Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:21]([F:29])[CH:20]=[CH:19][C:18]=1B(O)O>>[F:29][C:21]1[C:22]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[C:17]([F:16])[CH:18]=[CH:19][C:20]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)c(F)c1-c1ccncc1
Yield: 35.2 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid (66 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2,4-difluoro-3-pyridin-4-ylphenyl)-2-trifluoromethyl-[1,8]naphthyridine (30 mg, 36%). δH (360 MHz, CDCl3) 7.29 (1H, m), 7.41-7.50 (3H, m), 7.62 (1H, d, J 4.6), 7.85 (1H, d, J 8.8), 8.33 (1H, dd, J 2.3 and 8.6), 8.75-8.77 (2H, m), 9.34 (1H, d, J 4.6). m/z (ES+) 388 [MH]+.
Reaction SMILES: [C@H:1]12[CH2:55][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:48])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH2:37][CH2:36][C@@H:35]([C:38]([O:40]CC6C=CC=CC=6)=[O:39])[CH2:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2.[OH-].[Li+]>C1COCC1.CO>[C@H:1]12[CH2:55][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:48])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH2:37][CH2:36][C@@H:35]([C:38]([OH:40])=[O:39])[CH2:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 75 %

Procedure:
To a solution of (R)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,45)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (47.2 mg, 0.048 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added 1N lithium hydroxide (0.193 mL, 0.193 mmol). The reaction was stirred at 75° C. After 3 h the reaction mixture was concentrated and the crude material was dissolved in THF (2 mL)/H2O (150 μL), purified by reverse phase prep-HPLC using prep-HPLC method 15 and dried under vacuum to give (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (32.9 mg, 0.036 mmol, 75% yield) as a white solid. LC/MS: m/e 659.5 (M+H)+, 4.14 min (method 8). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 5.33 (br. s., 1H), 5.22-5.08 (m, 1H), 4.78 (s, 1H), 4.70 (s, 1H), 4.54 (s, 1H), 4.04 (d, J=8.8 Hz, 1H), 3.84 (br. s., 1H), 3.73 (dd, J=8.8, 1.5 Hz, 1H), 3.23-2.96 (m, 5H), 2.88-2.63 (m, 2H), 2.58-2.40 (m, 1H), 2.35-2.09 (m, 5H), 2.08-1.90 (m, 8H), 1.83-1.75 (m, 1H), 1.71 (s, 3H), 1.70-1.61 (m, 2H), 1.61-1.42 (m, 8H), 1.41-1.36 (m, 1H), 1.35 (s, 1H), 1.33-1.23 (m, 1H), 1.10 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[ClH:13]>>[Cl:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: Cl
Product: FC(F)(F)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
A 45 milliliter (ml) Teflon®-lined Parr bomb, which was equipped with a pressure gauge, rupture disk and needle valve, was charged with 2 grams (g) of 3-chloro-2-fluoro-5-trifluoromethylpyridine and then pressurized with anhydrous HCl to 200 psig. The bomb was placed in a heated rocker and kept at 110° C. for 20 hours. The maximum pressure was 220 psig. The bomb was removed from the heater and allowed to cool to room temperature, at which time it was placed in an ice bath. The bomb was vented to a caustic scrubber and 2.5 g of a light tan liquid consisting of HF and 84.3% 2,3-dichloro-5-trifluoromethylpyridine (by wt.). This represents a 97.7% yield of 2,3-dichloro-5-trifluoromethylpyridine (by wt.) with 0.4% of 3-chloro-2-fluoro-5-trifluoromethylpyridine remaining. No additional products were observed by analysis with gas chromatography.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:4]=[CH:5][N:6]=1.[H][H]>[Pt]=O.C(O)(=O)C>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=[CH:5][N:6]=1
Reactant: [H][H]
Reactant: Cc1nccn1CCc1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Cc1nccn1CCC1CCNCC1

