Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])=[O:4].C[Al](C)C.C1(C)C=CC=CC=1>C1COCC1>[CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([NH:2][CH3:1])=[O:9])=[O:4]
Reactant: CN
Reactant: COC(=O)c1cccc(C=O)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C=O)c1
Temperature: -50 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A 2M solution of methylamine in THF (44 mL, 5 eq, 87.5 mmol) was added to methyl 3-formylbenzoate (2.875 g, 1 eq, 17.5 mmol) in dry THF (65 ml). The reaction mixture was cooled to −50° C. under nitrogen and a 2M solution of trimethylaluminium in toluene (22 ml, 2.5 eq, 43.75 mmol) was added slowly over 15 mins. The reaction mixture was allowed to warm slowly to room temperature and stirred for 18 h. The reaction mixture was quenched with a 20% w/v solution of potassium sodium tartrate in water (50 ml). This was extracted with ethyl acetate (2×100 ml) and washed with water (50 ml), saturated sodium chloride solution (50 ml), dried over MgSO4 and evaporated under reduced pressure to give a gum. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 2.5% methanol in DCM. Pure fractions were combined and evaporated to afford 3-formyl-N-methylbenzamide (1.6502 g, 58%) as an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.CCN(C(C)C)C(C)C.Cl.[C:20]1([CH2:26][CH2:27][C:28]2[N:29]=[C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[S:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[C:20]1([CH2:26][CH2:27][C:28]2[N:29]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:7](=[O:9])[CH2:6][C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:35][CH2:34]3)[S:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccsc1)N1CCC(c2nc(CCc3ccccc3)cs2)CC1
Reaction time: 0.5 h

Procedure:
Thiophen-3-ylacetic acid (156 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred for 30 min. 4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg), prepared according to Process 1.2, is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (599 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives 1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-(thiophen-3-yl)ethanone (99 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Yield: 73.1 %

Procedure:
Benzyl 3-(4-benzyloxyphenyl)propionate (9.25 g) and a solution of 2.8 g potassium hydroxide in 95% ethanol (125 ml) were placed in a flask, and the mixture was heated under reflux for 30 minutes. At the end of reaction, the solvent was distilled off, ethyl acetate was added to the residue, and the resulting mixture was transferred to a separating funnel. After washing with 1N HCl and water, the ethyl acetate layer was collected and dried over anhydrous sodium sulfate, the solvent was distilled off from the dried solution, and the residue was recrystallized from ethyl acetate/hexane, affording 5 g (72.7%) of pure 3-(4-benzyloxyphenyl)propionic acid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:11]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>>[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c1Br
Yield: 60 %

Procedure:
3,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3,4dichlorobenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 144°-146° C., yield 60%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCc2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CCCC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(t-butoxycarbonyl)-4-(3-(2-pyridyl)propyl)piperidine (from Step A) (128 mg, 0.42 mmol) in methylene chloride (1 mL) was added TFA (1 mL). After stirring for 2 h at rt, the reaction was concentrated to give the title compound (36 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(/[CH:13]=[CH:14]/B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:19]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[O:29])[C:21](=[O:43])[CH:20]=1.O1CCOCC1.O>C(OCC)(=O)C.[Pd]>[CH3:42][C@@:27]([S:38]([CH3:41])(=[O:39])=[O:40])([CH2:26][CH2:25][N:22]1[CH:23]=[CH:24][C:19](/[CH:14]=[CH:13]/[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:20][C:21]1=[O:43])[C:28]([NH:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)=[O:29]
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Pd EnCat™ (133 mg, 0.04 mmol, 0.1 equiv), was added to a mixture of potassium carbonate (166 mg, 1.2 mmol, 3.0 equiv), [(E)-2-phenylvinyl]boronic acid (65 mg, 0.44 mmol, 1.1 equiv), and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (200 mg, 0.40 mmol), which may be synthesized as described Preparation 2B, in 2:1 1,4-dioxane-water (3.6 mL). The reaction was heated to 80° C. and allowed to stir overnight. The reaction was diluted with ethyl acetate (10 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography ((1:1-0:1 heptane/ethyl acetate) to provide a white residue (90 mg, 47%). MS (LCMS) m/z 473.7 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[K+].Cl[CH2:42][C:43](=[O:45])[CH3:44]>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])[CH2:42][C:43](=[O:45])[CH3:44]
Reactant: CC(=O)CCl
Reactant: COC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COC(=O)C(CC(C)=O)c1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 19 h
Yield: 51 %

