Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:13][CH2:12][CH:11]([CH3:26])[CH3:10])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, starting with 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone substituting 3-methyl-1-butanol in place of isobutanol (yield: 0.3932 g, 94%). mp 117–120° C. 1H NMR (300 MHz, DMSO d6) δ 0.79 (d, J=6 Hz, 6H), 1.41–1.59 (m, 3H), 3.30 (s, 3H), 4.42 (d, J=5 Hz, 2H), 7.36 (m, 2H), 7.65 (m, 2H), 7.90 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 431 (M+H)+, 448 (M+NH4)+. Anal. calc. for C22H23FN2O4S: C, 61.38; H, 5.39; N, 6.51. Found: C, 61.42; H, 5.30; N, 6.40.
Reaction SMILES: F[C:2]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[N:6]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31](O)=[O:32])=[CH:29][N:30]=[C:24]2[CH:23]=1.C(N1C2C=CC=C(N)C=2C=N1)C1C=CC=CC=1>>[CH2:4]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:31]([C:28]3[N:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]4=[N:30][CH:29]=3)=[O:32])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=1
Reactant: COc1ccn2c(C(=O)O)cnc2c1
Reactant: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Agent: Nc1cccc2c1cnn2Cc1ccccc1
Product: COc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with 7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=398 (M+H).
Reaction SMILES: C(OC([N:8]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[C:13]1=[O:26])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=3)[C:13]2=[O:26])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc2ccn(CCCN(C(=O)OC(C)(C)C)c3ccc(OC)cc3)c(=O)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccn(CCCNc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.9 %

Procedure:
To a solution of methyl 2-{3-[(tert-butoxycarbonyl)(4-methoxyphenyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (71 mg, 0.15 mmol) in methylene chloride (2 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (2.0 mL, 8.0 mmol). The reaction mixture was stirred at rt for 1 d. The mixture was then concentrated to dryness to afford methyl 2-{3-[(4-methoxyphenyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (56 mg, quant.). LC-MS: (FA) ES+ 367.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: C1CCNCC1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: Cc1sc2cc(OCCCCN3CCCCC3)ccc2c1-c1ccc(Br)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and piperidine were converted to yield 1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-piperidine, MS: 458 (MH+, 1Br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23](O)=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23]([Cl:30])=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)O)O2
Reactant: O=C(Cl)C(=O)Cl
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)Cl)O2
Yield: 105 %

Procedure:
Reaction of 11.8 g (33.3 mmol) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid with oxalyl chloride according to Cohen et al Helv. Chim. Acta, 1978 61, 837 afforded 13.0 g (105%) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetyl chloride as a yellow oil. This acid chloride was reacted according to Org. Synth., 1984, 63, 198 with 4.94 g (34.3 mmol) of Meldrum's acid and 6.58 g (6.73 mL, 83.2 mmol) of dry pyridine as described above for the racemic series to afford 16.5 g of crude adduct i.e. (S)-5-[2-[3,4-dihydro-2,5,7,8-tetramethyl-6-phenylmethoxy-2H-1-benzopyran-2-yl]-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione as a brownish foam. Crystallization attempts from several solvents or solvent mixtures failed.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[N:14]=[N:15][C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][CH:18]=1>>[CH2:7]([C:8]1[N:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=[CH:18][C:13]2=[N:11][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: Clc1ccc(-c2cccs2)nn1
Product: c1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1

Procedure:
The title compound was prepared as described in Example 17 from phenylacetic acid hydrazide (0.67 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.21 mmol). 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J=9.8 Hz), 7.66 (1H, dd, J=3.8 Hz, 1.3 Hz), 7.55 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.53 (2H, m), 7.46 (1H, d, J=9.9 Hz), 7.31 (2H, m), 7.24 (1H, t, J=7.5 Hz), 7.17 (1H, dd, J=5.0 Hz, 3.8 Hz), 4.60 (2H, s). ESI-MS (m/z): Calcd for C16H12N4S: 292.1; found 293.2 (M+H).
Reaction SMILES: [H][H].[N+]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]#[N:18])([O-])=O>C(O)C.C(O)(=O)C.[Pd]>[CH:16]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=[CH:15][C:6]=2[NH:18][CH:17]=1
Reactant: [H][H]
Reactant: N#CCc1c([N+](=O)[O-])ccc2ccccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc2c(c1)ccc1[nH]ccc12

