Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[NH:22])[CH2:5][C:6]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([OH:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)C.C(O[CH:26](OCC)[CH2:27][NH2:28])C.C(O)(=O)C.Cl>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:6]([OH:13])([CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH2:5][C:4]1[NH:22][CH:26]=[CH:27][N:28]=1
Reactant: CCOC(CN)OCC
Reactant: CCOC(=N)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC(Cc1ncc[nH]1)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 70 °C

Procedure:
A solution of 3-(2,4-dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrimidic acid ethyl ester free base (546 mg), aminoacetaldehyde diethylacetal (234 mg) and acetic acid (210 mg) in tetrahydrofuran (4 ml) was heated under reflux for 2 hours. Hydrochloric acid (4 ml, 5N) was added and the mixture heated to 70° C. for 30 minutes. The mixture was diluted with saturated sodium carbonate to pH8 and extracted with ethyl acetate (3×20 ml). The organic extracts were dried over magnesium sulphate and evaporated to yield a gum which was chromatographed on silica eluting with a mixture of methylene chloride, isopropanol and concentrated ammonium hydroxide (85:15:1 by volume). Fractions containing the desired product were pooled and evaporated to yield a gum which solidified on trituration with diethyl ether (246 mg). Recrystallisation from isopropanol gave the title compound as colourless crystals m.p. 168°-170° C. Found: C,49.8; H,3.9; N,20.9. C14H13Cl2N5O requires C,49.7; H,3.9; N,20.7%.
Reaction SMILES: C(=O)([O-])[OH:2].[Na+].F[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]>CCCCCCC>[OH:2][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]
Reactant: CCCCOC(=O)CCCCF
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Product: CCCCOC(=O)CCCCO
Yield: 92 %

Procedure:
87 mg (0.5 mmol) of butyl 5-hydroxypropionate purified by distillation, 0.39 g (0.6 mmol, 1.2 equivalents) of N,N-diethyl-α,α-difluoro-[4-(1H,1H,2H,2H-perfluorodecyl)benzyl]amine (compound c) produced in Example 1, and 0.5 ml of heptane were put into a PFA container, and reacted in a nitrogen atmosphere at 100° C. for 3 hours. After the reaction, an aqueous saturated sodium hydrogencarbonate solution was added thereto for neutralization, and then the product was extracted out with dichloromethane. The solvent was evaporated away, followed by purification through silica gel column chromatography (solvent: dichloromethane/diethyl ether mixed solvent) to give a product. The main product was butyl 5-fluoropentanoate, and its yield was 92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:14]3=[N:15][C:16]([CH3:27])=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[C:13]3[C:12]([CH3:28])=[CH:11]2)=[C:5]([CH3:29])[CH:4]=1.C(N(CC)C(C)C)(C)C.[NH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][C:46]#[N:47])[CH2:41][CH2:40]1.C(OCC)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:29])[C:6]([N:10]2[C:14]3=[N:15][C:16]([CH3:27])=[CH:17][C:18]([N:39]4[CH2:44][CH2:43][CH:42]([CH2:45][C:46]#[N:47])[CH2:41][CH2:40]4)=[C:13]3[C:12]([CH3:28])=[CH:11]2)=[C:7]([CH3:9])[CH:8]=1
Reactant: N#CCC1CCNCC1
Reactant: COc1cc(C)c(-n2cc(C)c3c(OS(=O)(=O)C(F)(F)F)cc(C)nc32)c(C)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(-n2cc(C)c3c(N4CCC(CC#N)CC4)cc(C)nc32)c(C)c1
Temperature: 150 °C
Yield: 56.1 %

Procedure:
A mixture of crude trifluoromethanesulfonic acid 1-(4-methoxy-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl ester (1.1 g), N,N-diisopropylethylamine (0.65 g) and piperidin-4-yl-acetonitrile (1.6 g) was heated at 150° C. in a sealed tube for 7 hours. After cooling to room temperature, ethyl acetate and water were poured into the mixture, and separated. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=3/1) to obtain {1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile (0.58 g) as a pale yellow crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>O1CCOCC1.[Cu]I.NCC(N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([N:22]2[C:23]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:7]=1
Reactant: COc1ccc(F)cc1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: CC(N)CN
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 260.9 %

Procedure:
2-Bromo-4-fluoroanisole (20 g, 10 mmol, 1 equiv) and carbazole (18.4 g, 11 mmol, 1.1 equiv) were dissolved in 1,4-dioxane (200 mL). Potassium phosphate tribasic hydrate (46 g, 20 mmol, 2 equiv), copper(I) iodide (1 g, 0.5 mmol, 0.05 equiv) and 1,2-diaminopropane (1 mL, 1.3 mmol, 0.13 equiv) were added and the reaction was refluxed for 18 hours. The reaction was cooled to room temperature and filtered through CELITE diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was purified over silica gel (250 g), eluting with gradient of 0 to 10% ethyl acetate in heptanes to give compound 4 (7.6 g, 26% yield) as an off white solid that was contaminated with carbazole. This material was used subsequently.
