Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:35])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]4)=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([OH:34])[CH:12]=3)=[CH:4][CH:3]=1.[OH-].[NH4+].[I:38]I>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:35])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]4)=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([OH:34])[C:12]=3[I:38])=[CH:6][CH:7]=1
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCC3CCCCN3)cc2)c1-c1ccc(Cl)cc1
Reactant: II
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCC3CCCCN3)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
To a solution containing 3-(4-chlorophenyl)-7-hydroxy-4-{(4-(2-piperidylethoxy)phenyl)methyl}-2H-chromen-2-one (0.500 g.) in methanol (10 mL) was added ammonium hydroxide (3 mL) and elemental iodine (0.259 g.). The reaction mixture was allowed to stir at room temperature for 10 minutes. The solvent was removed under reduced pressure. The resulting solid was extracted with methylene chloride (3×) and water. The organic layers were combined and dried over magnesium sulfate. The magnesium sulfate was filtered, and the solvent was removed under reduced pressure to afford a yellow solid. The solid was purified via preparative HPLC (20–50% acetonitrile/water, 20 mL/min.) to afford the title compound (0.290 g., 46% yield). 1H-NMR (CDCl3) δ 7.34 (dd, 3H), 7.20 (d, 2H), 6.92 (d, 2H), 6.84 (d, 1H), 6.75 (d, 2H), 4.13 (t, 2H), 3.97 (s, 2H), 2.84 (t, 2H), 2.61 (bs, 3H), 1.643 (m, 4H), 1.46 (m, 2H), 1.24 (m, 1H). MS (m/z) 616 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([Cl:19])[N:8]=2)=[CH:4][CH:3]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](O)=[O:33].CCOC(C)=O>C1COCC1>[Cl:19][C:9]1[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:11]([Cl:13])[N:12]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:32]([C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:33])=[CH:21][CH:20]=2)[N:8]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 669.2 %

Procedure:
A mixture of methyl [2-(4-aminobenzyl)-4,6-dichloropyrimidin-5-yl]acetate (0.073 g, 0.23 mmol), 2-naphthoic acid (0.048 g, 0.028 mmol), and WSCI (0.049 g, 0.026 mmol) in anhydrous THF (3 mL) was stirred at room temperature under Ar atmosphere for 10 hours. EtOAc (80 mL) was then introduced and the organic phase was washed sequentially with saturated NaHCO3, water, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained as a light orange oil was triturated with diisopropyl ether and the separated solids was collected by suction to give methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.090 g, 78% yield) as a white powder.
Reaction SMILES: CO[C:3]([C:5]1[C:10]2[N:11]=[CH:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][N:6]=1)=[O:4].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>CO>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:3]([C:5]1[C:10]2[N:11]=[CH:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CN(C)CCN
Reactant: COC(=O)c1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: CN(C)CCNC(=O)c1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 51 %

Procedure:
In 5 mL of methanol, 11 mg (0.037 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carboxylic acid methyl ester prepared in Step B was dissolved, and 100 μL of N,N-dimethylethylenediamine was added thereto and the solution was refluxed under heating with stirring for two hours. The solvent was distilled under reduced pressure, and the residue was separated by Megabond Elute Silica Gel (1 g, dichloromethane:methanol=30:1 to 4:1) to obtain 7.3 mg (51%) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carboxylic acid (2-(dimethylamino)ethyl)amide as a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:18][C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:29])=[CH:21][C:20]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:17])[CH3:16]>CC(C)=O>[C:15]([O:18][C:19]1[CH:24]=[C:23]([C:25]([CH3:26])([CH3:28])[CH3:27])[C:22]([O:29][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][C:20]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1cc(C(C)(C)C)c(OCc2ccccc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.9 %