Procedure:
At ambient temperature and under 4 bars of hydrogen, hydrogenate 33 g of (2-nitro-1-naphthyl)acetonitrile (0.155 mol) dissolved in 630 ml of ethanol containing 10% water and 6.3 ml of pure acetic acid, using 19 g of 10% palladium-on-carbon. After absorption has ceased, filter off the catalyst, concentrate the solvent in vacuo and then take up the residue in 250 ml of dichloromethane; wash the organic phase with 100 ml of 0.1N potassium hydroxide solution and then dry the organic phase over magnesium sulphate, filter and concentrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.Cl.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]2)[CH2:31][CH2:30]1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 53.9 %

Procedure:
A mixture of 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (0.90 g, 4.9 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (Example 204, step C) (1.20 g, 4.9 mmol) and K2CO3 (0.81 g, 5.8 mmol) in DMSO (15 mL) was heated at 100° C. for 48 h. The reaction was cooled to rt, poured into H2O and extracted exhaustively with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.09 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (s, 1H), 6.69 (s, 1H), 3.90 (s, 3H), 3.29-3.38 (m, 2H), 3.06-3.15 (m, 4H), 2.87 (s, 3H), 2.68-2.79 (m, 2H), 2.59-2.66 (m, 4H), 2.40-2.48 (m, 1H), 2.20 (s, 3H), 1.80-1.92 (m, 2H), 1.49-1.67 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:18][CH:17]=2)[N:6]1[C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=1[O:39][CH3:40].[OH-].[Na+]>O1CCOCC1>[CH3:28][C:24]1[CH:23]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:7]3[N:6]([C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=4[O:39][CH3:40])[CH:5]([CH2:4][C:3]([OH:41])=[O:2])[C:14]4[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=4)[N:8]=3)=[CH:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3cccc(C)c3)cc2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1N1C(c2ccc(-c3cccc(C)c3)cc2)=Nc2c(F)cccc2C1CC(=O)O

Procedure:
Starting from 450 mg (0.80 mmol) of the ester from Example 21A, reaction in analogy to general method [E] with 96 mg (2.40 mmol) of sodium hydroxide in 21.5 ml of dioxane results in 407.5 mg (93% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][O:27]C6CCCCO6)[CH:24]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:34])[C:8]2=[O:35])[C:4]([CH3:36])=[N:3]1.O1CCOCC1>CO>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][OH:27])[CH:24]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:34])[C:8]2=[O:35])[C:4]([CH3:36])=[N:3]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnn(CCOC5CCCCO5)c4)cc3c21
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnn(CCO)c4)cc3c21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 106.1.1, 95 mg, 0.195 mmol) in MeOH (2 ml) was added dioxane 4 M (0.248 ml, 0.993 mmol) and the RM was stirred at rt for 45 min. Then the RM was evaporated, before being quenched with saturated aqueous NaHCO3 (20 ml) and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was diluted with MeOH+2 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing product were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting layer was extracted with DCM, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=404 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.87 (s, 1H), 8.14-8.08 (m, 1H), 8.01-7.92 (m, 2H), 7.82-7.75 (m, 1H), 7.52-7.47 (m, 1H), 7.39-7.35 (m, 1H), 4.96-4.89 (m, 1H), 4.17-4.11 (m, 2H), 3.96 (s, 3H), 3.77-3.69 (m, 2H), 3.55 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:21])=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[N:15][CH:16]=2)=[CH:7][CH:6]=1>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:6]1[CH:7]=[C:8]([C:11]2[C:12]([CH3:21])=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[N:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)cc2)cn1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(I)c2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.8 %