Reaction SMILES: CCN(C(C)C)C(C)C.CN([C:13]([O:17][N:18]1N=NC2C=CC=C[C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[CH:46]=[CH:45][C:38]2[C:39]([C:42](O)=[O:43])=[N:40][S:41][C:37]=2[CH:36]=1.Cl.CNOC>CN(C=O)C>[Br:34][C:35]1[CH:46]=[CH:45][C:38]2[C:39]([C:42]([N:18]([O:17][CH3:13])[CH3:19])=[O:43])=[N:40][S:41][C:37]=2[CH:36]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1nsc2cc(Br)ccc12
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1nsc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
DIEA (11.7 mL, 67.4 mmol) and HBTU (7.03 g, 18.5 mmol) were added to a solution of 6-bromobenzo[d]isothiazole-3-carboxylic acid (4.35 g, 16.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.14 g, 21.9 mmol) in DMF (100 mL). The reaction was stirred at room temperature for 2 hours. The mixture was partitioned between water and EtOAc. The organic layer was washed with aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 3:1) to give 6-bromo-N-methoxy-N-methylbenzo[d]isothiazole-3-carboxamide (4.60 g, 91%) as a solid. 1H NMR (CDCl3, 400 MHz) δ □8.12 (m, 2H), 8.59 (d, J=8.8 Hz, 1H), 3.83 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:14]=[C:15]=[O:16])[CH2:12][CH3:13]>>[CH2:11]([NH:14][C:15]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:16])[CH2:12][CH3:13]
Reactant: O=c1[nH]sc2ccccc12
Reactant: CCCN=C=O
Product: CCCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6b (77% yield) was synthesized from benzo[d]isothiazol-3-one and n-propyl isocyanate as a white solid. mp 90-91° C.; IR(CHCl3) 3290, 1712, 1662, 1542 cm−1; 1H-NMR (CDCl3) δ1.00 (t, J=7.3 Hz, 3H), 1.52-1.72 (m, 2H), 3.39-3.44 (m, 2H), 7.42 (t, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 8.89 (br s, 1H); ESIMS m/e 237 (M++1).
