Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[NH:22]C(=O)C(C)(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[NH2:22][C:10]1[CH:11]=[CH:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: CN1CCN(c2ccc(NC(=O)C(C)(C)C)c(C(=O)c3ccccc3)c2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(N)c(C(=O)c3ccccc3)c2)CC1

Procedure:
A solution of 0.3 g (0.8 mmol) of N-[2-benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2,2-dimethyl-propionamide in 10 ml of 3 N aqueous hydrochloric acid was stirred for 20 h at room temperature. The reaction mixture was extracted once with ethyl acetate, the aqueous layer was made alkaline with concentrated sodium hydroxide solution and was extracted four times with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to yield 245 mg (quantitative) of the product as light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.Cl.Cl[CH2:24][CH2:25][N:26]([CH2:32][CH2:33]Cl)[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:33][CH2:32][N:26]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:25][CH2:24]1)=[O:20])[CH3:2]
Reactant: CCC(CC)N(CCCl)CCCl
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(C(CC)CC)CC2)cc1
Yield: 26 %

Procedure:
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-carboxylic acid ethyl ester was was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[4-(2-butynyloxy)phenyl]sulfonyl}acetate (8.8 g, 30.0 mmol) and bis-(2-chloro-ethyl)-(3-pentanyl)-amine dihydrochloride (7.4 g, 30 mmol), 3.5 g of product (brown oil) was isolated. Yield 26%; MS: 436 (M+H)+
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:9]([C:6]2[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=2)[NH2:10])=[CH:14][CH:13]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: NNc1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: NN(Cc1ccc(Br)cc1)c1ccc(Br)cc1

Procedure:
4-Bromophenylhydrazine hydrochloride (30 g, 134 mmol), p-bromobenzyl bromide (40 g, 161 mmol), disopropylethylamine (43 g, 335 mmol) and tetrabutylammonium bromide (13 g, 40 mmol) were stirred together in 400 mL of CH2Cl2 at r.t. overnight. The mixture was then washed with H2O, dried over MgSO4 and the title product was purified by flash chromatography on silica using EtOAc:hexane (30:70) and by a swish in hexanes. Yield 34 g (71%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C-:16]#[N:17].[Na+].[Cl-].[Na+]>>[C:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:17]
Reactant: [C-]#N
Reactant: ClCc1ccc(Sc2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Product: N#CCc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.7 %

Procedure:
The 1-chloromethyl-4-phenylthiobenzene (3.0 g) is dissolved in N,N-dimemthylformamide (15 ml), and thereto is added finely divided sodium cyanide (1.0 g), and the mixture is stirred at room temperature for 17 hours. To the reaction mixture are added saturated aqueous sodium chloride solution (50 ml) and ice water (50 ml), and the mixture is extracted with ethyl acetate (100 ml×3). The combined extracts are washed with saturated aqueous sodium chloride solution (50 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-cyanomethyl-4-phenylthiobenzene (2.9 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=O)=[CH:4][CH:3]=1.Cl.[O:28]([NH2:30])[CH3:29].O>CCO>[CH3:29][O:28][N:30]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:10]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CON
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CON=C(c1ccc(F)cc1)c1nc(Nc2cc(C)[nH]n2)c2ccccc2n1
Temperature: 60 °C
Yield: 108.7 %

