Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:28]3[C:27]4[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=4[N:21]=[C:20]([NH2:30])[C:19]=3[N:18]=[C:17]2[CH2:31][O:32][CH2:33][CH3:34])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].B1([C:42]2[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=2)OCCCO1.C(O)CC.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:28]3[C:27]4[CH:26]=[CH:25][C:24]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)=[CH:23][C:22]=4[N:21]=[C:20]([NH2:30])[C:19]=3[N:18]=[C:17]2[CH2:31][O:32][CH2:33][CH3:34])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCCO
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 105 °C
Yield: 64.1 %

Procedure:
tert-Butyl[4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate (1.15 g, 2.1 mmol), triphenylphosphine (0.005 g), pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.365 g, 2.2 mmol), and n-propanol (3.67 mL) were combined. Aqueous sodium carbonate (2M, 1.12 mL) and water (0.6 mL) were added to the mixture and the flask was flushed with nitrogen. Palladium(II) acetate (0.0013 g) in toluene (0.200 mL) was added, and the flask was again flushed with nitrogen. The flask was sealed and heated in an oil bath at a temperature of 105° C. for 16 hours. The reaction was allowed to cool to room temperature and the mixture was diluted with dichloromethane and water. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography eluting with a gradient of CMA/chloroform and subsequent recrystallization from acetonitrile yielded 0.725 g of tert-butyl{4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}carbamate as flocculent white crystals, m.p. 195.5–197.0° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[NH:5][C@H:6]1[C@@H:11]([CH3:12])[CH2:10][CH2:9][NH:8][CH2:7]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:2][O:3][C:4](=[O:13])[NH:5][C@H:6]1[C@@H:11]([CH3:12])[CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7]1
Reactant: COC(=O)N[C@@H]1CNCC[C@@H]1C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@@H]1C
Reaction time: 60 h
Yield: 80.9 %

Procedure:
A mixture of racemic cis (4-methyl-piperidin-3-yl)-carbamic acid methyl ester hydrochloride (7.35 mmol), benzaldehyde (818 μL, 8.09 mmol), diisopropylethylamine (3.9 mL, 22.1 mmol) and 4 Å molecular sieves (7 g) in DCE (50 mL) was stirred at ambient temperature for 5 hours before the addition of sodium triacetoxyborohydride (2.34 g, 11.03 mmol). The resulting mixture was stirred for 60 hours then filtered through Celite® and the filtrate concentrated under vacuum. The resulting residue was purified by Isolute® SCX-2 (gradient: DCM to 2M NH3 in methanol solution) then column chromatography on silica gel (gradient: 0 to 5% 2M NH3 in methanol solution in DCM) to afford 1.56 g (81%) of racemic cis (1-benzyl-4-methyl-piperidin-3-yl)-carbamic acid methyl ester as a clear oil. LCMS (Method H, ESI): RT=1.53 and 0.35 min, m+H=263.9; 1H NMR (400 MHz, CDCl3) δ: 7.31-7.23 (m, 5H), 5.42 (d, 1H), 3.78 (d, 1H), 3.66 (s, 3H), 3.45 (s, 2H), 2.80-2.77 (m, 2H), 2.20-2.12 (m, 1H), 1.94 (td, 1H), 1.72-1.48 (m, 1H), 1.38 (m, 2H), 0.90 (d, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:8]=[C:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=C(C=O)[N:10]2[CH:23]=1)=[O:5])[CH3:2].[C-]#N.[Na+].C(O)(=O)C.[C:31]([O:34][CH2:35]C)(=[O:33])[CH3:32]>CO.[O-2].[O-2].[Mn+4].CO.C(OCC)(=O)C>[CH3:35][O:34][C:31]([C:32]1[N:10]2[CH:23]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[N:8]=[C:9]2[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)=[O:33]
Reactant: CCNC(=O)Nc1cn2c(C=O)cc(-c3cccnc3)cc2n1
Reactant: CCOC(C)=O
