Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C:3]([O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[C:9](N)[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[ClH:25]>O.[Cu](Cl)Cl>[Cl:25][C:9]1[CH:10]=[CH:2][C:3]([O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(N)cc(C(=O)O)c1Oc1c(F)cccc1F
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1Oc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of methyl 5-amino-2-(2,6-difluorophenoxy)benzoic acid (step 3, 234 mg, 0.88 mmol) in 6 N hydrochloric acid (2.6 mL) was added a solution of sodium nitrite (74 mg, 1.07 mmol) in water (0.5 mL) at 0° C. for 15 min. The mixture was added to a slurry of copper chloride (120 mg) in concentrated hydrochloric acid (1.2 mL). The mixture was stirred for 1 day at room temperature. The mixture was extracted with dichloromethane. The organic layer was purified by column chromatography on silica gel eluting with dichloromethane/methanol (10/1) to afford 210 mg (84%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.77 (1H, d, J=2.7 Hz), 7.51 (1H, dd, J=9.0, 2.7 Hz), 7.40–7.20 (3H, m), 6.80 (1H, d, J=9.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[C:19]([C:42]([F:45])([F:44])[F:43])=[N:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:17][C:18]1[C:19]([C:42]([F:45])([F:43])[F:44])=[N:20][N:21]([C:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 72.9 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole (0.23 g, 0.49 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. over the weekend. The reaction mixture was evaporated and the residue was purified by flash chromatography, eluting with 3% methanol/dichloromethane, followed by drying under high vacuum to give (4S,7R)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (213 mg, 73%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH3:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1>CC#N>[CH3:12][C:13]1[N:14]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=2)[CH:15]=[CH:16][N:17]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Solvent: CC#N
Product: Cc1nccn1-c1ccc([N+](=O)[O-])c(O)c1
Yield: 78 %

Procedure:
A solution of 5-fluoro-2-nitrophenol (2.03 g) and 2-methylimidazole (2.14 g) in CH3CN (50 mL) was stirred at reflux under N2 for 16 h. The solvent was removed and the residue was purified by chromatography on silica gel with 0-10% MeOH in CH2Cl2 to give 2.21 g of 5-(2′-methylimdazol-1-yl)-2-nitrophenol. ESI mass spectrum z (rel. intensity) 220.1 (M+H, 100).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1>CO.[Pd]>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1ccc(C(F)(F)F)cc1