Procedure:
To (4-fluorophenyl)(4-(5-methyl-4H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (0.700 g, 2.15 mmol) in EtOH (10 mL) was added methoxylamine hydrochloride (0.336 g, 4.02 mmol) and the mixture was heated to 60° C. for 30 min. Water was added and the yellow precipitate was collected by filtration and washed with MeOH to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone O-methyloxime (0.88 g). LC-MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20]O)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][NH:36][CH3:37]>CN1C(=O)CCC1.C(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20][N:36]([CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])[CH3:37])[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Reactant: CNCCN(C)C
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)CCN(C)Cc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (compound of step C of example 31) (0.100 g, 0.25 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to N,N,N′-trimethylethylenediamine (1 mL, 7.50 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//90/10/1 then 80/20/1) to yield expected compound as a yellow solid (97 mg, 85% yield). LC-MS: m/z (ESI) 454.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:8])=[N:5][NH:6][CH:7]=1)[CH3:2].[Br:9][CH:10]([CH:13]=O)[CH:11]=O.C(O)(=O)C>C(O)C>[Br:9][C:10]1[CH:11]=[N:8][C:4]2[N:5]([N:6]=[CH:7][C:3]=2[CH2:1][CH3:2])[CH:13]=1
Reactant: O=CC(Br)C=O
Reactant: CCc1c[nH]nc1N
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1cnn2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-ethyl-1H-pyrazol-3-amine (0.50 g, 4.50 mmol) and 2-bromo-malonaldehyde (1.47 g, 9.72 mmol) in ethanol (8.0 mL) was added acetic acid (1.21 mL, 21.2 mmol). The reaction mixture was refluxed for 4 h, then stored in a freezer overnight. The mixture was warmed to rt, the resulting precipitate was removed by filtration and the filtrate concentrated. The resulting residue was portioned between ethyl acetate and 1M sodium hydroxide and the organic layer was washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C8H9BrN3: 226.0 (M+H+); Found: 226.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.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.CCN(C(C)C)C(C)C.[CH2:63]([SH:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:63]([S:70][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2[nH]ncc2cc1SCc1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A solution of 5-bromo-6-fluoro-1H-indazole (1-1, 1.0 g, 5.08 mmol, 1.0 equiv), Xantphos (0.294 g, 0.508 mmol, 0.1 equiv), and Pd2(dba)3 (0.465 g, 0.508 mmol, 0.1 equiv) was made in dioxane (25 mL) followed by the addition of DIEA (1.77 mL, 10.15 mmol, 2.0 equiv) and benzylmercaptan (0.630 mL, 5.33 mmol, 1.05 equiv) and the reaction was stirred at 120° C. overnight. The reaction mixture concentrated in vacuo and purified using normal phase chromatography. ESI+ MS [M+H]+ C14H11FN2S: 259.9 found, 259.3 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.O>ClC1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(CBr)cc1F
Yield: 109.4 %

Procedure:
1-Chloro-4-fluoro-2-methyl-5-nitrobenzene (1 g) was dissolved in chlorobenzene (6 mL) and N-bromosuccinimide (1.408 g) was added followed by benzoyl peroxide (0.183 mg). The reaction mixture was stirred at reflux for 4 hours. The reaction mixture was cooled and water was added. The mixture was extracted with dichloromethane (3×) and concentrated under reduced pressure. The crude oil obtained was triturated with diethyl ether, filtered and the filtrate concentrated under reduced pressure (3×) to yield the title compound (1.55 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:44])=[C:6]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:43])[NH:24][CH2:25][C@@H:26]([N:34](C(OC(C)(C)C)=O)[CH3:35])[CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][O:30][CH2:29]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:44])=[C:6]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:43])[NH:24][CH2:25][C@@H:26]([NH:34][CH3:35])[CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][O:30][CH2:29]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)NC[C@H](C[C@H]2CCCOC2)N(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](CNC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cc(Cl)ccc2C)C1)C[C@H]1CCCOC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
A 25 mL flask was charged with methyl 2-((R)-(5-chloro-2-methylphenyl)((R)-1-((S)-2-(Boc-methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (60 mg, 0.094 mmol). 20% TFA/CH2Cl2 solution (8 mL) was added and stirred for 0.5 h at 0° C. The mixture was concentrated to give the residue, which was purified by preparative HPLC to give the desired product methyl 2-((R)-(5-chloro-2-methylphenyl)((R)-1-((S)-2-(methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (4.35 mg, 9%) as its TFA salt. 1H-NMR (MeOD): 1.25 (m, 2H), 1.35-1.50 (m, 4H), 1.60-1.80 (m, 3H), 1.95 (m, 2H), 2.35 (s, 3H), 2.75 (s, 3H), 3.65 (s, 3H), 3.85 (m, 4H), 4.45 (d, 1H), 7.15 (m, 2H), 7.30 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH2:5][CH2:6][N:7]=1.I.[CH2:9]([N:11](CC)CC)[CH3:10].C([O:18][C:19](Cl)=[O:20])C>C(Cl)Cl>[CH3:1][S:2][C:3]1[NH:7][CH2:6][CH2:5][N:4]=1.[CH2:9]([NH:11][C:19](=[O:20])[O-:18])[CH3:10]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: CSC1=NCCN1
Agent: I
Solvent: ClCCl
Product: CCNC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-methylthio-2-imidazoline.HI (Aldrich) (10 g, 0.041 mole) and triethylamine (8.3 g, 0.0082 mole) in CH2Cl2 (50 mL) was added ethylchloroformate (Aldrich) (4.5 g, 0.041 mole) dropwise at ice bath temperature. The reaction was stirred overnight at room temperature. The precipitate was filtered and washed with CH2Cl2. The CH2Cl2 from the filtrate was washed with H2O (3×), dried over MgSO4 and removed under vacuum to yield 2-methylthio-2-imidazoline-N-ethylcarbamate (7.1 g) as a clear yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([F:22])[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[O:17]1[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13][CH:12]1[CH2:11][N:7]1[CH2:8][CH2:9][CH2:10][C:5]([CH2:3][OH:2])([F:22])[CH2:6]1
Reactant: COC(=O)C1(F)CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1(F)CCCN(CC2COc3ccccc3O2)C1
Temperature: -20 °C
Yield: 81.4 %

