Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][NH:5]1.Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>O.CS(C)=O>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][CH2:16][CH2:15][N:5]1[N:6]=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:3]
Reactant: BrCCOC1CCCCO1
Reactant: O=c1[nH]ncc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2ccccc2cnn1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 41.5 g of potassium hydroxide in 53 ml of water is added at room temperature to a solution of 61 g of 1-oxophthalazine in 430 ml of dimethyl sulfoxide. After 30 minutes, 130 g of tetrahydro-2-pyranyl 2-bromoethyl ether are added to the suspension obtained. The mixture is left stirring for 30 hours at room temperature and then concentrated, the residue is taken up in 400 ml of water and the product is extracted with dichloromethane. The organic phase is concentrated.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].Cl[C:23]1[N:27]([CH3:28])[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[N:24]=1.O>CN(C=O)C>[CH3:28][N:27]1[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[N:24]=[C:23]1[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:4]3[CH:3]=[CH:2][N:1]=[C:5]23)=[CH:14][CH:15]=1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2ccccc21
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (150 mg) in DMF (2 mL) was added sodium hydride (60% in oil, 28 mg) at room temperature by small portions. After stirring for 10 min, a solution of 2-chloro-1-methyl-1H-benzimidazole (117 mg) in DMF (1.5 mL) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/THF) and recrystallized from methanol to give the title compound (194 mg).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)=[O:24])[CH2:20]2)=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)([OH:24])[C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: CC(C)C#N
Reactant: O=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C#N)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 0.83 h

Procedure:
To a solution of 84 uL (0.928 mmol) of isobutyronitrile in 2 mL of THF was added a solution of 370 uL (0.928 mmol) of butyllithium (2.5M solution in hexanes), followed by stirring for 50 minutes at −55° C. to −40° C. Then a solution of 334 mg (0.773 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (as in Preparation 6) in THF was added at −78° C. and the solution was stirred for 5 h at −60° C. to −50° C. A solution of 2 mL of saturated NH4Cl was added to quench the reaction and the reaction mixture was poured into 30 mL of ether and washed with 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound. 1NMR(CDCl3) δ 1.24 (s, 3H), 1.34 (S, 3H), 2.58 (br, 1H), 3.12 (br, 1H), 3.40 (br, 2H), 3.60 (br, 1H), 4.26 (m, 1h) 4.43 (s, 1H), 6.76 (m, 1H), 7.06 (m, 2H), 7.25-7.34 (m, 8H); Mass Spectrum: m/e=501 (M+1 35Cl, 38Cl) and 503 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1)[C:22](=[O:23])[CH2:21][Br:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Br)CBr
Reactant: CCCCNc1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCN(C(=O)CBr)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to 0° C.; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion. The reaction mixture was allowed to stir for 5 hours at 0° C. and then was allowed to warm to room temperature. Saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with 1N H3PO4, water, and brine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.[CH:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([CH3:36])[CH3:35]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:47]2[CH2:48][CH2:49][CH:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][CH:34]([CH3:36])[CH3:35])[CH2:45][CH2:46]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: CC(C)Oc1ccccc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C1CCN(C2CCC(NC(=O)OC(C)(C)C)CC2)CC1
Reaction time: 48 h
Yield: 48 %

Procedure:
A (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester Compound 1b (1.54 g, 7.21 mmol), NaBH(OAc)3 (64.45 g, 21.0 mmol) and HOAc (0.3 mL) were added to a solution of 4-(2-isopropoxy-phenyl)-piperidine Compound 1a (1.32 g, 6.01 mmol) in CH2Cl2 (100 mL). The mixture was stirred under N2 for two days, then the reaction was quenched with MeOH. The mixture was evaporated and the resulting residue was redissolved with CH2Cl2, washed using 10% aqueous Na2CO3 and brine, then dried (Na2SO4). The crude product was purified by column chromatography to provide {4-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-carbamic acid tert-butyl ester Compound 1c as a mixture of cis/trans isomers (MS 416; yellowish oil; 1.19 g, 48% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27](=[O:40])[N:28]([CH3:39])[N:29]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:31]=[C:30]4[C:26]([C:27](=[O:40])[N:28]([CH3:39])[N:29]4[C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:25][CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
89 mg (purity 83%, 0.24 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/methanol gradient). Yield: 75 mg (56% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:34]1C=C(S(Cl)(=O)=O)C=C[CH:39]=1>>[CH2:34]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:16][CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:39]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1