Procedure:
Benzyl bromide (5.17 g) and potassium carbonate (4.15 g) were added to a solution of 2,5-di-t-butyl-4-hydroxyphenyl acetate (5.3 g) in acetone (40 ml). The mixture was stirred at ambient temperature for 48 hours. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sufate and concentrated. The residue was purified by chromatography on a silica gel column using c-hexane/diisopropyl ether=10/1 as the eluant to give the title compound (4.9 g).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[OH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 54 %

Procedure:
To a stirred suspension of 4-amino-2-nitrobenzoic acid (9.895 g, 54.326 mmol) in water (17 ml) was added concentrated H2SO4 (12 ml). The resulting homogenous solution was cooled in an ice bath and additional water (10 ml) added to aid stirring. Crushed ice (50 ml) was added followed by the drop-wise addition of NaNO2 (4.124 g, 59.759 mmol) in water (9 ml). The temperature was kept below 5° C. during the addition and then stirred for 1.25 h at 0° C. The reaction mixture was quenched by adding urea (6 g), stirred for 10 minutes at 0° C., filtered and the filtrate added drop-wise into a boiling solution of concentrated H2SO4 (39 ml) and water (27 ml). After the addition, the entire mixture was refluxed for 3 hours then cooled. The reaction mixture was extracted with ethyl acetate (6×50 ml) and the combined organics washed with brine, filtered and concentrated to a small volume which was then purified by flash chromatography on silica. The first column was eluted with ethyl acetate and 20% MeOH/EtOAc. The second column was eluted with 10% MeOH/CHCl3 and the third column was eluted with 60% EtOAc/Hexane. The purification process gave 4-hydroxy-2-nitrobenzoic acid (5.331 g, 29.112 mmol, 54%) as an orange solid, dec. 232-236° C. 1H NMR (DMSO-d6) δ 7.05 (dd, 1H), 7.15 (s, 1H), 7.78 (d, 1H) 11.10 (s, 1H), 13.38 (s, 1H); mass spectrum [ES(−)], m/z 182 (M−H)−.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)=[O:19])[CH2:13][CH2:12]2)=[CH:3][CH:2]=1>C(N(CC)CC)C.O>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)=[O:19])[CH2:13][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccnc4c3CCCC4)CC2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccnc4c3CCCC4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a similar manner to Example 42, the product of Example 45 (180 mg), and 0.5% v/v triethylamine/water (40 ml) gave, after stirring overnight at room temperature, washing with ether, filtration and lyophilisation, the title compound (121 mg) as an off-white fluffy solid: NMR (CDCl3) δ 1.75(2H,m), 1.90(2H,m), 2.61(2H,m), 2.75(4H,m), 3.08(2H,m), 3.23(4H,m), 3.78(2H,s), 4.66(2H,s), 6.79(1H,d), 6.99(2H,d), 7.98(2H,d), 8.41(1H,d); m/Z 410 (M+H)+ ; calculated for C23H27N3O4. 0.03 Et3N. 1.0 H2O: C, 64.7%; H, 6.89%; N, 9.86%; found: C, 64.4%; H, 6.6%; N, 9.5%.
Reaction SMILES: C(OC([N:8]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:20])[N:11]([CH2:21][C:22]([OH:24])=O)[CH:10]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:9]1)=O)(C)(C)C.[NH2:32][C:33]1[CH:34]=[C:35]2[C:48](=[CH:49][CH:50]=1)[CH2:47][C@:37]1([C:45]3[C:40](=[N:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]1=[O:46])[CH2:36]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:31][C:27]1[CH:26]=[C:25]([CH:10]2[N:11]([CH2:21][C:22]([NH:32][C:33]3[CH:34]=[C:35]4[C:48](=[CH:49][CH:50]=3)[CH2:47][C@:37]3([C:45]5[C:40](=[N:41][CH:42]=[CH:43][CH:44]=5)[NH:39][C:38]3=[O:46])[CH2:36]4)=[O:24])[C:12](=[O:20])[C:13]3([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]3)[NH:8][CH2:9]2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cccc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2(COCCOC2)NCC1c1cccc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.23 g (0.52 mmol) 2-(1-(tert-butoxycarbonyl)-3-(3-fluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)ethanoic acid, 0.15 mg (0.58 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.13 g (0.70 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 95 mg (0.7 mmol) HOBT, 0.08 ml (0.58 mmol) TEA and 2 ml DMF were stirred overnight at RT. The mixture was concentrated by rotary evaporation. The residue was combined with 15 ml of a 1.25M methanolic hydrochloric acid and stirred for 2 h at 50° C. The reaction mixture was evaporated down and purified by HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@@H:17]([NH:20]C(OC(C)(C)C)=O)[CH2:18][CH3:19])[CH2:13][CH:12]1[C:28](=[O:30])[NH2:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@@H:17]([NH2:20])[CH2:18][CH3:19])[CH2:13][CH:12]1[C:28](=[O:30])[NH2:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 1 h