Procedure:
A suspension of iodine (2.45 g, 9.66 mmol), silver sulfate (3.01 g, 9.66 mmol) and methyl 5-(4-methoxyphenyl)-4-methylpyridine-2-carboxylate (2.47 g, 9.59 mmol) in MeOH (20 mL) was stirred at room temperature for 3.5 hours. It was then heated at 36° C. for 4 hours and then at room temperature for another 16 hours. Additional iodine (0.8 g, 3.15 mmol) and silver sulfate (1 g, 3.2 mmol) were added and the reaction was heated to 36° C. for 3 hours. The volatiles were removed and the reaction was diluted with ethyl acetate and aqueous sodium thiosulfate. The organic was washed with brine, dried over sodium sulfate, filtered and then concentrated. The resultant oil was purified by column chromatography to yield methyl 5-(3-iodo-4-methoxyphenyl)-4-methylpyridine-2-carboxylate (2.35 g, 6.12 mmol) as a white solid. MS ESI calc'd. for C15H15INO3 [M+H]+ 384.0, found 384.0.
Reaction SMILES: [CH2:1]([N:5]([CH2:13][CH2:14][C:15]([B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)=[CH2:16])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]C=C.C(OCCOCCO)=C>CC1CCCCC1.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[CH3:23][C:20]1([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18][B:17]([C:15]2[CH2:14][CH2:13][N:5]([C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])[CH2:1][CH2:2][CH:16]=2)[O:21]1
Reactant: C=CCCN(CCC(=C)B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: C=COCCOCCO
Solvent: CC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 87B (7.28 g, 20.72 mmol) in methyl cyclohexane (1.5 L) was degassed with nitrogen and (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (250 mg, 0.294 mmol) was added. The mixture was stirred at room temperature overnight and diethyleneglycol vinyl ether (0.16 mL) was added to inactivate any remaining active catalyst. The mixture was stirred for 30 minutes, concentrated and purified by flash chromatography on silica using an Analogix system (0-10% ethyl acetate/heptane) to provide the title compound. MS (ESI+) m/z 346 (M+Na)+.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[F:25])[CH2:8]2)[O:4][NH:3]1.Br>>[F:25][C:18]1[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=1[C@H:9]1[CH2:8][C@@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)cc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3cc(F)c(F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
(2R,4S)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (259 mg, 0.73 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 4 mL, 22.84 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2,4,5-trifluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (161 mg, 74%). 1H NMR (600 MHz, dmso) δ 1.36 (q, 1H), 1.45 (dq, 1H), 1.83-1.90 (m, 1H), 1.91-1.97 (m, 1H), 2.74 (dt, 1H), 2.90 (tt, 1H), 3.06-3.13 (m, 1H), 3.91 (d, 1H), 5.74 (d, 1H), 7.44-7.57 (m, 2H). HRMS Calculated for [C14H13F3N2O2+H]+: 299.1007. Found: 299.1021
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[OH-].[Na+].[Br:12]Br>O>[Br:12][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 7 h
Yield: 78.5 %

Procedure:
3.50 g of 3-(trifluoromethyl)-1H-pyrazole was suspended in 45 ml of water, and 3.2 g of 50% aqueous solution of sodium hydroxide was added to it. The mixture was cooled to 0° C., and then 3.20 g of bromine was added to the mixture, followed by stirring at room temperature for 7 hours. The reaction mixture was extracted by ethyl acetate. The organic layer was washed with water dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane was added to the residue, as a result, a crystal was formed. The crystal was collected to obtain 3.38 g of 4-bromo-3-(trifluoromethyl)-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:22][C:21]3[CH:24]=[C:25]([CH3:28])[C:26]([OH:27])=[C:19]([CH3:18])[CH:20]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C=Nc2[nH]nc(Nc3cccc(Cl)c3)c2C(N)=O)cc(C)c1O