Procedure:
1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidine-3-carboxylic acid methyl ester (145 mg, 0.45 mmol) was dissolved in dry THF (4 ml), cooled to −20° C. and treated with LiAlH4 (34 mg, 0.90 mmol) for 3 h. Water (1 ml), 1 M NaOH (1 ml) and again water (1 ml) was added. The mixture was filtrated, concentrated and extracted with DCM three times. The organic layers were pooled and purified by flash chromatography (gradient of DCM/MeOH) to give 103 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[CH2:14][CH2:13][C:12]4[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=4[C:10]=3[NH:9][N:8]=2)=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>O1CCCC1>[NH:9]1[C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[CH2:13][CH2:14][C:15]=2[C:7]([C:4]2[CH:3]=[CH:2][N+:1]([O-:25])=[CH:6][CH:5]=2)=[N:8]1
Reactant: c1ccc2c(c1)CCc1c(-c3ccncc3)n[nH]c1-2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: [O-][n+]1ccc(-c2n[nH]c3c2CCc2ccccc2-3)cc1
Temperature: 57.5 °C

Procedure:
3-(4-Pyridyl)-4,5-dihydro-1H-benzo[g]indazole (100 mg, compound commercially available from Aldrich) was dissolved in tetrahydrofuran (5-10 ml) with warming and then 3-chloroperoxybenzoic acid (1.25 molar equivalents of 70-75% pure material) was added. The mixture was heated at 55-60° C. for 4 hours. A precipitate was collected by filtration, washed with tetrahydrofuran and then ether to give 4-(4,5-dihydro-1H-benzo[g]indazol-3-yl)pyridine 1-oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23][CH2:22]1>CN(C=O)C.C(OCC)C>[N:21]1([CH2:12][C:10]([OH:11])([CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[C:13]([F:16])([F:15])[F:14])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23][CH2:22]1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: c1ccc2c(c1)NCCN2
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCNc2ccccc21)C(F)(F)F
Yield: 39.3 %

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (see Example 1) (54.4 mg) and tetrahydroquinoxaline (124.8 mg) in DMF (0.6 mL) was heated at 100° C. for 6 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (eluted with 25% diethyl ether-benzene) to give the title compound as a clear oil (31.2 mg).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:27])([CH3:26])[O:6][CH:7]([CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:8][CH:9]([CH:11]1[C:19]2([CH3:20])[CH:14]([CH:15]([OH:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1C1C=CC=C[NH+]=1.[Cr](Cl)([O-])(=O)=O.C(O)(C)C>C(Cl)Cl.O>[CH3:1][C:2]([Si:5]([CH3:26])([CH3:27])[O:6][CH:7]([CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:8][CH:9]([CH:11]1[C:19]2([CH3:20])[CH:14]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])([CH3:3])[CH3:4]
Reactant: C=C(C)CC(CC(C)C1CCC2C(O)CCCC12C)O[Si](C)(C)C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: C=C(C)CC(CC(C)C1CCC2C(=O)CCCC21C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.24 g of [1R-[1alpha(R*,S*)-3abeta,4abeta,7aalpha]]-octahydro-1-[3-((1,1-dimethylethyl)-dimethylsilyloxy)-1,5-dimethyl-5-hexenyl)-7a-methyl-1H-inden-4-ol in 15 ml of dry methylene chloride was treated with 0.35 g of anhydrous sodium acetate and 0.71 g of 2,2'-bipyridinium chlorochromate and the mixture stirred at room temperature for 3 hours. After this time an additional 0.355 g of 2,2'-bipyridinium chlorochromate was added. The mixture was stirred 2 hours then 1 ml of isopropanol was added, mixture stirred for 20 minutes then diluted with water and extracted with ether/ethyl acetate 1:1. The combined organic phases were washed with water, then brine, dried over anhydrous sodium sulfate, filtered and the solvents removed in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (4:1) to give 0.238 g of pure [1R-[1alpha(R*,S*)-3abeta,7aalpha]]octahydro-1-[3-((1,1-dimethylethyl)-dimethylsilyloxy)-1,5-dimethyl-5-hexenyl)-7a-methyl-1H-inden-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[Br:11])=[O:8]
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: Nc1ccccc1Br
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Br)c1cncc(Br)c1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 5-bromonicotinoyl chloride 5 (7.5 g, 33 mmol), 2-bromoaniline (5.86 g, 33 mmol) and triethylamine (14 mL, 100 mmol) in anhydrous dichloromethane (100 ml) was stirred under argon overnight. The resulting mixture was worked up with water and extracted with dichloromethane (200 mL×2). The organic phase was collected and dried over Na2SO4. After concentrated to 150 mL, white crystalline solid was crashed out. Filtration and washing with hexanes gave a white solid 6 (10.0 g, 85% yield).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]([O:12]C)=[O:11])[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)[CH:2]=[CH2:3].O.[OH-].[Li+]>C1COCC1.O.CO>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]([OH:12])=[O:11])[N:7]=[C:6]([C:14]([F:16])([F:17])[F:15])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(F)(F)F)nn1CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCc1cc(C(F)(F)F)nn1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Methyl 2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (120 mg, 0.48 mmol) was dissolved in THF (1 mL). To this solution was added lithium hydroxide monohydrate (70 mg) in water (1 mL) and MeOH (0.1 mL). The resulting solution was stirred at room temperature overnight. Upon completion of the reaction, the product was purified by reverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford 2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (110 mg, 99%) as an oil. MS (m/z): 235.3 [M+H]+; HPLC retention time 3.03 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[CH2:36][C:35](=[O:41])[CH:34]=1>C(O)(=O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:34]4[C:35](=[O:41])[CH2:36][C:37]([CH3:40])([CH3:39])[CH2:38][C:33]=4[N:32]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2C1
Temperature: 100 °C
Yield: 40.3 %