Procedure:
To a solution of 84% 4-((S)-1-tert-butoxycarbonylamino-propyl)-2-carbamoyl-piperidine-1-carboxylic acid benzyl ester (0.7 g, 1.4 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (2 mL). After 1 hour, the reaction was monitored by HPLC-MS. Additional TFA (1 mL) was added. After 30 minutes, the reaction was concentrated to afford 4-((S)-1-amino-propyl)-2-carbamoyl-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([C:22]4[CH:23]=[C:24]([NH:28][C:29]([C:31]5[N:32]([CH3:37])[N:33]=[C:34]([CH3:36])[CH:35]=5)=[O:30])[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:38])=[CH:5][CH:4]=1.Cl.[CH3:40][N:41]([CH2:43][C:44](Cl)=[O:45])[CH3:42].C(N(CC)CC)C>CN(C=O)C>[CH3:37][N:32]1[C:31]([C:29]([NH:28][C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:20]([C:16]2[CH:15]=[C:14]3[C:19]([C:11](=[CH:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:44](=[O:45])[CH2:43][N:41]([CH3:42])[CH3:40])=[CH:8][CH:7]=4)[C:12](=[O:38])[NH:13]3)=[CH:18][CH:17]=2)=[O:21])=[O:30])=[CH:35][C:34]([CH3:36])=[N:33]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CO)cc3)c2)n(C)n1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(COC(=O)CN(C)C)cc3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
In a dry 50 mL round bottomed flask, 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-{3-[(4-hydroxymethyl-phenylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carbonyl}-phenyl)-amide (as prepared in Example 331, 0.020 mg, 0.039 mmol) was dissolved in DMF (1 mL), under Ar(g). Dimethylaminoacetyl chloride hydrochloride (9.32 mg, 0.059 mmol) was then added followed by triethylamine (0.016 mL, 0.117 mmol). The mixture was stirred at room temperature for 2 hours after which the reaction mixture was partitioned between EtOAc (˜5 mL) and brine (˜5 mL). The organic layer was extracted with brine (3×5 mL). The organic layers were combined and then concentrated in vacuo. The crude residue was then chromatographed over silica (EtOAc/MeOH gradiant was used starting from 1% MeOH up to 5% MeOH). The pure product was isolated as a yellow solid (15.5 mg, 0.026 mmol, 67%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH:35]=O)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CO.C(Cl)Cl>[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]3[CH:18]=[CH:17][C:12]4[NH:13][C:14](=[O:16])[O:15][C:11]=4[CH:10]=3)[CH2:7][CH2:8]2)=[CH:31][CH:32]=1)([CH3:25])[CH3:26]
Reactant: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CC(C)c1ccc(CCC=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1ccc(CCCN(C)[C@H]2CC[C@H](c3ccc4[nH]c(=O)oc4c3)CC2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of amine 15 (670 mg, 2.40 mmol) in 1:1 CH2Cl2:MeOH (30 mL) was added solid NaHCO3 (200 mg, 2.40 mmol) and, after 10 minutes, 3-(4-isopropylphenyl)propionaldehyde (420 mg, 2.40 mmol). After stirring for 5 minutes, NaBH(OAc)3 (760 mg, 3.60 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was brought to pH 8 with solid NaOH and concentrated under reduced pressure. Purification by flash chromatography (silica, 95:5 CH2Cl2:MeOH followed by 89:10:1 CH2Cl2:MeOH:NH4OH), followed by formation of the HCl salt and recrystallization (MeOH:Et2O) gave 6-(trans-4-{[3-(4-isopropylphenyl)-propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (514 mg, 48%), as a white solid: mp 179-181° C.; IR (KBr): 2959, 1771, 1498, 1451 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.48 (s, 1H), 10.10 (s, 1H), 7.17-7.15 (m, 5H), 7.00 (br s, 2H), 3.32-3.29 (m, 1H), 3.19-3.11 (m, 1H), 3.06-2.99 (m, 1H), 2.89-2.83 (m, 1H), 2.70 (d, J=4 Hz, 3H), 2.63-2.52 (m, 3H), 2.15-1.95 (m, 4H), 1.93-1.87 (m, 2H), 1.66-1.50 (m, 4H), 1.19 (d, J=7 Hz, 6H); ESI (m/z): 407 [M+H]+; method B, 12.69 minutes (>99%); Anal. Calcd for C26H34N2O2.HCl: C, 70.49; H, 7.96; N, 6.32. Found: C, 70.29; H, 8.05; N, 6.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(COc2ccc(F)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)cnc1N1CC(COc2ccc(F)cc2)C1
Temperature: 140 °C
Yield: 111.2 %