Procedure:
4-{[1-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=453.2 (M−H), was prepared in analogy to example 57, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.C(O)(=O)C.Cl.[C:23]([NH:27][NH2:28])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([N:27]1[C:5]2[C:4](=[O:3])[CH2:9][CH2:8][CH2:7][C:6]=2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(C(C)(C)C)c2c1CCCC2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate 10 g (42.6 mmol) and acetic acid 5 ml in absolute ethanol (150 ml) at room temperature was added tert-butyl hydrazine hydrochloride 6 g (48 mmol). The mixture was stirred at 60° C. for 3 hours. The volatiles were removed under vacuum, the residue was diluted with DCM and washed with sat. aqueous solution of NaHCO3, and with brine. The organic phase was dried with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane (1:2) to give ethyl 1-tert-butyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 90% yield. LC/MS (254 nm) HPLC method 2 Rt 6.08 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.18 (q, J=6.83 Hz, 2H) 2.93-2.30 (3 m, 6H) 1.58 (s, 9H), 1.16 (t, J=6.83 Hz, 3H). HRMS (ESI) calcd for C14H20N2O3 [M+H]+ 287.1366 found 287.1356.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9]1=[O:34])[CH2:4][CH3:5])[CH3:2].[CH3:35][C:36]1[CH:37]=[C:38]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:39]=[CH:40][CH:41]=1>>[CH2:4]([N:3]([CH2:6][CH2:7][N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][N:45]3[CH2:46][CH2:47][N:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([CH3:35])[CH:37]=4)[CH2:43][CH2:44]3)=[CH:17][CH:18]=2)[CH2:11][CH2:10][C:9]1=[O:34])[CH2:1][CH3:2])[CH3:5]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCN(CC)CCN1C(=O)CCC1c1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: CCN(CC)CCN1C(=O)CCC1c1ccc(CCCCN2CCN(c3cccc(C)c3)CC2)cc1

Procedure:
N-(2-(N,N-diethylamino)ethyl)-5-[4-(4-(p-toluenesulfonyloxy)butyl)phenyl]pyrrolidin-2-one and 1-(3-methylphenyl)piperazine are reacted together to give N-(2-(N,N-diethylamino)ethyl)-5-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>C1COCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1
Reactant: CSc1nncc(-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnnc(-c3ccc(F)cc3)n2)ccc1F
Temperature: 50 °C

Procedure:
To a mixture of 4,2′-difluoro-5′-(3-methylsulfanyl-[1,2,4]triazin-5-yl)biphenyl-2-carbonitrile (0.11 g, 0.32 mmol), cuprous 3-methylsalicylate (0.153 g, 0.711 mmol) and 4-fluorobenzeneboronic acid (0.1 g, 0.711 mmol) in dry THF (8 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.037 g, 0.032 mmol) and the mixture heated at 50° C. for 5 h. The reaction was allowed to cool to ambient temperature, diluted with DCM (20 ml) and filtered through a glass fibre filter. The dark brown solution was evaporated to give a brown solid. The crude product was chromatographed on silica (eluted with 3% MeOH in DCM) to give the product as a yellow solid. Recrystallisation from DCM/MeOH gave the title compound as a pale yellow solid (52 mg): δH (400 MHz, CDCl3) 7.24 (2H, m), 7.44-7.49 (2H, m), 7.55-7.62 (2H, m), 8.36-8.39 (2H, m), 8.64-8.69 (2H, m), 9.62 (1H, s); m/z (ES+) 389 (M++H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([Cl:15])[N:11]([CH2:16][CH:17]=[CH2:18])[C:10]=2[C:9](=[O:19])[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5].[NH:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH2:28]O)[CH:23]=[N:22]1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:15][C:12]1[N:11]([CH2:16][CH:17]=[CH2:18])[C:10]2[C:9](=[O:19])[N:8]([CH2:28][CH2:27][CH2:26][C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)[C:7](=[O:20])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: OCCCc1cn[nH]c1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
Reaction time: 18 h
Yield: 42.5 %

Procedure:
3-Pentyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (5 g, 16.86 mmol) and 3-(1H-pyrazol-4-yl)propan-1-ol (2.12 g, 16.8 mmol) were stirred in dry THF (150 ml) at 3° C. Dibenzyl azodicarboxylate (10.05 g, 33.7 mmol) was added followed by the dropwise addition of triphenylphosphine (8.83 g, 33.7 mmol) in dry THF (70 ml). The mixture was allowed to warm to it and stirred for 18 h. Water (1 ml) was added and the solvents evaporated. The residue was taken up in Et2O (200 ml) from which a white solid, mostly triphenylphosphine oxide, crystallised and was filtered off. The filtrate was concentrated and further by-products crystallised from ether-cyclohexane. The remaining filtrate was concentrated (19.2 g) and purified on a Biotage™ system (400 g) eluting with EtOAc-cyclohexane (2:1) to afford the title compound as a white solid (2.89 g).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12](=[O:30])[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:15])[CH3:14].C(OCC)(=O)C>C(O)(=O)C>[CH3:10][O:11][C:12](=[O:30])[C:13]([C:16]1[CH:21]=[C:20]([N+:6]([O-:9])=[O:7])[CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C(C)(C)c1ccccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a mixture of sulfuric acid (0.27 ml) and nitric acid (0.34 ml), a solution of the compound (1.0 g) obtained in Example 561 in acetic acid (30 ml) was added dropwise at 5° C. The reaction mixture was stirred at 45° C. for 4 h, poured into ice cold water and ethyl acetate was added to the mixture. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=9:1) to give 530 mg of the titled compound (yield, 46%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.F[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([O:15][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[CH:14]=2)=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: COC(=O)Cc1cc(O)c2ccccc2c1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc3ccccc23)cc1

