Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][CH:13]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile (D76) (150 mg), acetic acid (0.044 mL) and sodium acetate (63 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (175 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (204 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D83) (188 mg). The crude product was used for next step without further purification. MS (ES): C28H31N3O3S requires 489. found 490.2 (M+H+).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[N:14]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=3)[N:6]2[N:5]=1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[NH:26][C:27](=[O:29])[CH3:28]>>[C:20]([CH2:19][CH2:18][N:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:22][C:23]3[CH:24]=[C:25]([NH:26][C:27](=[O:29])[CH3:28])[CH:30]=[CH:31][CH:32]=3)=[N:5]2)=[CH:10][CH:11]=1)#[N:21]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CS(=O)c1ncc2ccc(-c3cccn3CCC#N)n2n1
Product: CC(=O)Nc1cccc(Nc2ncc3ccc(-c4cccn4CCC#N)n3n2)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 3-[2-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyrrol-1-yl]-propionitrile (93 mg, 0.31 mmol) was coupled to 3′-aminoacetanilide (62 mg, 0.41 mmol) at 120° C. for 135 h to afford titled compound. Yield of TFA salt: 29 mg (19%) of gold powder. LC/MS: 386 (M+H); HPLC: 97% pure, RT=2.65 min; mp: 131-139° C.; 1H NMR: (DMSO, δ) 9.75 (s, 1H), 9.44 (s, 1H), 8.96 (s, 1H), 7.69 (s, 1H), 7.53 (d, J=7.4 ,1H), 7.12 (m, 3H), 6.95 (d, J=4.4, 1H), 6.90 (d, J=4.4, 1H), 6.58 (dd, J=7.9, 3.6, 1H) 6.26 (dd, J=3.6, 3.4, 1H), 4.24 (t, J=6.3, 2H), 2.83 (t, J=6.3, 2H), 2.04 (s, 3H).
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:7][NH:6][CH2:5]1)#[N:3].N1CCCC1.CC(O[C:18]([NH:20][C@@H:21]([C:25]([OH:27])=O)[CH:22]1[CH2:24][CH2:23]1)=[O:19])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH3:44][N:45]1[CH:49]=[C:48]([C:50]2[N:55]=[C:54]3[C:56](C(O)=O)=[CH:57][N:58](COCC[Si](C)(C)C)[C:53]3=[N:52][CH:51]=2)[CH:47]=[N:46]1.C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)CO>>[C:2]([CH:4]1[CH2:7][N:6]([C:25](=[O:27])[C@H:21]([NH:20][C:18]([C:56]2[C:54]3[C:53](=[N:52][CH:51]=[C:50]([C:48]4[CH:47]=[N:46][N:45]([CH3:44])[CH:49]=4)[N:55]=3)[NH:58][CH:57]=2)=[O:19])[CH:22]2[CH2:23][CH2:24]2)[CH2:5]1)#[N:3]
Reactant: N#CC1CNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: Cn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: C1CCNC1
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CC(C#N)C4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 3-cyanoazetidine hydrochloride for pyrrolidine, Boc-D-cyclopropyl glycine for Boc-D-tert-leucine, and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. N-Boc deprotection was achieved using 2,2,2-trifluoroethanol in a microwave reactor. MS: (M+H)+=405.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.OO.C([O-])([O-])=[O:32].[K+].[K+]>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:32])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C(N)=O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 2, 25 mg, 0.062 mmol) in 2 mL DMSO at 0° C. was added lint of 30% H2O2 (aq). A catalytic amount of K2CO3 was added and the reaction was stirred at 50° C. for 60 min. The reaction mixture was diluted with MeOH and the product was purified by reverse phase HPLC. The fractions containing the product were collected and diluted with EtOAc, washed with aq NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.23 (d, 2H), 7.84 (d, 2H), 7.78 (m, 2H), 7.58 (m, 3H), 7.28 (d, 2H), 7.08 (d, 2H), 6.23 (broad s, 1H), 5.82 (broad s, 1H), 3.72 (s, 3H). LCMS: m/z 420 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.CO[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].[C:36](=O)([O-])[O-:37].[K+].[K+]>C(#N)C.CCOC(C)=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>[NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:30]3[CH:29]=[CH:28][C:27]([CH:25]([OH:26])[CH2:36][OH:37])=[CH:32][CH:31]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(O)CO)cc3)cc2N=C(N)C1
Temperature: 100 °C
Yield: 19 %

