35 (m, 3H), 4.54 (s, 2H), 3.79 (m, 4H), 3.60 (d, 2H), 3.08 (m, 5H), 2.42 (d, 2H), 2.12 (m, 2H), 1.30 (t, 3H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH2:15]([OH:17])[CH3:16]>C(OCC)(=O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:5](=[N:1][C:2]#[N:3])[O:17][CH2:15][CH3:16])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCO
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Solvent: CCOC(C)=O
Product: CCOC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diethyl (N-cyanoimido)carbonate (1.59 g.) in ethanol (15 ml.) at room temperature was added a solution of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole (2.58 g.) in ethanol (25 ml.) over 15 minutes with sufficient cooling to maintain the temperature at about 20° C. The solution was stirred at room temperature for a further 30 minutes and then more diethyl (N-cyanoimido)carbonate (0.318 g.) in ethanol (3 ml.) was added. The solution was stirred at room temperature for 15 minutes and then evaporated to dryness under reduced pressure to give a pale yellow paste. This residue was dissolved in ethyl acetate (20 ml.) and the solution was washed with water (20 ml., 2×10 ml.) then dried (magnesium sulphate) and evaporated under reduced pressure to give 2-guanidino-4-[2-(3-cyano-2-ethylisoureido)ethylthiomethyl]thiazole containing a small amount of ethyl acetate. The n.m.r. spectrum in CDCl3 using tetramethylsilane as internal standard had the following resonances (δ): 6.5 (5H, very broad); 6.4 (1H, singlet); 4-4.5 (obscured by ethyl acetate); 3.6 (2H, singlet); 3.4 (2H, multiplet); 2.7 (2H, multiplet); 2.0 (ethyl acetate); 1.2-1.5 (obscured by ethyl acetate).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12](C3CCCCO3)[CH:11]=[N:10][C:9]=2[C:8]2=[N:20][N:21]=[CH:22][N:7]2[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:5]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[C:8]2=[N:20][N:21]=[CH:22][N:7]2[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n2cnnc2c2ncn(C3CCCCO3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n2cnnc2c2nc[nH]c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-isobutyl-7-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (20 mg, 0.06 mmol) in methylene chloride (0.8 mL) was added TFA (0.1 mL, 1 mmol) dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated to give the crude product which was used for next step without further purification. LCMS calculated for C10H13N6O (M+H): 233.1. found: 233.1.