Reaction SMILES: C[N:2]([CH3:20])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:10]=[CH:11][CH:12]=1)=O.N[C:22]1[C:26]([C:27]#[N:28])=C[NH:24][N:23]=1>>[C:27]([C:26]1[CH:22]=[N:23][N:24]2[C:5]([C:7]3[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:20]=12)#[N:28]
Reactant: COC(=O)NCCc1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Product: COC(=O)NCCc1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A 2.76 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, methyl ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13, giving 2.6 g of the desired product, mp 162°-164° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[C:15]2=[O:27])=[CH:9][CH:8]=1)[CH3:2].[C:29]1([CH3:38])[C:30]([N:35]=[C:36]=[O:37])=[CH:31][CH:32]=[CH:33][CH:34]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:36]([NH:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH3:38])=[O:37])=[CH:22][CH:21]=3)[C:15]2=[O:27])=[CH:11][CH:12]=1)[CH3:2]
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc(N)cc3)c2=O)cc1
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc(NC(=O)Nc4ccccc4C)cc3)c2=O)cc1

Procedure:
3-{4-[3-(4-Aminophenyl)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}propionic acid ethyl ester (P8, 60 mg, 0.16 mmol) and o-tolyl isocyanate (40 [2 L, 0.32 mmol) were stirred at room temperature in dichloromethane (5 mL) for 3 hours, then the reaction mixture was concentrated. Trituration with diethyl ether afforded the title compound as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([CH3:3])[CH3:2].[Li]CCCC.Cl[C:22]([O:24][CH3:25])=[O:23].CCOC(C)=O>C1COCC1.CCCCCC>[CH:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:10][CH2:11][O:12][CH3:13])=[C:8]([CH:9]=1)[C:22]([O:24][CH3:25])=[O:23])([CH3:3])[CH3:2]
Reactant: COCOc1ccc(C(C)C)cc1OC
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1c(OC)cc(C(C)C)cc1C(=O)OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-isopropyl-2-methoxy-1-methoxymethoxy-benzene (2.0 g, 9.51 mmol) in 35 mL dry THF cooled to 0° C., BuLi (9 mL of a 1.6 m solution in hexane, 1.5 eq.) was added dropwise via a syringe and the reaction mixture was stirred 2.5 h at 0° C. This solution was then slowly added to a solution of methyl chloroformate (9 g, 95.1 mmol, 10 eq.) in 10 mL dry THF at 0° C. The mixture was stirred 12 h at r.t. Saturated KHCO3 solution and EtOAc were then added to the solution and the phases were separated. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane EtOAc 9:1→6:1) to yield the title compound as a yellowish oil.
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26][CH2:27][CH2:28]C)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].O.[C:32]1(C)C=CC(S(O)(=O)=O)=C[CH:33]=1.[C:43](O)(=O)C>>[CH2:26]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH:32]=[CH2:33])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30])[CH:27]([CH3:43])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O
Solvent: O
Product: C=CC1CN(c2ncc(C(=O)N(CC(C)C)c3cccc(C(F)(F)F)c3)c(N)n2)C(=O)N1
Reaction time: 2.5 h
Yield: 53.2 %

Procedure:
A mixture of 3.14 g (7 mmol) of a compound II (R1 =CH=CH2 ; R2, R3, R5, R6 =H; R4 =CH2CH(CH3)2), 5 ml of glacial acetic acid and 1.05 g (5.5 mmol) of p-toluenesulfonic acid monohydrate was stirred at 67°-69° for 2.5 hours and then worked up as in Example 5. 1.67 g (53.2% yield) of TLC-pure 4-amino-2-(4-vinyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-isobutyl-N-(3-trifluoromethylphenyl)amide were obtained, melting point 85°-186°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:39])[CH2:37][CH3:38].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:39][CH2:36][CH2:37][CH3:38])=[O:34])=[C:18]([CH3:23])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (48 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propylamine (20 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 30 mg (yield 47%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][C@H:27]([CH3:33])[CH2:28][NH:29][C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[CH3:34]>>[CH3:34][C:10]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][C@H:27]([CH3:33])[CH2:28][NH:29][C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: ClCc1nccs1