Procedure:
A suspension containing 41.8 g (0.22 mol) of the compound prepared in (a) above, 450 ml of glacial acetic acid and 5.4 g of platinum oxide in a pressure bottle was affixed to a Parr Hydrogenation apparatus under 50 psi. of hydrogen and maintained at room temperature until the hydrogen uptake was completed. The reaction mixture was filtered through Celite, and the filter bed was then washed with approximately 100 ml of acetic acid. The combined filtrates were then concentrated in vacuo and the resultant residue was distilled in a Kugelrohr apparatus to yield a low melting white solid.
Reaction SMILES: C1(P(=[CH:20][C:21]#[N:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]>C(Cl)Cl.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:40]=[CH:39][C:36](/[CH:37]=[CH:20]/[C:21]#[N:22])=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#C/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To the mixture of (triphenylphosphanylidene)acetonitrile (19.8 g, 51.9 mmol) and NaOH (2.59 g, 64.9 mmol) in DCM (30 mL) and water (60 mL) was added 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (13.0 g, 43.2 mmol)) at 0° C. It was stirred at rt for 4 h. Purification via a flash chromatography afforded the title compound as a white solid (12 g).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([N:6](S(C(F)(F)F)(=O)=O)[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])(=[O:5])=[O:4].[OH-].[Na+].CO.O>Cl>[F:24][C:2]([F:1])([F:25])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:5]
Reactant: COC(=O)c1cccc(N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(NS(=O)(=O)C(F)(F)F)c1

Procedure:
A solution of methyl 3-{bis[(trifluoromethyl)sulfonyl]amino}benzoate (5.4 g, 13.0 mmol), sodium hydroxide (3.12 g, 78.0 mmol), methanol (125 ml) and water (125 ml) was stirred for 2 hours. The solution from concentration to 75 ml by spin evaporation in vacuo and dilution with 100 ml water was extracted with ethyl acetate. The aqueous layer was acidified with 12 N hydrochloric acid and again extracted with ethyl acetate. The organic layer was washed with water and concentrated by spin evaporation in vacuo, with the addition of dichloromethane (3 times) to give a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo to 3-{[(trifluoromethyl)sulfonyl]amino}benzoic acid as a solid (2.3 g, 66%). 1H-NMR (400 MHz, DMSO-d6): ): δ 7.83-7.78 (m, 2H), 7.55-7.50 (m, 1H), 7.50-7.46 (m, 1H). ES-LCMS m/z 269 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[Mg].[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C@H:19]2[CH2:23][CH:24]=[CH:25][CH2:26][C@@H:18]12>O1CCCC1>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[C:17]([C@H:18]2[CH2:26][CH:25]=[CH:24][CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:27])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OC1CCCC1
Reaction time: 18 h

Procedure:
A solution of 100 mmol of 1-Bromo-3-cyclopentyloxy-4-methoxybenzene in tetrahydrofuran was added slowly to a mixture of 1.1 equivalent of magnesium. After complete addition, the mixture was refluxed for 5 h and left at room temperature for additional 18 h. The mixture was added slowly to a solution of (cis)-1,2,3,6-tetrahydrophthalic anhydride in tetrahydrofuran at 0° C. After complete addition the mixture was refluxed for 6 h and left at room temperature for addition 18 h after which the reaction was quenched with ammonium chloride and the solvent removed under reduced pressure. The residue was acidified with concentrated hydrochloric acid and the mixture extracted with diethyl ether. The organic layer was dried over magnesium sulfate and evaporated. The residue was dissolved in dichloromethane and the solution filtered over silica. After evaporating this dichloromethane solution, the compound was crystallized from diethyl ether. M.p. 114-115° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH:14]=[CH:13][C:12](=O)[NH:11][C:10]=12)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.C(OCC)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:12]1[CH:13]=[CH:14][N:9]2[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn2ccc(=O)[nH]c12
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(Cl)nc12
Temperature: 90 °C
Yield: 73 %