Procedure:
A three-neck round bottom flask with magnetic stirrer was charged with crude (2-nitro-phenyl)-acetic acid methyl ester (7.23 g, 37.0 mmol), potassium carbonate (46.1 g, 33.3 mmol), 18-crown-6 (0.650 g), and potassium iodide (0.650 g) under an argon atmosphere. To the flask was added acetonitrile (80 mL) and the mixture heated at 70° C. for one hour. To the reaction was added chloroacetone (3.50 mL, 44.0 mmol) and the reaction stirred at 70° C. under argon for 18-20 hours. The reaction was cooled to room temperature and filtered through a pad of celite. The resulting filtrate was concentrated in vacuo to afford 9.64 g of crude material. Purification via flash chromatography (0-40% ethyl acetate/hexanes eluent) yielded 4.74 g of 2-(2-nitro-phenyl)4-oxo-pentanoic acid methyl ester (51%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:27][C:28]1[CH:29]=[C:30]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (3-fluoro-4-isopropoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.15 g, 80%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[S:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])=[O:4].[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].[F-].[Cs+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(COC)OC.ClCCl>[CH3:10][O:9][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:24]2[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)(=[O:5])=[O:4]
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)CS(=O)(=O)N(C)Cc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 2-({methyl[(4-bromophenyl)methyl]amino}sulfonyl)acetate (300 mg, 0.9 mmol) in dimethoxyethane (5 ml) was added 4-cyanophenylboronic acid (Preparation 6, 150 mg, 1.0 mmol), caesium fluoride (290 mg), tri-ortho-tolyl phosphine (28 mg, 0.09 mmol) and bis(benzylideneacetone)palladium(0) (25 mg, 0.04 mmol) and the mixture was heated to reflux for 1 hour under an atmosphere of nitrogen. The mixture was cooled to ambient temperature, diluted with dichloromethane (30 ml) and washed with water. The organic layer was dried (Na2SO4), the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1 as eluent) to give the titled compound as a pale yellow low melting solid (230 mg).
Reaction SMILES: [SH:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[N:3]=1.CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.O.O(C(C)(C)C)[Na].[Br:35][C:36]1[C:44](I)=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1>[Cu]I.CN(C=O)C>[Br:35][C:36]1[C:44]([S:1][C:2]2[NH:10][C:9]3[C:4](=[N:5][CH:6]=[N:7][C:8]=3[NH2:11])[N:3]=2)=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1
Reactant: Brc1cc2c(cc1I)OCO2
Reactant: Nc1ncnc2nc(S)[nH]c12
Agent: [Cu]I
Agent: CC(C)(C)O[Na]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2nc(Sc3cc4c(cc3Br)OCO4)[nH]c12
Temperature: 110 °C
Reaction time: 24 h

Procedure:
8-Mercaptoadenine (602 mg, 3.6 mmol), neocuproine hydrate (81 mg, 0.36 mmol), CuI (69 mg, 0.36 mmol), NaO-t-Bu (692 mg, 7.2 mmol), 5-bromo-6-iodo-benzo[1,3]dioxole (3.53 g, 10.8 mmol) and anhydrous DMF (24 mL) were charged in a nitrogen box. The vessel was sealed with Teflon tape, placed in an oil bath (110° C.) and magnetically stirred for 24 h. The solvent was removed under high vacuum and the crude purified by column chromatography on silica gel
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:6][C:5]([CH2:7][OH:8])=[N:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: OCc1nnc(Br)s1
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
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCc1nnc(-c2ccc(F)cc2)s1
Temperature: 100 °C
Yield: 65.7 %