Procedure:
A solution of 4-trifluoromethylcinnamic acid (commercial available) in methanol is hydrogenated with Pd/C (5 wt %) at 2 bar until 4-trifluoromethylcinnamic acid has reacted completely. After removal of the catalyst by filtration the 4-trifluoromethylhydrocinnamic acid is further reacted in step 2 to compound 2.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5 chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as an off-white powder (50 mg, 81%). HPLC, Rt: 3.33 min. (purity 94.3%). LC/MS, M+(ESI): 336.2, M−(ESI): 334.1.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:17][CH:16]3[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][NH:21][S:22]([C:25]4[C:26]([CH3:31])=[N:27][O:28][C:29]=4[CH3:30])(=[O:24])=[O:23])[CH2:15]3)[CH2:11]2)=[CH:5][CH:4]=1)#[N:2].[C:34]([O-])([O-])=O.[Cs+].[Cs+].IC>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:17][CH:16]3[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][N:21]([CH3:34])[S:22]([C:25]4[C:26]([CH3:31])=[N:27][O:28][C:29]=4[CH3:30])(=[O:24])=[O:23])[CH2:15]3)[CH2:11]2)=[CH:32][CH:33]=1)#[N:2]
Reactant: Cc1noc(C)c1S(=O)(=O)NCCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Product: Cc1noc(C)c1S(=O)(=O)N(C)CCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
N-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)-3,5-dimethylisoxazole-4-sulfonamide (43 mg, 0.09 mmol, from example 9 above ) and Cs2CO3 (86 mg, 0.26 mmol) were suspended in acetouitrile (2 mL). Iodomethane (17 μl , 0.26 mmol) was added and the reaction mixture was stirred at room temperature overnight under a nitrogen amosphere. More iodomethane (17 μl, 0.26 mmol) was added. The reaction mixture was left to stir for a further 20 h at room temperature overnight under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 39 mg (88%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[C:19](C(O)=O)=[N:20][N:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=2)([N:14]=[C:15]=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.CN(C)CCCN=C=NCC>O1CCCC1.ClCCl>[C:23]([N:21]1[CH:22]=[C:18]2[C:19]([C:15](=[O:16])[NH:14][C:11]3([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:17]2)=[N:20]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cn(C(C)(C)C)nc2C(=O)O)(N=C=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cn(C(C)(C)C)nc1C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
A solution of 4-((1-(tert-butoxycarbonyl)-4-isocyanatopiperidin-4-yl)methyl)-1-tert-butyl-1H-pyrazole-3-carboxylic acid (180 mg, 0.44 mmol) in tetrahydrofuran (5 mL) was treated with 2 N aqueous sodium hydroxide (0.664 mL, 1.33 mmol). The mixture was stirred 3 hours at room temperature, tetrahydrofuran and water were removed on a rotary evaporator and the resultant colorless solid was slurried in acetonitrile (10 mL) and then concentrated to dryness. The trituration was repeated twice more from acetonitrile (10 mL). The resultant colorless solid was taken up in dichloromethane (10 mL) and treated with (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (170 mg, 0.89 mmol). The mixture was stirred 18 hours at room temperature and then diluted with dichloromethane (50 mL) and washed with water (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was then purified by flash chromatography (30-100% ethyl acetate/heptanes, 10 g silica gel) to yield tert-butyl 2′-tert-butyl-7′-oxo-2′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (70 mg) as a colorless solid. +ESI (M+H) 363.3; 1H NMR (400 MHz, DMSO-d6, δ): 7.68 (s, 1H), 7.57 (s, 1H), 3.47 (m, 2H), 3.20 (m, 2H), 2.73 (s, 2H), 1.53 (t, J=5.7 Hz, 4H), 1.49 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]1([CH2:14][CH:15]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:14][CH:15]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)=[O:29])=[CH:31][CH:32]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)c1ccc(OC(Cc2ccccc2)Cc2ccccc2)cc1
Product: O=C(Nc1ccncc1)c1ccc(OC(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
4-Aminopyridine 17-7 (0.471 g, 5 mmol) was acylated with 17-6 (1.75 g, 5 mmol) using the conditions of Example 13. The amide 17-8 was obtained as a solid foam.
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[K+].[K+].[Br:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.Br[CH:19]([CH3:21])[CH3:20]>O>[Br:10][C:11]1[CH:12]=[C:13]([O:17][CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)Br
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cccc(Br)c1
Temperature: 78 °C
Yield: 89.8 %

Procedure:
The following reagents were combined sequentially: anhydrous ethanol (880 ml), potassium carbonate (448.0 g), 3-bromophenol (386.7 g), 2-bromopropane (400.0 g) and finally water (88 ml). The mixture was heated at reflux (78° C.) for 16 hours. Water (880 ml) was added to the reaction mixture and 900 ml of solvent was removed by distillation at atmospheric pressure during a 4 hour period. Heptane (880 ml) was added to the reaction mixture and later separated. The aqueous layer was extracted with heptane (80 ml) and the combined organic fractions were washed sequentially with 1N HCl (300 ml), water (300 ml), 1N NaOH (300 ml) and water (300 ml). Removal of the solvent by rotary evaporation (50° C., 5 mmHg) afforded 453.6 g (97%) of crude product. This was distilled through a short path distillation column (81°-85° C., 2 mmHg) to provide 431.5 g of the product as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.I[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=1>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=3)[C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)=[CH:14][CH:15]=3)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]c(-c4ccc(F)cc4)nc3n2)CC1
Reactant: CSc1nccc(I)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
KN(TMS)2 (812 mg, 3.85 mmol) in toluene (3.85 ml) is added at 0° C. to a solution of 2-(4-Fluorophenyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine (1.4 g, 3.5 mmol) in DMF (7 ml). After stirring at room temperature for 30 min., 4-iodo-2-methylthiopyrimidine (970 mg, 3.85 mmol) in toluene (3.85 ml) is added and the reaction stirred at room temperature for 1 h. Toluene is evaporated, the reaction mixture heated to 120° C. for 18 h, poured on water and extracted with ethyl acetate (containing 5% EtOH) three times. The combined organic phases are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification over SiO2 (acetone/hexanes 20/80) renders the title compound (950 mg, 52%) as colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](I)=[N:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:24]([C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[C:16]([OH:17])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:14]=1)#[N:25]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(F)cc3)noc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3ccc(F)cc3)noc2c1O
Temperature: 110 °C
Yield: 45.5 %

