Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[C:10](Br)(Br)([Br:12])[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:11][C:10]([Br:12])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(C=C(Br)Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
6-Methylnicotinaldehyde (1.0 g, 0.00826 mol) was dissolved in DCM (100 mL). Carbon tetrabromide (5.48 g, 0.0165 mol) and triphenylphosphine (8.66 g, 0.033 mol) was added to the solution followed by stirring at RT for 3 h. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography (8% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (1.6 g, 70% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]([F:22])([F:21])[F:20])([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]([F:22])([F:20])[F:21])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(C(F)(F)F)CC1

Procedure:
A solution of ethyl 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-4-carboxylate (3b) (1 equiv.) and 1.0 N NaOH (1.2 equiv.) in EtOH is heated at 50° C. When the reaction is complete, the solvents are removed in vacuo, and the residue is taken up in H2O. The solution is acidified to pH 5-6 with dilute HCl, and the precipitate is collected and washed with H2O. Drying in high vacuum gives the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[O:9])=[CH:6][CH:5]=1
Reactant: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NC(=O)c1ccc(N)cc1)C(=O)O

Procedure:
2 g. 4-Nitrobenzoylalanine in 50 ml. ethanol were hydrogenated in the presence of 0.2 g. palladium-charcoal (5%). Removal of the catalyst and of the solvent gave a solid which was crystallised from ethanol-diethyl ether (1:2 v/v) to give 4-aminobenzoylalanine; m.p. 198°-199° C.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:52]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[CH:52]([N:65]1[CH2:70][CH2:69][N:68]([C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:67][CH2:66]1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CCOCC
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 85.4 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 1, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.408 mL, 2.34 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid benzhydrylpiperazine (0.295 g, 1.17 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexanes) to provide 0.49 g (85%) of the pure titled compound as a white foam; mp 66-74° C. APCI-MS m/z 491.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]1=[O:8])[CH3:15]
Reactant: Oc1ncccc1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)Cn1cccc(Br)c1=O
Yield: 55 %

Procedure:
As described for example 320a, 3-bromo-2-hydroxy-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound as a light yellow oil (yield: 55%), which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11].[CH:14]([C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)=O.[BH4-].[Na+].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[NH:19]1[CH:20]=[C:16]([CH2:14][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[N:17]=[CH:18]1
Reactant: O=Cc1c[nH]cn1
Reactant: COC(=O)/C=C/c1ccccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccccc1NCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A solution of methyl (E)-3-(2-aminophenyl)propenoate (531.6 mg) and 4-formylimidazole (317.1 mg) in methanol. (7.0 ml) was stirred at ambient temperature for 18 hours. To the reaction mixture was added sodium borohydride (56.5 mg) under stirring and cooling in an ice-bath. After the mixture was stirred for 2 hours at ambient temperature, sodium borohydride (56.5 mg) was added thereto. The mixture was stirred for 2 hours at ambient temperature. To the reaction mixture was added acetic acid in order to decompose the excess sodium borohydride and the methanol was removed under reduced pressure. To the residue were added diluted hydrochloric acid and ethyl acetate under stirring. The separated aqueous layer was basified with aqueous sodium bicarbonate and extracted twice with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to give a residue, which was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (20:1) to afford pure methyl (E)-3-[2-(4-imidazolylmethylamino)phenyl]propenoate (0.7 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:29][CH2:28]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C:12]([CH2:13][C:14](=[O:15])[N:27]1[CH2:28][CH2:29][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:31][CH2:32]1)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccc(CC)c(CC)c1)C(=O)OCC
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc(CC)c(CC)c1)C(=O)OCC