Procedure:
To a solution of (5-bromo-1,3,4-thiadiazol-2-yl)methanol (1.2 g, 6.153 mmol) in toluene (40 mL) and ethanol (40 mL) was added 4-fluorophenyl boronic acid (1.026 g, 7.384 mmol) and 2 M solution of aqueous Na2CO3. The reaction mixture was degassed with argon, Pd(PPh3)4 (0.354 g, 0.355 mmol) was added, the reaction mixture again degassed with argon for 10 min, and the mixture heated to 100° C. for 2 h. The reaction mixture was evaporated under vacuum to remove the ethanol, diluted with water (50 mL), extracted with ethyl acetate (200 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column (using 30% ethyl acetate and hexane) to give (5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol as pale yellow solid (0.85 g, 65% yield); LC-MS m/z calculated for [M+H]+ 211.03. found 211.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:16][CH:15]=1.Cl>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.23 (s, br, 1H), 7.74-6.88 (m, 11H), 5.20-5.12 (m, 1H), 3.68-3.52 (m, br, 2H), 3.02-2.82 (m, br, 2H), 2.82-2.60 (m, 4H), 2.58-2.38 (m, br, 2H), 2.12-2.02 (m, br, 1H), 2.02-1.80 (m, br, 5H), 1.68-1.52 (m, br, 1H), 1.52-1.36 (br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH3:18])[CH:3]=1.[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:4]([CH3:18])[CH:3]=1
Reactant: BrC1CCCC1
Reactant: Cc1cc(Br)ccc1N=C1NC2(CCCC2)CS1
Product: Cc1cc(Br)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-bromo-2-methylphenyl isothiocyanate according to Method C2a to give 2-(4-bromo-2-methylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method1 D2b to give 2-(4-bromo-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:12][C:4]2[CH:5]=[C:6]([CH3:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccc(F)cc2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3,5-dimethyl-4-nitrophenol (0.97 g, 5.79 mmol), 4-fluorobenzyl chloride (1.26 g, 8.69 mmol) and anhydrous potassium carbonate (1.24 g, 9.0 mmol) in 50 ml of acetone was stirred under reflux for 22 hours. TLC showed this reaction is complete. The reaction mixture was cooled to room temperature and filtered and washed with acetone. The filtrate was evaporated to dryness to give the crude product, which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3](=O)[CH2:4][C:5]#[N:6].[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.ClCCl>C(O)C>[F:1][C:2]([F:12])([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=2)[N:20]=1)[C:8]([F:9])([F:11])[F:10]
Reactant: N#CCC(=O)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(NN)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(F)(F)C(F)(F)F)cc2N)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Heat a mixture of 4,4,5,5,5-pentafluoro-3-oxo-pentanenitrile (4.0 g, 21.4 mmol) and p-tolyl-hydrazine (10 g, 64.1 mmol) in ethanol (20 mL) to 95° C. in a sealed tube apparatus for 15 hours. After cooling to room temperature, remove the solvent under reduced pressure to give a yellow solid. Distribute the solid between dichloromethane (250 mL), distilled water (150 mL) and a saturated aq. sodium bicarbonate solution (50 mL). Isolate the aqueous phase and extract with dichloromethane (100 mL). Dry the combined organic phases over sodium sulfate and concentrate to give a dark gold oil. Subject oil to silica gel chromatography eluting with ethyl acetate and hexanes to give a light brown solid (3.24 g, 52% yield). MS(ES+): m/z=292.1 [M+H].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[C:10]([O:19][CH:20]([CH3:22])[CH3:21])[C:11]([CH3:18])=[C:12]([CH:17]=1)[C:13](OC)=[O:14]>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([O:19][CH:20]([CH3:22])[CH3:21])[C:11]([CH3:18])=[C:12]([CH2:13][OH:14])[CH:17]=1
Reactant: COC(=O)c1cc(Br)cc(OC(C)C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CO)cc(Br)cc1OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a suspension of LiAlH4 (1.90 g, 50.2 mmol) in dry THF (60 mL) was added dropwise methyl 5-bromo-2-methyl-3-(propan-2-yloxy)benzoate (Cpd PP, 17.0 g, 65.6 mmol) in THF (40 mL) at −5° C. After the addition, the resulting mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was quenched with 20% NaOH (10 mL) at −5° C. and then stirred at room temperature for 30 minutes. The resulting mixture was filtered and the solids were washed with EtOAc (3×30 mL). The filtrate was concentrated under vacuum to give [5-bromo-2-methyl-3-(propan-2-yloxy)phenyl]methanol (108a, 8 g, 74%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(C(=O)OCC)n(CC(=O)N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94–7.0 (m, 2H), 6.82–6.90 (dd, 2H), 6.7 (s, 1H), 5.5 (s, 2H), 4.26–4.32 (q, 2H), 3.62–3.82 (m, 4H), 3.04–3.18 (m, 4H), 2.58–2.64 (t, 2H), 1.64–1.74 (m, 2H), 1.34–1.38 (t, 3H), 0.96–1.0 (t, 3H). 13C NMR (400 MHz, CDCl3): 165, 160, 156.2, 152.4, 146.8, 132.8, 118.2, 118.1, 115.8, 115.4, 110.2, 61, 53, 50.6, 50.2, 45, 42, 30, 22.8, 14.2, 14.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=1.C(N(CC1C=CC(OCC(OCC)=O)=C(C)C=1)[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:29]=[CH:28][N:27]=1)CCC>>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([N:5]([CH2:6][C:7]3[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=3)[CH2:4][CH2:3][O:2][CH3:1])[N:31]=2)=[CH:37][CH:36]=1
Reactant: CCOC(=O)COc1ccc(CNCCOC)cc1C
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Product: CCOC(=O)COc1ccc(CN(CCOC)c2nccc(-c3ccc(Cl)cc3)n2)cc1C