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(=O)Nc1cn2c(C(=O)OC)cc(-c3cccnc3)cc2n1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Activated manganese dioxide (600 mg) was added to a solution of the alcohol (12) (90 mg, 0.29 mmol) in a mixture of ethyl acetate (20 mL) and methanol (10 mL) and the mixture was stirred vigorously at 23° C. for 2 h. APCI-MS Found [M+H]=310. The reaction mixture was filtered through Celite, washing through with more ethyl acetate/methanol. The combined filtrates were concentrated to dryness to give the aldehyde, 1-Ethyl-3-(5-formyl-7-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl)-urea (13), which was used directly in the next step. To a solution of the crude aldehyde (13) in methanol (20 mL) was added NaCN (75 mg, 1.53 mmol) and acetic acid (26 μL, 0.46 mmol). Activated manganese dioxide (600 mg) was added last and the mixture was stirred at 23° C. for 3 h, then filtered through Celite, washing through with more methanol. The combined filtrates were concentrated to dryness to leave a solid which was adsorbed onto silica. Silica gel chromatography (ethyl acetate gradient to methanol/ethyl acetate (8:92)) provided 2-(3-Ethyl-ureido)-7-pyridin-3-yl-imidazo[1,2-a]pyridine-5-carboxylic acid methyl ester (14) (36 mg). HRFAB-MS Found: [M+H]=340.1413. C17H18N5O3 requires 340.1410.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:6]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:6]=[C:2]2[CH3:1])=[CH:22][N:21]=1
Reactant: Fc1ccc(Cl)nc1
Reactant: Cc1nc(C#Cc2cccc(C(F)(F)F)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(C(F)(F)F)c2)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=362.3 (M+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(3-trifluoromethyl-phenylethynyl)-1H-imidazole and 2-chloro-5-fluoro-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:34]([CH2:35]OS(C)(=O)=O)=[C:33]([CH3:41])[O:32][N:31]=1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:34]2[C:30]([CH3:29])=[N:31][O:32][C:33]=2[CH3:41])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cc1noc(C)c1COS(C)(=O)=O
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with methanesulfonic acid 3,5-dimethyl-isoxazol-4-ylmethyl ester (prepared by mesylation of the commercially available 1,5-dimethyl-1H-pyrazol-3-yl)-methanol) gave the title compound. ES-MS m/e (%): 508.2(M+H+).
Reaction SMILES: [CH:1](=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.Cl.C([C@@H]1NC(C)(C)N(C)C1=O)C1C=CC=CC=1>CCOC(C)=O>[CH2:4]([C@H:3]1[C@H:10]2[CH2:11][C@H:12]([CH:8]=[CH:9]2)[C@H:2]1[CH:1]=[O:7])[CH2:5][CH3:6]
Reactant: C1=CCC=C1
Reactant: CCC/C=C/C=O
Agent: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC[C@@H]1[C@H](C=O)[C@H]2C=C[C@@H]1C2
Yield: 92 %

Procedure:
Prepared according to the general procedure with (E)-hex-2-enal (142 μL, 1.22 mmol), cyclopentadiene (302 μL, 3.66 mmol), and 5 (16 mg, 0.061 mmol) to provide the title compound as a colorless oil in 92% yield (184 mg, 1.12 mmol) after silica gel chromatography (10% EtOAc/hex); 1.0:1.0 endo:exo; endo 90% ee; exo 86% ee. Product ratios were determined by GLC (Bodman Γ-TA column, 100° C. isotherm, 23 psi); exo isomers tr=25.6 min and 26.7 min, endo isomers tr=30.2 min and 30.9 min. 1H NMR, 13C NAMR and IR data for the endo isomer were consistent with previously reported values (Ishiara et al. (1998), supra). Exo isomer: IR (CH2Cl2)1719, 1466, 1456 cm−1; 1H NMR (400 MHZ, CDCl3)δ9.76 (d, J=2.7 Hz, 1 H, CHO), 6.19 (dd, J=5.6, 3.2 Hz, 1H, CH=CH), 6.11 (dd, J=5.6, 2.9 Hz, 1H, CH=CH), 3.00 (br s, 1H, CHCH=CH), 2.85 (br s, 1H, CHCH=CH), 2.23-2.30 (m, 1H, CHCH2CH2), 1.72-1.76 (m, 1H, CHCHO), 1.00-1.47 (m, 6H, CHCH2CH, CH2CH2CH3), 0.86 (t, J=7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHZ, CDCl3)δ203.9, 136.0, 135.9, 58.7, 47.0, 45.7, 44.8, 41.6, 36.4, 21.6, 14. 