Procedure:
Prepared analogously to Example 76c) from 4-(3,4-diethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic acid and 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.O>CN(C)C=O.C(OCC)(=O)C>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([O:25][CH2:24][CH2:23][CH2:22][N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:14][CH2:13]2)=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(OCCCBr)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCCOc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
1.44 g of 4-tert-butoxycarbonylaminopiperidine was dissolved in 14 ml of N,N-dimethylformamide. Thereafter, 1.99 g of potassium carbonate and 1.87 g of 4-(3-bromopropoxy)benzonitrile were successively added to the above solution, followed by stirring at room temperature for 24 hours. Water and ethyl acetate were added to the reaction mixture, so that the organic layer was separated. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed under a reduced pressure. The obtained solid was filtrated with a mixed solution consising of n-hexane and diisopropyl ether to obtain 2.12 g of tert-butyl 1-[3-(4-cyanophenoxy)propyl]-4-piperidinylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4](I)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][N:17]([CH3:35])[C:18]([C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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:8]([C:6]1[C:5]([O:11][CH2:12][CH3:13])=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([C:18]([N:17]([CH3:35])[CH3:16])=[O:19])=[N:21][CH:22]=2)[C:3]([CH3:15])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (0.69 g, 2.0 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (0.68 g, 2.4 mmol) in 1,4-dioxane (10 mL), potassium carbonate (0.56 g, 4.1 mmol) in water (3 mL, 200 mmol) was added. The reaction was bubbled with N2. Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) was added and N2 was bubbled. Reaction was stirred overnight at 95° C. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 90% EtOAc in hexanes) to give the desired product (0.6 g, 82%). LCMS calculated for C19H22ClN2O3 (M+H)+: m/z=361.1; Found: 361.0.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[C:23]([O:27][C:28]([NH:30][C:31]([CH3:38])([CH3:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[CH3:39][NH:40][C@H:41]([CH2:64][C:65]1[CH:74]=[CH:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=1)[C:42]([N:44]([CH3:63])[C@@H:45]([C:57]1[O:61][N:60]=[C:59]([CH3:62])[N:58]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)=[O:43].FC(F)(F)C(O)=O.C(N(CC)CC)C>CN(C)C=O>[C:23]([O:27][C:28](=[O:29])[NH:30][C:31]([CH3:38])([CH3:37])/[CH:32]=[CH:33]/[C:34](=[O:36])[N:40]([C@@H:41]([C:42](=[O:43])[N:44]([CH3:63])[C@@H:45]([C:57]1[O:61][N:60]=[C:59]([CH3:62])[N:58]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)[CH2:64][C:65]1[CH:74]=[CH:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=1)[CH3:39])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccc2ccccc2c1)c1nc(C)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)/C=C/C(C)(C)NC(=O)OC(C)(C)C)n1

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.31 g, 1.6 mmol) and 1-hydroxy-7-azabenzotriazole (0.22 g, 1.6 mmol) were added to a solution of (2E)-4-tertbutoxycarbonylamino-4-methylpent-2-enoic acid (0.37 g, 1.6 mmol) in N,N-dimethylformamide (5 ml). After 30 min at 20° C. a mixture of (2R)-2-methylamino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid (0.68 g, 1.2 mmol) and triethylamine (0.12 g, 1.2 mmol) in N,N-dimethylformamide (5 ml) were added. After 18 h at 20° C. the reaction mixture was poured on water (80 ml) and extracted several times with ethyl acetate (total 55 ml). The organic phases were collected and washed with aqueous citric acid (10%, 15 ml), a saturated solution of sodium hydrogencarbonate (3×15 ml) and water (3×15 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and chromatographed on silica gel (80 g) using heptane and ethyl acetate (3:7) as eluent to give 0.75 g of {(2E)-1,1-dimethyl-3-[N-((1R)-1-{N-methyl-N-{(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl}carbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]allyl}carbamic acid tertbutyl ester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: c1coc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccco1

Procedure:
The title compound, yellow oil, MS: m/e=311 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-furan-2-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=3)[CH:17]=1)[N:5]=2)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.451 mmol) produced in Example C33(iv) in N,N-dimethylformamide (4.0 mL) was added chloroacetyl chloride (50 μL, 0.631 mmol), and the mixture was stirred at room temperature for 2 hr. Chloroacetyl chloride (25 μL, 0.314 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C:19]([CH2:25][CH3:26])([C:22]([OH:24])=O)[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:44])[NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1)=[NH:35])([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[C:17](=[O:18])[N:16]2[C:19]([C:22](=[O:24])[NH:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]([NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:44])=[NH:35])=[CH:37][CH:38]=3)([CH2:25][CH3:26])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Reactant: CCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Product: CCC1(C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 100 %