Procedure:
Prepared from ethyl (4-{[(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate using the synthetic procedure described for Intermediate 45. Purification by Biotage™ chromatography (silica, 90 g) eluted with 100:15 to 100:25 cyclohexane:EtOAc afforded the title compound as a colourless gum (165 mg).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N+:26]=1[O-:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(C)CCNc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29.6 %

Procedure:
H2O2 (70%, 0.33 mL, ca. 6.7 mmol) was added dropwise to a stirred solution of TFAA (0.94 mL, 6.7 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 6 (182 mg, 0.7 mmol) and TFA (0.10 mL, 1.3 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 5° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 7 (60 mg, 31%) as a red solid: mp (MeOH/EtOAc) 153-156° C.; 1H NMR δ 8.12 (d, J=8.7 Hz, 1H, H-5), 7.70 (d, J=8.7 Hz, 1H, H-6), 7.37 (br s, 1H, NH), 3.71 (br t, J=7.4 Hz, 2H, H-9), 3.60-3.64 (m, 2H, CH2N), 3.03 (br t, J=7.8 Hz, 2H, H-7), 2.61 (t, J=6.0 Hz, 2H, CH2N), 2.30 [s, 6H, N(CH3)2], 2.17-2.26 (m, 2H, H-8); 13C NMR δ 149.1, 144.7, 138.6, 138.4, 132.7, 129.1, 115.8, 57.6, 45.2 (2), 38.8, 35.1, 32.9, 24.6; MS m/z 289 (M+, 0.5%), 273 (2), 256 (3), 58 (100); HRMS calcd for C14H19N5O2 (M+) m/z 289.1539, found 289.1536.