1; HRMS (EI) exact mass calcd for (C11H16O) requires m/z 164.1201, found m/z 164.1200; [α]D=+89.4 ©=2.7, CHCl3).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](I)=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:23]([O:27][C:28](=[O:47])[N:29]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[C:32]([F:38])[N:31]=1)([CH3:26])([CH3:25])[CH3:24].O>O1CCCC1>[C:23]([O:27][C:28](=[O:47])[N:29]([C:30]1[C:35]([CH3:34])=[C:36]([OH:37])[C:33]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:6]([Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:7]=2)=[C:32]([F:38])[N:31]=1)[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)c(F)n1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N(Cc2ccc(Cl)cc2)C(=O)OC(C)(C)C)nc(F)c(-c2cn([Si](C)(C)C(C)(C)C)c3ncccc23)c1O
Temperature: 0 °C

Procedure:
To 1-(tert-butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (66, 0.53 g, 0.0015 mol) and tetrahydrofuran (15.0 mL), under an atmosphere of nitrogen at −20° C., was added isopropylmagnesium chloride (0.78 mL, 2.0 M in tetrahydrofuran). The reaction was allowed to warm to 0° C. (around 80 minutes), then cooled to −20° C., followed by addition of (4-Chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (65, 0.200 g, 0.55 mmol) in tetrahydrofuran (6.0 mL). The reaction was allowed to warm to room temperature in 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a yellow solid (67, 0.20 g, 61.1%). MS (ESI) [M+H+]+=597.4.
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH3:12])[CH:10]=[C:9]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:34])[C@@H:23]4[C@H:27]([O:29][Si](C)(C)C)[CH3:28])[C:20]=3[C:35]([O:37]CC=C)=[O:36])[S:16][CH:17]=2)[CH2:8]1)=O)C=C.O.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C1COCC1>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:34])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:9]3[CH2:8][NH:7][C@H:11]([CH3:12])[CH:10]=3)[N:14]=1)=[C:20]2[C:35]([OH:37])=[O:36])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@@H](C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1C=C(c2csc(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)n2)CN1
Reaction time: 0.17 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(5R)-1-[(allyloxy)carbonyl]-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (42 mg, 0.070 mmol) in ethyl acetate (4 ml) was added water and then 2N hydrochloric acid and the solution was adjusted to pH 2. After stirring for 10 minutes, THF was further added thereto and the solution was stirred for 20 minutes. To the obtained mixture was added a saturated aqueous sodium hydrogen carbonate solution and the solution was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To a solution of the residue (37.6 mg) in dichloromethane (2 ml) were added at 0° C. tributyltin hydride (0.17 ml), acetic acid (10 μl) and bis(triphenylphosphine)palladium chloride(5 mg) and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture were added phosphate buffer (50 mM, pH7, 25 ml) and dichloromethane (20 ml). The aqueous layer was separated and the dichloromethane layer was extracted twice with water. The combined aqueous layer was washed with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-({4-[(5R)-5-methyl-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[C:13]([C:14]([NH2:16])=O)=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]1([CH:7]([N:9]2[C:13]([C:14]#[N:16])=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)n1cncc1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(c1ccccc1)n1cncc1C#N
Temperature: 25 °C

Procedure:
To a stirred and cooled (-10° C.) solution of 3.7 parts of (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxamide in 50 parts of pyridine are added dropwise, during a 15 minute period, 3.4 parts of phosphoryl chloride. The mixture is allowed to reach room temperature; then heated in a boiling water-bath for 1.5 hrs. The reaction mixture is cooled to room temperature and poured onto 250 parts of ice-water. The precipitated product is filtered off, washed with water and dissolved, in trichloromethane. The solution is dried, filtered and evaporated. The solid residue is crystallized from a mixture of 2,2'-oxybispropane and ethanol, yielding (-)-1-(1-phenylethyl)-1H-imidazole-5-carbonitrile; m.p. 128.7° C.; [α] = -40.23° (c = 1% CH3OH).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[NH2:23][C@@H:24]1[CH2:27][C@H:26]([N:28]2[CH:32]=[C:31]([NH:33][C:34](=[O:46])[CH2:35][C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38][CH:37]=3)[N:30]=[CH:29]2)[CH2:25]1.[OH-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:36]1([CH2:35][C:34]([NH:33][C:31]2[N:30]=[CH:29][N:28]([CH:26]3[CH2:27][CH:24]([NH:23][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[O:10])[CH2:25]3)[CH:32]=2)=[O:46])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: N[C@H]1C[C@@H](n2cnc(NC(=O)Cc3cccc4ccccc34)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC2CC(n3cnc(NC(=O)Cc4cccc5ccccc45)c3)C2)n1
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
A solution of 6-methylpicolinic acid (9.4 mg, 0.07 mmol) in methylene chloride was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg) and DMAP (2 mg) at 23° C. After stirring for 10 min, N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Example 6, 20 mg, 0.06 mmol), was added. The resulting mixture was then stirred for 3 h. Water was added, the solution was made neutral with aqueous NaOH and was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (20:1 CHCl3—MeOH) gave 26 mg (95% yield) of 6-methyl-pyridine-2-carboxylic acid {3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 1H NMR (400 MHz, CDCl3) δ9.15 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.81 (dd, J=2.4, 6.6 Hz, 1H), 7.72 (m, 1H), 7.5 (m, 5H), 7.2 (m, 1H), 7.16 (s, 1H), 4.45 (m, 1H), 4.25 (m, 1H), 4.18 (s, 2H), 2.98 (m, 2H), 2.60 (s, 3H), 2.40 (m, 2H); MS (AP/Cl): 440.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]2[N:6]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:7](=[N:10][C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[N:8]([CH3:9])[C:4]=2[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]2[N:6]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:7](=[N:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cn2c(=Nc3ccc(OC)cc3)n(C)c3cc(Cl)c(Cl)cc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c(=Nc3ccc(O)cc3)n(C)c3cc(Cl)c(Cl)cc32)cc1
Temperature: -78 °C

Procedure:
To the title compound of Example 19 Step C (0.11 mmol, 50 mg) in CH2Cl2 (0.5 mL) cooled to −78° C. was added dropwise BBr3 (0.33 mol, 330 μL of a 1 M solution in CH2Cl2). After addition, the reaction was removed from the cold bath for 30 min, then cooled to −78° C. and diluted with MeOH. The mixture was concentrated under reduced pressure and the product was isolated by chromatography on silica eluting with 4% MeOH in CH2Cl2 as a white solid. LC-MS (ESI, Method B): 1.80 min, m/z 456.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH:18][CH:19]1[CH:23]=[CH:22][S:21](=[O:25])(=[O:24])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:19]1[CH:23]=[CH:22][S:21](=[O:25])(=[O:24])[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)C=CC(NCc2ccccc2)C1
Reactant: O=C=NCc1ccccc1
Solvent: c1ccccc1
Product: O=C(NCc1ccccc1)N(Cc1ccccc1)C1C=CS(=O)(=O)C1
Yield: 73.3 %

Procedure:
Benzylisocyanate (2.26 g, 17.0 mmol, 135 mol %) was added to a mixture of amine 3 (2.80 g, 12.6 mmol) in a benzene (75 mL). After 10 hr of reflux, the solution was cooled and filtered, and the solvent was evaporated from the filtrate to afford the crude product (3.29 g, 74% yield). A portion was purified by column chromatography on silica gel with dichloromethane-ethyl acetate. 1H N NMR (CDCl3) δ 1.7 (1H, s, NH), 3.02 (1H, dd, CHSO2), 3.65 (1H, dd, CHSO2), 4.4 (4H, m, CH2Ph), 4.95, (1H, m, CHN), 6.57 (2H, m, CH=CH), 7.23 (10H, s, arom).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[N:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[N:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)n1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)n1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}propanoate (1.28 g, 3.05 mmol) in methanol (6 ml) was added 2N aqueous sodium hydroxide solution (3.05 ml, 6.1 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (1.20 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[ClH:27].[NH2:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C([BH3-])#N.[Na+]>C(O)C>[ClH:27].[CH2:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37][CH:29]1[NH:28][CH:14]1[CH2:15][CH2:16][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([C:18]#[N:19])[CH2:12][CH2:13]1
Reactant: NC1Cc2ccccc2C1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C2(C#N)CCC(NC3Cc4ccccc4C3)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexanone (0.71 g, 2.74 mmol), triethylamine (0.38 ml, 2.74 mmol), 2-amino-2,3-dihydro-1H-inden hydrochloride (0.46 g, 2.74 mmol) and sodium cyanoborohydride (0.17 g, 2.7 mmol) in 10 ml ethanol was stirred at 25° C. for 3 days, filtered and the volatiles were removed in vacuo. The residue was diluted with ethyl acetate, washed with water, 1N NaOH and brine and dried (MgSO4). The volatiles were removed in vacuo. The residue was treated with ethyl acetate and anhydrous HCl. The volatiles were removed in vacuo. Recrystallization of the residue with aqueous ethanol gave the product, m.p. >250° C. ##STR20##
Reaction SMILES: C([NH:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:5]1=2)=O.[ClH:23]>O1CCOCC1>[ClH:23].[NH2:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:5]1=2
Reactant: COC(=O)c1ccc2c(c1)C(NC=O)c1ccccc1CO2
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)C(N)c1ccccc1CO2
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Add 600 mg. of methyl 6,11-dihydro-11-formamidodibenz[b,e]oxepin-2-carboxylate to a mixture of 20 ml. of dioxane and 24 ml. of 10% hydrochloric acid. Stir and heat the mixture at 40° C. for 18 hours. Strip to dryness and triturate the residue in tetrahydrofuran. Separate the solids by filtration. Dissolve the solids in water and basify with aqueous sodium hydroxide. Extract into ether, dry over anhydrous sodium sulfate and filter. Bubble gaseous hydrogen chloride through the solution for 15 minutes and separate the solids. Triturate in tetrahydrofuran and filter to obtain the title product (m.p. 224° C. dec.).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH2:21][C:22](O)=[O:23])#[N:20].C(OC(=O)C)(=O)C>CCOCC>[CH2:1]([N:8]([C:22](=[O:23])[CH2:21][C:19]#[N:20])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)Nc1cccc(Cl)c1
Reactant: N#CCC(=O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)N(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1
Temperature: 77.5 °C
Reaction time: 16 h

Procedure:
A mixture of 1-benzyl-3-(3-chlorophenyl)urea (44.78 g) and cyanoacetic acid (16.11 g) was ground together and then acetic anhydride (48 ml) added. The resulting mixture was heated and stirred at 75-80° C. for 16 h. It was then allowed to cool, diluted with ether and the product filtered off and washed with ether. This was then recrystallised from toluene with a hot filtration. Yield=20.15 g.