Procedure:
To a solution of methyl 5-chloro-2-(3-((4-fluorophenoxy)methyl)azetidin-1-yl)nicotinate (D82) (52.1 mg, 0.148 mmol) in a mixture (3:1) 1,4-dioxane/water (1.6 ml), lithium hydroxide monohydrate (9.3 mg, 0.22 mmol) was added and the resulting mixture was heated under microwave irradiation 6 min at 140° C. After solvent evaporation the residue was taken in a mixture water/1M HCl (20 ml/5 ml) and extracted with ethylacetate (3×20 ml). Collected organics after solvent evaporation afforded the title compound (D113) (55.4 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](O)=[O:34]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (62 mg, 58%), MS (ISP) m/z=429.3 [(M+H)+], mp 145° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-tetrahydro-furan-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O.Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:30]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Yield: 65 %

Procedure:
A solution of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (514 mg, 1.4 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was stirred at room temperature for 94 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 320 mg (65%) of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a yellow solid. 1H NMR (DMSO-d6) δ 10.45 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.5-7.2 (m, 4H), 7.05 (d, 1H, J=8 Hz), 6.95 (m, 1H), 6.6 (d, 1H, J=8 Hz), 6.35 (t, 1H, J=8 Hz), and 5.9 (s, 2H). IR (KBr, cm−1) 3350, 3125, 1628, 1598, and 1583. MS (ES) m/e 351, 353.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]2[C@H:12]([F:13])[C@H:11]([O:14]CC3C=CC=CC=3)[C@:10]([CH2:25][O:26]CC3C=CC=CC=3)([CH:22]([F:24])[F:23])[O:9]2)[C:4](=[O:34])[N:3]=1>Cl.CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]2[C@H:12]([F:13])[C@H:11]([OH:14])[C@@:10]([CH:22]([F:24])[F:23])([CH2:25][OH:26])[O:9]2)[C:4](=[O:34])[N:3]=1
Reactant: Nc1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2F)c(=O)n1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Nc1ccn([C@@H]2O[C@@](CO)(C(F)F)[C@@H](O)[C@H]2F)c(=O)n1
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
A mixture of compound 40 (160 mg, 0.34 mmol), Pd(OH)2/C (0.8 g) and concentrated aqueous HCl (2 drops, 37%) in methanol (10 mL) was stirred under an atmosphere of hydrogen for 10 min, filtered and evaporated to dryness under reduced pressure. Purification by preparative HPLC afforded 41 as a white solid (26 mg, 25%). LC-MS (M+H)+=296.1
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:36][CH3:37])[N:19]=[C:20]([C:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=3)[CH:21]=2)[N:16]([CH3:38])[CH:15]=1.[H][H]>[Pd].FC(F)C(F)(F)O>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:2]=2[F:1])=[C:6]([C:14]2[C:22]3[C:17](=[C:18]([O:36][CH3:37])[N:19]=[C:20]([CH:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:16]([CH3:38])[CH:15]=2)[CH:7]=1
Reactant: COc1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: [H][H]
Agent: [Pd]
Agent: OC(F)(F)C(F)F
Product: COc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 107.4 %