Procedure:
According to the procedure for the preparation of intermediate 19c, intermediate 22b (34.5 mg, 0.0965 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester to afford 57 mg (100%) of intermediate 22c.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][O:16][C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])(=[O:7])=[O:6].[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][O:16][C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCOC(=O)Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])[C@@H](OCc1ccccc1)C(=O)OCOC(=O)Cc1ccccc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, (2-phenylacetyloxy)methyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (28a) (0.44 g, 0.84 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 140 mg (2.1 mmol) of sodium azide (NaN3). After work-up, the crude title compound (28b) was used in the next step without further purification. MS (ESI) m/z 556.12 (M+Na)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C@@:11]([C@@H:14]3[C@@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]3([CH3:22])[CH3:21])([OH:13])[CH3:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[N:30]([Si](C)(C)C)=[C:31]=[O:32]>ClCCl>[OH:13][C@@:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:1][N:2]([C:31]([NH2:30])=[O:32])[CH2:3][CH2:4]2)([C@@H:14]1[C@@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]1([CH3:21])[CH3:22])[CH3:12]
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@H]1CCCC(C)(C)[C@@H]1[C@@](C)(O)c1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CCCC(C)(C)[C@@H]1[C@@](C)(O)c1ccc2c(c1)CCN(C(N)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of compound of the crude product of Example 13c (28 mg, 0.1 mmol) in dichloromethane (2 mL) was added triethylamine (55 mg, 0.5 mmol) and isocyanatotrimethylsilane (47 mg, 0.4 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a yellow oil (15 mg). Mass spectrum (LC ESI +ve) m/z 345 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:13]([C@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Di-isopropylazodicarboxylate (5.7 mL, 29.38 mmol) was added to an ice-cooled solution of (R)-(−)-N-boc-3-pyrrolidinol (5 g, 26.71 mmol), phenol (2.51 g, 26.71 mmol) and triphenyl phosphine (7.71 g, 29.38 mmol) in tetrahydrofuran (70 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was twice triturated with diethyl ether and filtered. The filtrate was washed with 1N sodium hydroxide solution (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 90:10 to 83:17, afforded the title compound as a colourless oil in 75% yield, 5.27 g.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10](C(O)=O)[S:9][N:8]=2)[CH:2]=1.CCCCCC>ClC1C=CC=CC=1Cl>[C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][S:9][N:8]=2)[CH:2]=1
Reactant: Cc1cccc(-c2nsc(C(=O)O)c2C(=O)O)c1
Solvent: CCCCCC
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(-c2nscc2C(=O)O)c1
Yield: 85.1 %

Procedure:
3-(m-Tolyl)-4,5-isothiazoledicarboxylic acid (7.98 g, 0.0303 mol) was heated in 25 ml of o-dichlorobenzene at vigorous reflux for 15 minutes and cooled. Hexane was added and the resultant precipitate was filtered off to yield 5.52 g (0.0258 mol, 83.1%) of a light pink solid, m.p. 144.5°-146°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([OH:23])[CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.O>ClCCl.CS(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:23])[CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:10][CH:9]=1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 0 °C
Yield: 92.7 %

Procedure:
A solution of oxalyl chloride (74.8 g) in dry dichloromethane (1350 mL) at below -70° C. under a nitrogen atmosphere was treated with dry dimethyl sulfoxide (91.5 mL) in methylene chloride (270 mL) dropwise over 15 to 20 minutes while maintaining the temperature of the reaction mixture below -50° C. After an additional 5 minutes a solution of (±)-1-(4-(4-chlorophenyl)-2-hydroxybutyl)imidazole (128.3 g) in a mixture of dimethyl sulfoxide (50 mL) and methylene chloride (200 mL) was added over a period of 20 minutes keeping the reaction mixture at temperatures below -65° C. After a further 15 minutes dry triethylamine (300 mL) was added rapidly and after 15 minutes the reaction mixture was allowed to warm to 0° C. Water (20 mL) was then added to the reaction mixture, the methylene chloride then removed by evaporation and the resulting slurry was then treated with water and filtered. The filter cake was washed well with ice-water, cold ethyl acetate and then dried in air to yield 118.0 g of 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one. The hydrochloride salt crystallized from methanol/acetone had a melting point of 172.5°-174.0° C.