Procedure:
Reaction of (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dioxolan-2-one as follows yielded (1E,4E)-2-amino-8-(4-(2-oxo-1,3-dioxolan-4-yl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (9%). (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. 1H NMR (400 MHz, DMSO-d6) δ 7.74-7.80 (m, 2H), 7.55-7.60 (m, 2H), 7.26-7.42 (m, 3H), 6.78 (s, 1H), 5.89-5.96 (m, 1H), 4.88-4.95 (m, 1H), 4.45-4.52 (m, 1H), 2.78 (s, 2H), 1.50-1.63 (m, 4H), 0.71-0.93 (m, 6H); m/z (APCI-pos) M+1=448.2. (1E,4E)-2-amino-8-(4-(1,2-dihydroxyethyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (19%) was obtained as the more polar product. (19%). 1H NMR (400 MHz, DMSO-d6) δ 7.59-7.64 (m, 2H), 7.39-7.44 (m, 2H), 7.33-7.38 (m, 1H), 7.26-7.28 (m, 1H), 7.20-7.24 (m, 1H), 6.84 (br s, 1H), 6.74 (s, 1H), 5.23-5.27 (m, 1H), 4.71-4.75 (m, 1H), 4.54-4.62 (m, 1H), 3.44-3.50 (m, 2H), 3.28-3.35 (m, 4H), 2.74 (s, 2H), 1.51-1.61 (m, 4H), 0.73-0.90 (m, 6H); m/z (APCI-pos) M+1=422.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1.[NH2:12][C:13]1[C:14]([C:18]2[N:19]([CH2:29][CH3:30])[C:20]3[C:25]([CH:26]=O)=[CH:24][N:23]=[CH:22][C:21]=3[N:28]=2)=[N:15][O:16][N:17]=1>>[NH2:12][C:13]1[C:14]([C:18]2[N:19]([CH2:29][CH3:30])[C:20]3[C:25]([CH2:26][NH:11][CH:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]4)=[CH:24][N:23]=[CH:22][C:21]=3[N:28]=2)=[N:15][O:16][N:17]=1
Reactant: COCCN1CCC(N)CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(C=O)c21
Product: CCn1c(-c2nonc2N)nc2cncc(CNC3CCN(CCOC)CC3)c21

Procedure:
The title compound was prepared from the product of Step 2 the product of Example 310 using the method of Example 149; MS (ES+) m/e 401 [M+H]+.
Reaction SMILES: O.[C:2]1(C)[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](OC(=O)C)C>>[C:4]1([CH3:13])[C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
The present invention is to provide a compound (I') which comprises (d) reacting the produced compound (I) with p-toluenesulfonic acid monohydrate in the presence of ethylacetate to produce toluenesulfonic acid 1,1-dioxppenicillanoyl oxymethyl D-6-[(α-methyleneamino) phenylacetamido]-penicillanate (I') in accordance with the present invention.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][CH:8]=1.CN(C)[CH:29]=[O:30].Cl>CCCCCC.O1CCCC1>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1/[CH:14]=[CH:13]/[C:10]1[CH:11]=[CH:12][C:7]([CH:29]=[O:30])=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(C=O)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of n-butyllithium in hexane (1.6M, 28.7 ml) was added dropwise to a solution of (E)-4-[2-(4-bromophenyl)vinyl]-5-methyl-2-phenyloxazole (13.0 g) in tetrahydrofuran (140 ml) at -70° C. The mixture was stirred at -70° C. for 15 minutes, and then a solution of N,N-dimethylformamide (4.2 g) in tetrahydrofuran (10 ml) was added dropwise at the same temperature. The reaction mixture was stirred at -70° C. for 30 minutes, and then warmed to room temperature. 1N hydrochloric acid (150 ml) was added dropwise, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:2, v/v) gave (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]-benzaldehyde (5.9 g, 54%). The product was recrystallized from ethyl acetate-hexane. Pale brown prisms, mp: 158-159° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[C:5]([N:10]=1)=[N+:6]([CH2:14][CH2:13][CH2:19][S:16]([O-:18])(=[O:17])=[O:15])[CH:7]=[CH:8][CH:9]=2
Reactant: CC1=Nc2ncccc2C1(C)C
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1=Nc2c(ccc[n+]2CCCS(=O)(=O)[O-])C1(C)C
Temperature: 60 °C
Yield: 138.7 %