Procedure:
Ethyl 3-(4-fluorophenyl)-7-hydroxy-4-iodoisoxazolo[4,5-c]pyridine-6-carboxylate (290 mg, 0.678 mmol) and CuCN (182 mg, 2.03 mmol) were added to 4.5 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (4 mL, 15% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 101 mg of the title compound. MS: (+) m/z 328.32 (M+1).
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([N:9]2[C:10](=[O:13])[CH2:11][CH2:12][C@H:8]2[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1c1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCC(=O)N1c1ccc([N+](=O)[O-])cc1

Procedure:
(S)-1-(4-nitro-phenyl)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (800 mg, 2.6 mmol) is treated with trifluoroacetic acid (5 mL) at room temperature. After 1 h trifluoroacetic acid is evaporated in vacuo and the concentrate treated with ice/water. Precipitated light brownish solid is filtered washed with water and dried to give the title compound, ESI m/z 251 [M+H]+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O[N:62]=[C:63]([O:65][CH2:66][CH3:67])[NH2:64]>CN(C)C=O>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:12][CH:13]([C:25]3[O:26][N:64]=[C:63]([O:65][CH2:66][CH3:67])[N:62]=3)[CH2:14][N:15]([C:17]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)=[O:18])[CH2:16]2)=[CH:7][CH:6]=1)([F:4])[CH3:3]
Reactant: CCOC(N)=NO
Reactant: CC(F)(F)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(C(C)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.376 mmol, 2:1 cis/trans isomer mixture) of the carboxylic acid from Example 73A in 5.2 ml of N,N-dimethylformamide were added, at RT, 172 mg (0.452 mmol) of HATU and 0.14 ml (0.83 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 43.1 mg (0.414 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at room temperature for 2 h. The reaction solution was purified directly by means of preparative HPLC. The resulting intermediate (118 mg) was taken up in toluene (24 ml), admixed with 4 Å molecular sieve and stirred under reflux overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by means of preparative HPLC. Yield: 55.4 mg (32% of theory)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@H:27]2[CH2:31][O:30]C3(CCCCC3)[O:28]2)[N:12]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@H:27]([OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: O=S(=O)(Nc1cc(OC[C@H]2COC3(CCCCC3)O2)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cc(OC[C@H](O)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Reaction time: 20 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2S)-1,4-dioxaspiro[4.5]dec-2-ylmethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step ii) (0.34 g) in methanol (5 mL)/H2O (0.1 mL) was added pyridinium p-toluenesulfonate (78 mg) and the mixture was stirred at reflux for 2 h and then ambient temperature for 20 h. The reaction mixture was evaporated, suspended in H2O and extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using DCM/MeOH (98:2) as eluent to give the title compound as a white solid. Yield: 0.15 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:33])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([CH2:21][O:22][C:23]([CH3:32])([CH3:31])[C:24]([O:26]C(C)(C)C)=[O:25])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:33])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([CH2:21][O:22][C:23]([CH3:31])([CH3:32])[C:24]([OH:26])=[O:25])[CH2:16]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](COC(C)(C)C(=O)O)C1
Temperature: 25 °C