Procedure:
To a suspension of 5-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (prepared according to Gavrin, L. K. et al, J. Org. Chem. 2007, 72, 1043-1046) (3.00 g, 14.5 mmol, 1 equiv) in phosphorus oxychloride (30 mL) was added diisopropylethylamine (2.00 mL, 11.6 mmol, 0.8 equiv). The mixture was heated to 90° C. for 4.5 hours. After cooling, the mixture was carefully quenched with ice-water and extracted with dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to give a solid. Trituration (diethyl ether) afforded 2.38 g (73%) of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate as a solid. LCMS (ESI) m+H=226.2 (mono chlorinated isotope pattern); 1H NMR (400 MHz, CDCl3) δ: 8.63 (d, 1H), 8.56 (s, 1H), 6.99 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].N1C2C(=CC=CC=2)C2(COC3C=[C:36]4[C:40](=[CH:41][C:31]2=3)[CH2:39][CH2:38][O:37]4)C1=O>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:39][CH:38]1[CH2:31][CH2:41][CH2:40][CH2:36][O:37]1)[C:11]3=[O:19]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Product: COc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 6-methoxy-5-methyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (68%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ 7.28 (dd, J=7.8, 7.8 Hz, 1H), 7.13-6.97 (m, 3H), 6.47 (s, 1H), 6.43 (d, J=4.3 Hz, 1H), 4.91 (dd, J=8.9, 2.1 Hz, 1H), 4.66 (dd, J=8.9, 3.3 Hz, 1H), 4.02-3.59 (m, 4H), 3.79 (s, 3H), 3.43-3.31 (m, 1H), 1.99 (s, 3H), 1.92-1.77 (m, 1H), 1.71-1.26 (m, 5H); MS (ES+) m/z 380.4 (M+1).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:20](O)=[O:21])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH3:37]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:21])[NH2:37])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(N[C@@H](Cc1ccc(Cl)cc1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: N
Product: NC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 20 %

Procedure:
The title compound (3 mg, 20%) was prepared from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid and NH3 (0.5 M in dioxane) as in Example 1, Part C. HPLC: RT=10.08 min. MS (ESI−): mass calcd. for C22H16Cl3N5O4S2, 582.97; m/z found, 582/584 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.34 (s, 1H), 8.37 (dd, J=7.1, 1.0, 1H), 8.24 (dd, J=8.8, 1.0, 1H), 7.84 (s, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.36 (s, 1H), 7.36-7.32 (m, 2H), 7.24-7.20 (m, 2H), 6.84 (br d, J=6.9, 1H), 5.47 (br s, 1H), 5.41 (br s, 1H), 4.68 (ddd, J=8.6, 7.0, 5.0, 1H), 3.18 (dd, J=13.7, 4.9, 1H), 3.01 (dd, J=13.6, 8.6, 1H).
Reaction SMILES: [NH:1]([CH3:3])[CH3:2].[O-:4][N+:5]1[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[N:8]=[C:7]([CH2:18][CH2:19][CH:20]=O)[N:6]=1)[CH2:15][CH2:14][CH2:13]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:2][N:1]([CH3:3])[CH2:20][CH2:19][CH2:18][C:7]1[N:6]=[N+:5]([O-:4])[C:10]2[CH:11]=[C:12]3[C:16]([CH2:15][CH2:14][CH2:13]3)=[CH:17][C:9]=2[N:8]=1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reaction time: 0.33 h
Yield: 55.1 %

Procedure:
A solution of anhydrous Me2NH (2.4 g, 52 mmol) in MeOH (50 mL) was added to a solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (50 ml) at 0° C. and the solution stirred for 20 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred for 30 min, then HOAc (2 ml) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 ml), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 78 (930 mg, 55%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.17 (s, 1H, H-9), 7.81 (s, 1H, H-5), 3.06-3.12 (m, 4H, H-6, H-8), 2.94-3.03 (m, 4H, 2×CH2), 2.66 [s, 6H, N(CH3)2], 2.07-2.18 (m, 4H, H-7, CH2); 13C NMR δ 164.1, 155.0, 149.2, 146.8, 131.9, 122.4, 113.7, 56.6, 43.0 (2), 33.3, 32.7, 32.4, 25.4, 22.7; HRMS (FAB+) calcd for C15H21N4O (MH+) m/z 273.1715, found 273.1714.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[NH:18][CH2:19][CH2:20][CH3:21])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Br[C:23]1[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:23]3[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=3)[CH2:14][C@H:13]2[NH:18][CH2:19][CH2:20][CH3:21])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCCN[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 65.2 %

Procedure:
The same operation as in Example (196c) was performed using cis(±)-4-chloro-5-ethyl-N-[3-(propylamino)piperidin-4-yl]-1H-imidazole-2-carboxamide obtained in Example (205a) (17.0 mg, 0.054 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (15 mg, 0.060 mmol) and sodium carbonate (17 mg, 0.163 mmol), to obtain 17 mg of the title compound (65%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>[OH-].[Na+]>[CH3:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)O)cc(N2CCCC2)n1