Procedure:
A mixture of 9 g of 2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridine and 20.6 g of 1,3-propanesultone is heated at 60° C. for 3 h. The reaction mixture is then dissolved in 100 mL of acetonitrile, and 300 mL of ethyl acetate is added. The resulting sticky solid is again stirred in 300 mL of ethyl acetate to yield 22 g of the product.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:49])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([NH:19]C(=O)OC(C)(C)C)(=[O:18])=[O:17])=[C:11]([CH3:27])[CH:10]=2)[C:5](=[O:28])[N:4]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][S:38][CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44].C(Cl)Cl.CCOC(C)=O>C(OCC)C>[CH3:2][C:3]1([CH3:49])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([NH2:19])(=[O:18])=[O:17])=[C:11]([CH3:27])[CH:10]=2)[C:5](=[O:28])[N:4]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][S:38][CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:44])([F:45])[F:46]
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(=O)(=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O
Temperature: 0 °C
Reaction time: 60 h
Yield: 76 %

Procedure:
A solution of HCl in ethyl ether (2N, 3 ml) is added in 31-ml portions to a solution of Example 29 (250 mg, 0.36 mmole) in a CH2Cl2/AcOEt mixture (5 ml/3 ml) cooled down to 0° C., and the mixture is stirred for 60 hours at 23° C. The volatiles are evaporated off under vacuum and the residue is taken up in a CH2Cl2 (50 ml) and NaHCO3 (50 ml) mixture. After stirring and decantation, the organic phase is washed with water (50 ml) followed by salt water. After drying over Na2SO4, filtration and concentration to dryness, the residue is purified on a silica column (Heptane/AcOEt:10/0 to 1/1). The expected product is obtained in the form of a white solid with a yield of 76%. Melting point: 102-104° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]([CH3:11])=[CH:8][CH2:9]Br.[N+:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([O-:14])=[O:13]>C(#N)C>[CH3:6][C:7]([CH3:11])=[CH:8][CH2:9][N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)=CCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)=CCn1ccnc1[N+](=O)[O-]

Procedure:
Sodium bicarbonate (0.42 g, 50 mmol) and dimethylallyl bromide (3.28 g, 22 mmol) were added to a suspension of 2-nitroimidazole (2.26 g, 20 mmol) in dry acetonitrile (10 mL). The mixture was stirred under reflux for 16 hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was filtered, and dried with anhydrous sodium sulfate. Removal of the solvent gave an oil which was recrystallized from petroleum ether (35°-50° C.). Yield 1.83 g, m.p. 48°-49° C. 1H NMR (CDCl3) δ 7.24 (s, 1H), 7.22 (s, 1H), 5.46 (m, 1H), 5.1 (d, 2H), 1.91 (s, 3H) and 1.90 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:9][C:10](=[O:20])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[NH2:19])[CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([N:9]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[NH:19][C:23]1=[O:24])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC[C@H](NC(=O)c1cc(OC)ccc1N)C(=O)OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2ccc(OC)cc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 136 %