Procedure:
To a solution of tert-butyl(1-(4-(3-(dimethylamino)-2-phenylacryloyl)phenyl)cyclobutyl)carbamate (166 mg, 0.40 mmol) in acetic acid (1 mL) was added molecular sieves (10 mg) and 3-amino-5,5-dimethylcyclohex-2-enone (82 mg, 0.59 mmol) under nitrogen. The resulting mixture was heated at 100° C. for 2 h. After cooled down to room temperature, the mixture was partitioned between water (10 mL) and dichloromethane (10 mL). The layers were separated and the aqueous phase extracted into dichloromethane (2×10 mL). The combined organic phases were washed with saturated NaHCO3 solution (20 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 20% EtOAc in hexane) to give the title compound (80 mg, 41%). 1H NMR (500 MHz, CDCl3): 8.27 (1H, s), 7.37 (2H, d), 7.30 (2H, d), 7.25-7.24 (3H, m), 7.19-7.17 (2H, m), 5.06 (1H, br s), 3.13 (2H, s), 2.59 (2H, s), 2.55-2.25 (4H, m), 2.09-2.01 (1H, m), 1.82-1.77 (1H, m), 1.44-1.15 (9H, br), 1.17 (6H, s).
Reaction SMILES: Cl.C([N:5]1[CH2:32][CH2:31][C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:7]=2[CH2:6]1)(=O)C.Cl>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:7]3[CH2:6][NH:5][CH2:32][CH2:31][C:8]=3[N:9]=[C:10]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)[N:11]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(C(F)(F)F)cc3)nc(-c3ccc(Cl)cc3)c2C1
Agent: Cl
Product: FC(F)(F)c1ccc(Nc2nc3c(c(-c4ccc(Cl)cc4)n2)CNCC3)cc1
Temperature: 25 °C
Yield: 151.1 %

Procedure:
A mixture of 6-acetyl-4-(4-chlorophenyl)-2-(4-trifluoromethylphenylamino) -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine monohydrochloride (1.6 g, 3.3 mmol) in 40 mL of aqueous 10% hydrochloric acid was heated to reflux for 60 hours. The mixture was cooled to room temperature and the resulting solid was collected by filtration and recrystallized from water to give 1.1 g (75%) of 4-(4-chlorophenyl)-2-(4-trifluoromethylphenylamino) -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine monohydrochloride. m.p.>250° C. MS: 405 (MH+).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3].[CH3:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][N:35]([C:27]3[N:26]([CH3:25])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3]
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Reactant: CCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCCNC(=O)C1(CCCCN2CCN(c3nc4ccccc4n3C)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-propylamide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.