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4nccs4)c(C)c3)c12
Yield: 25 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)-1,3-thiazole and N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting materials) to give the title compound as a light brown solid in 25% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.25 (s, 3H), 3.42 (dt, 1H), 3.60 (dt, 1H), 4.88 (m, 1H), 5.45 (s, 2H), 7.11 (d, 1H), 7.22 (d, 1H), 7.31 (d, 1H), 7.56 (d, 1H), 7.63 (dd, 1H), 7.68 (t, 1H), 7.76 (d, 1H), 7.83 (d, 1H), 8.23 (t, 1H), 8.43 (s, 1H), 9.97 (s, 1H); Mass spectrum MH+ 464.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([O:12][C:13]([NH:15][C@H:16]([CH3:23])[CH2:17]OS(C)(=O)=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>CN(C=O)C.C(OCC)(=O)C>[C:8]([O:12][C:13](=[O:14])[NH:15][C@H:16]([CH3:17])[CH2:23][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: c1cn[nH]c1
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Cn1cccn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
1H-Pyrazole (70 mg, 1.03 mmol) was dissolved in DMF (5 ml) and cooled in an ice bath. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.03 mmol) was added and the reaction was stirred for 15 min. Methanesulfonic acid (R)-2-tert-butoxycarbonylamino-propyl ester (200 mg, 0.79 mmol) was then added and the mixture was stirred at 50° C. for 16 h. The reaction was cooled to room temperature and water and ethyl acetate were added. The aqueous layer was extracted twice more with ethyl acetate and the combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 129 mg (72%) of ((R)-1-methyl-2-pyrazol-1-yl-ethyl)-carbamic acid tert-butyl ester. (M+H)+=226.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC[O-].[Na+].Cl>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2ccccn2)noc1C
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccccn2)noc1/C=C/c1ccccc1
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
To a solution of 5-methyl-3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (3.0 g, 13 mmol) and benzaldehyde (1.32 mL, 13 mmol) in ethanol (20 mL) was added sodium ethylate (0.97 g, 14 mmol) and the reaction mixture was stirred at reflux for 40 min. Aqueous hydrochloric acid (1 M, 14 mL) was added and stirring was continued for 15 min. The precipitate was filtered and dried to afford the title compound (2.3 g, 61%) as an off-white solid. MS: m/e=290.9 [M−H]−.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[CH:4]1([CH2:10][CH2:11][CH2:12][CH2:13]N)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>>[N:1]([CH2:13][CH2:12][CH2:11][CH2:10][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[O:3]
Reactant: NCCCCC1CCCCC1
Reactant: [N-]=C=O
Product: O=C=NCCCCC1CCCCC1
Yield: 91 %

Procedure:
Following the synthetic procedure of 4b′ as described in Example 17, isocyanate 4d′ (91% yield) was synthesized from 4-(cyclohexyl)butylamine as an oil. 1H-NMR (CDCl3) δ0.80-0.95 (m, 2H), 1.10-1.30 (m, 6H), 1.32-1.45 (m, 2H), 1.52-1.75 (m, 7H), 3.28 (t, J=6.6 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:8][C:3]([CH3:9])([CH2:2][NH:1][S:18]([CH3:17])(=[O:20])=[O:19])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CNS(C)(=O)=O
Reaction time: 48 h
Yield: 31.2 %

Procedure:
To a solution of methyl 3-amino-2,2-dimethylpropanoate (249 mg, 1.90 mmol) and Et3N (0.80 mL, 5.70 mmol) in 2 mL CH2Cl2 was added methanesulfonyl chloride (0.29 mL, 3.80 mmol). The reaction was stirred for 2 days, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCl3, and chromatographed (1:1 hex:EtOAc) to provide methyl 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoate (124 mg, 31%) as a clear oil. 1H NMR (400 MHz, CDCl3), 4.95 (t, 1H, J=6.8 Hz), 3.69 (s, 3H), 3.16 (d, 2H, J=6.8 Hz), 2.95 (s, 3H), 1.24 (s, 6H). Methyl 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoate was hydrolyzed using aqueous NaOH to provide 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoic acid, which was used without further purification. 