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 3,5-dimethyl-4-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([C:19]([O:21]CC)=[O:20])=[CH:8][N:7]=1)[CH3:2].Cl>[OH-].[Na+].C1COCC1>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([C:19]([OH:21])=[O:20])=[CH:8][N:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ncc(C(=O)OCC)c(Nc2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ncc(C(=O)O)c(Nc2ccccc2)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
A suspension of iv (0.479 g, 1.46 mmol) in 2M NaOH (aq, 15 mL) and THF (2 mL) was stirred at 65° C. for 24 h. The mixture was cooled to 0° C. and the pH adjusted to pH˜2-3 using conc. HCl (35%). The resulting tan precipitate was filtered, washed with water, air-dried and further dried in vacuo to give compound v (0.321 g, 1.07 mmol, 73%) as a tan powder. 1H NMR (300 MHz, DMSO-d6): δ 10.47 (1H, br s), 9.90 (1H, br s), 8.84 (1H, app. t), 8.72 (1H, s), 7.65 (2H, d, J 7.7), 7.42 (2H, t, J 7.7), 7.21 (1H, t, J 7.2), 3.12-3.01 (2H, m), 0.90 (3H, t, J 7.2); [M+H]+ m/z=302.2.
Reaction SMILES: Br[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]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>O>[CH:20]1([NH:23][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]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Solvent: O
Product: O=C(Nc1nc2cccc(NC3CC3)n2n1)c1cccnc1

Procedure:
N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 50 mg; 0.16 mmol; 1.0 eq.) in cyclopropylamine (1 mL) was heated at 80° C. overnight. The reaction mixture was diluted with H2O and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The title compound was obtained by recrystallization in EtOAc/c-Hex as a white powder (16.60 mg; 35%). HPLC, Rt: 1.77 min. (purity 98.3%). LC/MS, M+(ESI): 295.4, M−(ESI): 293.4.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:18][N:19]([CH3:24])[S:20]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CN(C)S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (5.0 g, 35 mmol) in THF (25 mL) was added triethylamine (5 mL, 36 mmol) followed by N,N-dimethylsulfamoyl chloride (3.7 mL, 35 mmol). The resulting white mixture was stirred at room temperature for 1 h. The solids were removed by filtration and the solution was concentrated to give the title compound as a white solid (8.7 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ: 3.93 (4H, s), 3.35 (4H, t, J=5.8 Hz), 2.78 (6H, s), 1.73 (4H, t, J=5.8 Hz). LCMS (M+H) calcd for C9H19N2O4S: 251.10; found: 251.24.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:25]2[CH2:26][C:27]([CH3:34])([CH3:33])[O:28][C:29]([CH3:32])([CH3:31])[CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)O
Yield: 94.8 %

Procedure:
The general hydrolysis protocol, described for 195 was followed. Thus, 1,1-dimethylethyl (2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methyl-2-propenoate (212) (0.190 g, 0.41 mmol) was treated with TFA in CH2Cl2 to afford 0.158 g (95%) of the title compound 213 as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 7.68 (s, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.1 Hz, 2H), 2.83 (d, J=5.7 Hz, 4H), 2.11 (s, 3H), 1.22 (s, 12H). LCMS (ESI): m/z 405 (M−H)−. Anal. Calcd for C26H30O4, C, 76.82; H, 7.44. Found: C, 74.81; H, 7.42.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C@H:39]2[CH2:44][NH:43][CH2:42][CH2:41][NH:40]2)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C@@H:39]2[NH:40][CH2:41][CH2:42][N:43]([C:6]3[C:5]4[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:44]2)=[CH:35][CH:36]=1
Reactant: COc1ccc(CC[C@H]2CNCCN2)cc1
Reactant: FC(F)(F)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Product: COc1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)cc1
Yield: 71.2 %

Procedure:
Using a method similar to Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.40 g, 1.8 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (0.625 g): mass spectrum (APCI+, m/e): 488 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.58 (s, 1H), 7.13–7.03 (m, 2H), 6.99–6.86 (m, 3H), 6.85–6.78 (m, 2H), 6.75–6.69 (m, 1H), 4.22–3.97 (br. m, 2H), 3.70 (s, 3H), 3.44–2.87 (m, 6H), 2.68–2.46 (m, 2H), 1.84–1.71 (m, 2H).