Procedure:
Starting with (4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (108 mg, 0.5 mmol) and 1-fluoro-4-methanesulfonyl-benzene (174 mg, 1.0 mmol), using a method analogous to the one described for example 1-1, the final two steps), 4-(4-methanesulfonyl-phenoxy)-naphthalen-2-yl]-acetic acid (65.8 mg, 37%) was obtained as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.89-7.94 (m, 4H), 7.71 (s, 1H), 7.54 (dt, J=8.08, 4.04 Hz, 1H), 7.48 (s, 2H), 7.14-7.19 (m, 3H), 3.80 (s, 2H), 3.11 (s, 3H); MS cald. for C19H16O5S 356, obsd. (ESI+) [(M+H)+] 357.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[N:27]1[O:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([OH:50])=O)=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12.[NH2:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[N:27]1[O:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([NH:52][CH2:53][C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)=[O:50])=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12
Reactant: Cc1nc(N2CCN(Cc3ccc4nonc4c3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc4nonc4c3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 34% yield: mp 110-112° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.54-8.52 (m, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.72-7.69 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.28 (m, 1H), 6.14 (br s, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.57 (s, 2H), 4.15 (t, J=6.0 Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 2.62 (s, 3H); MS (ES+) m/z 450.2 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[F:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[F:13][CH:14]1[CH:15]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:5])[CH:16]=[CH:17][CH:18]=[C:19]1[C:20]([F:21])([F:22])[F:23]
Reactant: Fc1c([Mg]Br)cccc1C(F)(F)F
Reactant: CON(C)C(=O)c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccn1)C1C=CC=C(C(F)(F)F)C1F

Procedure:
Then a solution of pyridine-2-carboxylic acid methoxy-methyl-amide (1.5 g, 9 mmoles) was allowed to react with 2-flouro-3-trifluoromethylphenylmagnesium bromide (2.72 g, 10 mmoles) in THF (30 mL) at 60° C. overnight. The reaction mixture was cooled and diluted with ethyl acetate and ammonium chloride. The organic portion was washed with brine and dried over MgSO4 and stripped to afford a crude product, which was purified by chromatography with CH2Cl2 to give (6-fluoro-5-trifluoromethyl-cyclohexa-2,4-dienyl)-pyridin-2-yl-methanone as a colorless liquid (1.6 gr., 65%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]([OH:19])[CH2:11][O:10]1.[F:20][C:21]([F:50])([F:49])[C:22]1[CH:23]=[C:24]([C@H:32]([O:34][C@@H:35]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:39]([CH:47]=O)[CH2:38][CH2:37][O:36]2)[CH3:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[C:24]([C@H:32]([O:34][C@@H:35]2[C@@H:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:39]([CH2:47][N:16]3[CH2:17][CH2:18][C:13]4([CH2:9][O:10][CH2:11][CH:12]4[OH:19])[CH2:14][CH2:15]3)[CH2:38][CH2:37][O:36]2)[CH3:33])[CH:23]=[C:22]([C:21]([F:50])([F:49])[F:20])[CH:27]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC1COCC12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COCC3O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
Triethylamine (140 μL, 1.0 mmol) was added to a suspension of 2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1 g, 0.54 mmol) in 1,2-dichloroethane (2 ml). After 10 minutes, (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde (see Example 43 in WO 00/56727; 0.24 g, 0.54 mmol) was added as a solution in 1,2-dichloroethane (3 ml). The mixture was stirred at room temperature for 30 minutes then sodium triacetoxyborohydride (0.2 g, 0.94 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to give the title compound (72 mg, 23%).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[N:18][CH:19]([CH3:21])[CH3:20])[CH3:17])=[C:10](F)[CH:9]=1.C(Cl)Cl>CNC=O>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]2[N:15]=[C:16]([CH3:17])[N:18]([CH:19]([CH3:21])[CH3:20])[C:10]=2[CH:9]=1
Reactant: CC(=NC(C)C)Nc1c(F)cc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CNC=O
Product: Cc1nc2c(F)cc(Br)cc2n1C(C)C
Temperature: 100 °C
Yield: 99.9 %

Procedure:
Add potassium tert-butoxide (811.43 mg) to a solution of N-(4-bromo-2,6-difluoro-phenyl)-N′-isopropyl-acetamidine (2 g) in N-methyl formamide (20 mL). Heat the mixture at 100° C. for 2 h. Cool to RT, add DCM (150 mL), wash three times with saturated sodium chloride aqueous (brine, 300 mL), dry over magnesium sulfate and remove the solvent under vacuum. Add hexane and shake over ultrasound for a few minutes. Filter the solid, repeat addition of hexane/filtration twice to afford 1.86 g of the title compound. MS (ES+): m/z=272 (M+H)+.