Procedure:
A mixture of Example 183A (200 mg, 0.338 mmol), tetrafluoroethanol (20 mL), and 5% Pd/C (45 mg, 0.188 mmol) in a 50 mL pressure bottle was stirred at ambient temperature for 16 hours under 30 psi of hydrogen and at ambient temperature. The mixture was filtered through a nylon membrane. The filtrate was concentrated to give the title compound (205 mg, 0.363 mmol, 101% yield), which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:3][CH2:4][O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10]CCCCCC[Si](C)(C)O[Si](C)(C)C.CC(CCC=C(C)C)CCOC(=O)CCCCCCCCC=C.[CH3:55][SiH:56]([CH3:62])[O:57][Si:58]([CH3:61])([CH3:60])[CH3:59]>>[CH3:1][CH:2]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[CH2:3][CH2:4][O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][Si:56]([CH3:62])([CH3:55])[O:57][Si:58]([CH3:61])([CH3:60])[CH3:59]
Reactant: C[SiH](C)O[Si](C)(C)C
Reactant: CC(C)=CCCC(C)CCOC(=O)CCCCCCCCCC[Si](C)(C)O[Si](C)(C)C
Agent: C=CCCCCCCCCC(=O)OCCC(C)CCC=C(C)C
Product: CC(C)=CCCC(C)CCOC(=O)CCCC[Si](C)(C)O[Si](C)(C)C

Procedure:
According to the same procedure, 11-(1,1,3,3,3-pentamethyl-disiloxanyl)-undecanoic acid 3,7-dimethyl-oct-6-enyl ester was prepared from undec-10-enoic acid 3,7-dimethyl-oct-6-enyl ester and pentamethyldisiloxane.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15](C)[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[OH-].[Li+].O>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C@H:16]([C:17]([OH:19])=[O:18])[CH:21]([CH3:23])[CH3:22])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: C=C=CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=C=CCOc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Yield: 89.3 %

Procedure:
The procedure of Example 12 was followed using the product from Example 14 (300 mg, 0.85 mmol) and lithium hydroxide (41 mg, 1.7 mmol) in tetrahydrofuran (3 ml), methanol (3 ml), and water (1.5 ml) to give 247 mg (86%) of the product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20]([CH2:22][NH2:23])[CH:19]=[N:18]1.C(N(CC)CC)C.O>CS(C)=O>[CH3:16][N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=2)[CH:19]=[N:18]1
Reactant: CCOC(=O)c1cc(Cl)n2nccc2n1
Reactant: Cn1cc(CN)cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(NCc2cnn(C)c2)n2nccc2n1
Temperature: 100 °C

Procedure:
To a solution of ethyl 7-chloropyrazolo[1,5-a]pyrimidine-5-carboxylate (2.0 g, 8.9 mmol) in 15 mL DMSO were added (1-methyl-1H-pyrazol-4-yl)methanamine and triethylamine (2.69 g, 3.71 mL, 26.6 mmol), and the mixture was heated at 100° C. under microwave irradiation for 15 minutes. The reaction was then added to water (50 mL), and the precipitate was collected by filtration. The resulting white solid was carried forward without further purification. MS (Electrospray): m/z 301.2 (MH+).