Procedure:
0.07 g of tert-butyl 2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-yl-methoxy]cyclohexylmethoxy}-2-methylpropionate is dissolved in 1 ml of dichloromethane, 1 ml of trifluoroacetic acid is added and the mixture is stirred at room temperature. The reaction is monitored (LCMS), showing complete conversion after 30 minutes. The reaction mixture is extracted with water/dichloromethane and, after removal of the solvent under reduced pressure, purified by preparative HPLC. This gives 0.06 g of the carboxylic acid 2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexylmethoxy}-2-methylpropionic acid as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([N:12]1[C:17](=[O:18])[C:16]([Cl:19])=[C:15]([O:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=[N:13]1)[CH2:5][CH:6]([CH2:10][CH3:11])[CH2:7][CH2:8][CH3:9].[OH-].[Na+]>CO>[Cl:19][C:16]1[C:17](=[O:18])[N:12]([CH:4]([CH2:5][CH:6]([CH2:10][CH3:11])[CH2:7][CH2:8][CH3:9])[C:3]([OH:27])=[O:2])[N:13]=[CH:14][C:15]=1[O:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCCC(CC)CC(C(=O)OC)n1ncc(OCC2CCCC2)c(Cl)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(CC)CC(C(=O)O)n1ncc(OCC2CCCC2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.4 %

Procedure:
A solution of 2-(5-chloro-4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-4-ethyl-heptanoic acid methyl ester (341.7 mg, 0.89 mmol) in methanol (0.6 mL, 1.49M) was treated with a 4N aqueous sodium hydroxide solution (0.24 mL, 0.98 mmol) and stirred at 25° C. for 3.5 h. After this time, the reaction was concentrated in vacuo. The residue was diluted with water (20 mL) and acidified with a 1N aqueous hydrochloric acid solution. The resulting gummy solids were collected by filtration, rinsed with water and dried in vacuo to afford 2-(5-chloro-4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-4-ethyl-heptanoic acid (296.1 mg, 90%) as a tacky, white solid; ES+-HRMS m/e calcd for C18H25N2O4Cl [M+H+] 369.1576, found 369.1575. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.19 (m, 2H), 1.28-1.84 (m, 15H), 1.91-2.03 (m, 1H), 2.15-2.27 (m, 1H), 2.27-2.38 (m, 1H), 4.26 (d, J=6.8 Hz, 2H), 5.37 (dd, J=11.0, 4.2 Hz, 1H), 8.32 (s, 1H), 13.10 (br s, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:32]=[CH:31][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([NH:27]C(=O)C)[CH:19]=[C:20]([N:22]5[CH:26]=[CH:25][CH:24]=[CH:23]5)[CH:21]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)[CH:6]=[N:5]1>C(O)C.C(OCC)(=O)C>[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:32]=[CH:31][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([CH:19]=[C:20]([N:22]5[CH:23]=[CH:24][CH:25]=[CH:26]5)[CH:21]=4)[NH2:27])[CH:14]=[N:15][C:11]=3[CH:10]=2)[CH:6]=[N:5]1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-n3cccc3)c2)cn1
Yield: 68 %

Procedure:
A mixture of 20% sodium hydroxide (5 ml) and the compound of Example 87 (1.15 g, 2.9 mmol) in 25 ml ethanol was heated at 100° C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with water (50 ml) and brine (25 ml). The solvent was removed under reduced pressure and the crude was purified by column chromatography over silica gel to give the product in 68% yield (0.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:37]3[CH2:38][CH2:39][N:34]([C:31](=[O:33])[CH3:32])[CH2:35][CH2:36]3)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Reactant: CC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(C(C)=O)CC3)c1)C(C)(C)C2
Temperature: 120 °C
Reaction time: 12 h
Yield: 54.8 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (410 mg, 1 mmol), palladium acetate (6.73 mg, 0.03 mmol), cesium carbonate (0.65 g, 2 mmol), xantphos (23 mg, 0.04 mmol) and N-acetylpiperazine (192 mg, 1.5 mmol) in toluene (10 mL) was stirred at 120° C. for 12 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium chloride (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(20% ethyl acetate/hexanes) to afford 2-[3-(4-acetyl-piperazin-1-yl)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.25 g, 54%) as a white solid: LC/MS m/e calcd for C25H30ClN3O3 M+: 455.99, observed: 456.1.