Procedure:
A solution of 2-chloro-6-methyl-isonicotinic acid (1.03 g, 5.98 mmol) in pyrrolidine (5 mL) is stirred at 85° C. for 6 days. The mixture is diluted with 1 N aq. NaOH (40 mL) and the solvent is removed in vacuo. The crude product is again dissolved in 1 N aq. NaOH (3 mL) and methanol (1 mL) and purified by MPLC on RP-C18-silica gel to give 2-methyl-6-pyrrolidin-1-yl-isonicotinic acid (1.18 g) as a beige solid; LC-MS: tR=0.52 min, [M+H]+=207.06; 1H NMR (D6-DMSO): δ 1.89-1.94 (m, 4H), 2.27 (s, 3H), 3.33-3.38 (m, 4H), 6.61 (s, 1H), 6.77 (s, 1H).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[C:17]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:23])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Product: O=C(NC1CCOCC1)c1ccc(OCc2conc2-c2ccccc2)nc1
Yield: 73 %

Procedure:
As described for example 321d, 6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (67 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (60 mg, 73%) which was obtained as an off white solid. MS: m/e=380.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13](=[O:29])[NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]([CH2:30][C:31](=[O:47])[NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:9]=1)(C)(C)C.Cl.O1CCOCC1>ClCCl>[CH2:22]([O:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[NH:14][C:13]([C:11]1[N:10]([CH2:30][C:31](=[O:47])[NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:9]=[C:8]([NH2:7])[CH:12]=1)=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Reaction time: 6 h
Yield: 96.7 %

Procedure:
To a solution of {5-(2-Benzyloxy-cyclohexylcarbamoyl)-1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazol-3-yl}-carbamic acid tert-butyl ester (0.5 gm) in 5 ml of dichloromethane was added 1 ml of 4N hydrochloric acid/dioxane. After stirring for 6 hours the mixture was evaporated to dryness to obtain 0.41 gm of title product as the hydrochloride salt. ESI M+1=560.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[C:5]([O:9][C:10]([C:12]1[C:20]2[CH2:19][CH:18]([CH2:21][NH2:22])[O:17][CH2:16][C:15]=2[S:14][C:13]=1[NH2:23])=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(#N)C>[C:5]([O:9][C:10]([C:12]1[C:20]2[CH2:19][CH:18]([CH2:21][N:22]3[CH2:16][C:15]4[C:2](=[CH:21][CH:18]=[CH:19][CH:20]=4)[C:1]3=[O:4])[O:17][CH2:16][C:15]=2[S:14][C:13]=1[NH2:23])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Reactant: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1Cc3ccccc3C1=O)OC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.4 %

Procedure:
Phthalic dicarboxaldehyde (52 mg, 0.36 mmol) was dissolved in a mixture of anhydrous acetonitrile (2 ml) and acetic acid (44 μl, 0.72 mmol). The above 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.11 g, 0.36 mmol) was added and the reaction stirred for 20 minutes at room temperature. The volatiles were evaporated in vacuo and the residue dissolved in ethyl acetate (25 ml). The organic mixture was washed with saturated sodium bicarbonate (5 ml), 1% hydrochloric acid (5 ml), brine (5 ml), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography using a gradient from 15% ethyl acetate/dichloromethane to 17% ethyl acetate/dichloromethane as eluent affording 45 mg (30%) of 2-amino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH2:8]Br)[CH:7]=1.[OH:13][CH2:14][C:15]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH:7]=1)[CH2:8][O:13][CH2:14][C:15]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: COc1c(C)cc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)cc(Br)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Bromo-1-(bromomethyl)-2-methoxy-3-methylbenzene (0.88 g, 3.0 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.79 g, 2.7 mmol) were combined in dimethylformamide (9 mL) and cooled to 0° C. The reaction was treated with sodium hydride (144 mg, 5.99 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 1.24 g (82%). 1H-NMR (CDCl3, 500 MHz) δ 7.34-7.35 (m, 4H), 7.21-7.24 (m, 1H), 7.19-7.20 (m, 1H), 7.10 (m, 1H), 4.34 (s, 2H), 3.72-3.76 (m, 2H), 3.53 (s, 3H), 3.43 (s, 2H), 3.01-3.07 (m, 2H), 2.21 (s, 3H), 2.17-2.19 (m, 2H), 1.85-1.91 (m, 2H), 1.43 (s, 9H). Mass spec.: 506.45 (MH)+.