Procedure:
To a solution of (S)-2-(2-amino-5-methoxy-benzoylamino)-hexanoic acid methyl ester (410 mg, 1.39 mmol) in THF (30 mL) is added trichloromethyl chloroformate (200 mg, 1.01 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated to give (S)-2-(6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (440 mg, 98%).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[N:12](C(OC(C)(C)C)=O)[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N>>[N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: Cl
Agent: N
Product: CN[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
(±)-cis-2-Pyrrolidinyl-N-t-butyloxycarbonyl-N-methylcyclohexylamine (247 gm) was slowly added to 6M hydrochloric acid at 60° C. with vigorous stirring. The solution was stirred an additional 5 minutes at 60° C. and poured onto ice (200 gm). Excess concentrated aqueous ammonia was added and the mixture was extracted with methylene chloride. The combined extracts were dried (Na2SO4) and the solvent removed on a rotary evaporator. The residue was distilled (78° C. at 0.3 mm Hg) to give the product as a colorless oil.
Reaction SMILES: C[Si](Cl)(C)C.[C:6]([C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1)#[N:7].O.C(=O)([O-])[O-:18].[Na+].[Na+]>C(O)C>[C:6]([C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1)(=[O:18])[NH2:7]
Reactant: N#Cc1cc(CO)ccn1
Reactant: O=C([O-])[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cc(CO)ccn1
Temperature: 50 °C
Reaction time: 5.5 h

Procedure:
Trimethylsilyl chloride (27 mL) and a suspension of 2-cyanopyridine-4-methanol (1.6 g, 11 mmol, Reference compound 11-1) in ethanol (20 mL) were added to ethanol (14mL) at room temperature under a nitrogen atmosphere, and then the mixture was stirred at 50° C. for 5.5 hours. The mixture was allowed to stand, and water (27 mL) and sodium carbonate (2.3 g, 22 mmol) were added thereto. The solvent was evaporated under reduced pressure, ethanol (100 mL) was added thereto, and the resulting insoluble matter was filtered out. The filtrate was evaporated under reduced pressure, then the resulting residue was dried at 50° C. under reduced pressure to the title reference compound including inorganic salt.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23].C(N(CC)CC)C>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(O)CCN
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1NCCC(C)O
Temperature: 60 °C
Yield: 82.3 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.38 g of 4-amino-2-butanol and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 12 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.38 g of 4-(4-nitro-2-methylphenylamino)butan-2-ol (27) were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[F:15][CH:16]([F:37])[O:17][C:18]1[CH:19]=[C:20]2[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[C:21]2=[N:22][CH:23]=1.[H-].[Na+]>CN(C=O)C>[F:37][CH:16]([F:15])[O:17][C:18]1[CH:19]=[C:20]2[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:32][CH:31]=3)[C:21]2=[N:22][CH:23]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OC(F)F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(OC(F)F)cc21
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (62 mg) and 6-(difluoromethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (86 mg) in DMF (3 ml) was added NaH (13 mg) at room temperature, and the mixture was stirred at 180° C. under microwave irradiation for 30 min. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, NH silica gel, eluted with 50%-100% AcOEt in hexane) and recrystallized from AcOEt/hexane to give 6-(difluoromethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (56 mg) as white crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:15]([CH:16]=1)=[CH:14][N:13]=[C:12]1[C:8]=2[CH:9]=[CH:10][NH:11]1)=[O:4].[Li+].[OH-].C(O)(=O)C>C1COCC1.O>[S:6]1[C:7]2[C:15](=[CH:14][N:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:16]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2cnc3[nH]ccc3c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cnc3[nH]ccc3c2s1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid methyl ester (100 mg, 0.43 mmol), LiOH (25.5 mg, 1.07 mmol) is dissolved in THF (4 ml) and H2O (1 mL). The mixture is stirred at 60° C. for 3 hours. Acidification with acetic acid results in a brown solid which is collected by filtration. It is then dried in vacuo and used for the next step without any further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Reactant: COCC(=O)Cl
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)COC)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].N1C=CC=CC=1.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:17]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:19])[CH3:18]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 72 h

Procedure:
A mixture of 2.87 g of (S)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester, 2.0 ml of acetic anhydride, 2.0 ml of pyridine and 20 mg of 4-dimethylaminopyridine in 25 ml of dichloromethane was stirred for 72 hours. Methanol (2 ml) and dichloromethane (50 ml) were added. The dichloromethane solution was washed with 40 ml each of 1N hydrochloric acid and 5% sodium bicarbonate solution, dried, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 3.1 g of (S)-3-(acetyloxy)-1-pyrrolidinecarboxylic acid, phenylmethyl ester as a colorless oil, [α]D26 =+17° (dichloromethane).