1H NMR (400 MHz, CDCl3), δ 10.28 (br. s, 1H), 5.56 (br. s, 1H), 3.14 (s, 2H), 2.94 (s, 3H), 1.25 (5, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.CS(Cl)(=O)=O.C(N(CC)C(C)C)(C)C.[NH2:28][C@@H:29]1[C:55](=[O:56])[N:31]2[C:32]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)=[O:44])=[C:33]([C@@H:36]3[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[O:37]3)[CH2:34][S:35][C@H:30]12.N1C=CC=CC=1>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:28][C@@H:29]2[C:55](=[O:56])[N:31]3[C:32]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=4)=[O:44])=[C:33]([C@@H:36]4[CH2:40][CH2:39][C:38]([CH3:41])([CH3:42])[O:37]4)[CH2:34][S:35][C@H:30]23)=[O:10])[N:6]=1
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3CCC(C)(C)O3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCC(C)(C)O3)CS[C@H]12)c1csc(N)n1
Yield: 69.2 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (13 mg, 0.065 mmol) in DMF (2 ml) was treated with methanesulphonyl chloride (5 μl, 0.064 mmol) and N,N-diisopropylethylamine (11 μl, 0.063 mmol) as described in Example 7 (a). This was then treated successively with a solution of the amine from Example 29 (e) (25 mg, 0.060 mmol) in DMF (2 ml) and pyridine (5 μl, 0.062 mmol). After work-up the product was purified by chromatography on silica gel eluting with 50, 70 and 100% ethyl acetate in hexane to yield the title compound (25 mg, 70%) as a yellow foam; νmax (CH2Cl2) 3389, 1784, 1722, 1690, 1607 and 1516 cm-1 ; δH (CDCl3, 250 MHz) 1.23 (3 H, s), 1.29 (3 H, s), 1.61-1.84 (3 H, m), 2.31 (1 H, m), 3.40 and 3.63 (2 H, ABq, J 18.7 Hz), 3.81 (3 H, s), 4.20 (3 H, s), 4.99 (1 H, d, J 4.8 Hz), 5.05 (1 H, dd, J 8.1, 8.1 Hz), 5.13 and 5.23 (2 H, ABq, J 11.8 Hz), 5.90 (1 H, dd, J 8.9, 4.8 Hz), 6.90 (2 H, d, J 8.7 Hz), 7.23 (1 H, s), 7.34 (2 H, d, J 8.7 Hz), 7.50 (2 H, br s, exch.) and 7.68 (1 H, br d, J 8.9 Hz, exch). [Mass spectrum: +ve ion (ammonia) MH+ (602)].
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15]O.[CH:17]1([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[NH:22][C:21]2=[O:29])[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[CH:17]1([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:22]([CH2:15][C:7]3[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][F:1])[C:14]4[C:9]([N:8]=3)=[N:10][CH:11]=[CH:12][CH:13]=4)[C:21]2=[O:29])[CH2:19][CH2:18]1
Reactant: OCc1nc2ncccc2n1CCCCF
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3ncccc3n2CCCCF)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a suspension of (1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 42-5 (958 mg, 4.3 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (950 mg, 5.15 mmol) and triphenylphosphine (1350 mg, 5.15 mmol) in 30 ml dry THF was added (E)-diisopropyl diazene-1,2-dicarboxylate (1.26 ml, 6.43 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed with some diethyl ether to obtain the title product as a white powder (1036 mg, 63%).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[N:4]([CH3:6])C.N1CCCC1.CO[C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-])=O)=CN=1>CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:22]=[C:20]2[CH:21]=[CH:16][NH:23][C:19]2=[CH:6][N:4]=1
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc2cc[nH]c2cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
10.76 g of N,N-dimethylformamide dimethyl acetal and 2.45 ml of pyrrolidine are added, in succession, to a solution of 5 g of the product obtained in Step 1 in 60 ml of dimethylformamide. The mixture obtained is first heated at 100° C. for 8 hours and then at 150° C. for 1 hour. Concentration is carried out under a vacuum of 10−1 mbar and the residue is taken up in 150 ml of tetrahydrofuran. The solution obtained is hydrogenated under a pressure of 10 bars for 4 hours in the presence of 10% Pd/C. After filtration and concentration, the residue is chromatographed over silica (eluant CH2Cl2/EtOH: 95/5) to yield the expected product.