Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].O>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)=[O:23]
Reactant: OCCC1CCNCC1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CCC(CCO)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(2-hydroxyethyl)piperidine (5.0 g) and triethylamine (5.39 ml) in methylene chloride (50 ml) was added dropwise a solution of 3-methoxybenzoyl chloride (5.44 ml) in methylene chloride (15 ml) at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica eluting with chloroform and the fractions containing the object product were collected and evaporated to give 2-[1-(3-methoxybenzoyl)piperidin-4-yl]ethanol (9.6 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:28]=5)[C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:35]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[C:21]([C:24]6[CH:25]=[N:26][N:27]([CH:29]7[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]7)[CH:28]=6)[C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(Cl)nn12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(-c3ccccc3)nn12
Temperature: 100 °C

Procedure:
A suspension of 7-[(S)-1-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)furo[3,2-c]pyridin-6-ylamine (0.289 mmol, 1 eq), phenylboronic acid (0.507 mmol, 2.7 eq), Pd(PPh3)4 (83.6 mg, 0.0723 mmol, 25 mol %), and K2CO3 (200.4 mg, 1.45 mmol, 5.0 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated in a microwave reactor at 100° C. for 0.5 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by chromatography on an SCX column and HPLC giving the title compound as a diformate salt. 1H NMR (400 MHz, CD3OD): δ=2.18 (d, J=6.8 Hz, 3H), 2.24-2.40 (m, 4H), 3.18-3.27 (m, 2H), 3.59 (dt, J=12.8, 3.3 Hz, 2H), 4.59 (dddd, J=10.0, 5.1, 4.9 Hz, 1H), 6.42 (q, J=6.7 Hz, 1H), 7.38-7.50 (m, 3H), 7.73-7.83 (m, 4H), 7.88 (d, J=9.9 Hz, 1H), 8.01 (s, 1H), 8.05 (s, 1H), 8.25 (d, J=9.9 Hz, 1H), 8.35 (br s, 2H). MS (ES+): m/z 522.20 (20) [MH+]. HPLC: tR=2.12 min (ZQ3, polar—5 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:2]1.[C:15]([O:19][C:20](=O)[O:21]C(C)(C)C)([CH3:18])([CH3:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:2]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Yield: 105.9 %

Procedure:
A solution of 3.15 g of ethyl indole-3-carboxylate, 4.36 g of di-tert-butylcarbonate and 0.02 g of 4-DMAP in 30 ml of acetonitrile is stirred at room temperature for 15 min. The reaction mixture is then diluted with 200 ml of ethyl acetate. The organic phase is washed with dilute hydrochloric acid, water and saturated sodium chloride solution in succession, dried over sodium sulfate and concentrated. Purification by means of FC over 80 g of silica gel with a 15:1 mixture of hexane and ethyl acetate as the mobile phase gives 5.1 g of the title compound: Rf (G)=0.41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:15]([Cl:19])[C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: [Cl-]
Reactant: Sc1ccc(Cl)cc1
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: COc1ccc(C(Cl)Sc2ccc(Cl)cc2)cc1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
144 g of 4-chlorothiophenol in 300 ml of methylene chloride are initially introduced, and 136 g of 4-methoxybenzaldehyde in 300 ml of methylene chloride are added. After the addition of 80 g of calcium chloride, dry hydrogen chloride is introduced into the mixture for 6 hours. After the mixture has stood overnight, it is filtered and the methylene chloride solution is concentrated. The solid product is recrystallised from petroleum ether. 210 g of crystals of melting point 76° to 77° C. are obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:22]=[C:21]([O:23][C:24]3[CH:25]=[N:26][C:27]([NH:30][C:31]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])=[CH:28][CH:29]=3)[CH:20]=[CH:19][N:18]=2)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH3:8].[C:34]([NH:33][C:31](=[O:32])[NH:30][C:27]1[N:26]=[CH:25][C:24]([O:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH:22]=2)=[CH:29][CH:28]=1)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(Cc4ccccc4)CC3)c2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCNCC3)c2)cn1
Product: N
Temperature: 70 °C
Reaction time: 2 h
Yield: 105.3 %
Yield: 0 %

Procedure:
4-Benzyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (0.151 g, 0.284 mmol), 10% Pd/C (50% H2O, 0.121 g, 0.057 mmol) and ammonium formate (0.054 g, 0.852 mmol) were combined in MeOH (5 mL) and stirred with heating at 70° C. After 2 h, the reaction was cooled to RT and filtered through diatomaceous earth. The cake was washed well with MeOH and the combined filtrates were concentrated to afford crude product (0.11 g). This was purified by silica gel chromatography (10% MeOH/CH2Cl2; then 0-10% 7M NH3 in MeOH/CH2Cl2) to afford N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (66 mg; 53%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 10.44 (s, 1H), 9.18 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.11 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.33-3.31 (m, 4H), 2.63 (t, J=4.9 Hz, 4H), 2.47 (m, 1H), 1.21 (s, 9H); MS (ESI) m/z: 442.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=2.Br[C:24]([Br:27])([CH3:26])C.[C:28](=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C)C=O>[Br:27][CH2:24][CH2:26][CH2:28][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=3)[O:7]2)=[CH:12][CH:11]=1
Reactant: COc1cc(OC)cc(-c2cc(=O)c3ccc(O)cc3o2)c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Br)Br
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCCCBr)cc3o2)c1

Procedure:
This compound (60) was prepared from 3′,5′-dimethoxy-7-hydroxy-flavone, 26 (1.1 g, 3.7 mmol), dibromo propane (1.9 mL, 18.5 mmol) and potassium carbonate (1.5 g, 11.1 mmol) in dry dimethyl formamide (100 mL) using the identical procedure as described for 56. Yield 1.1 g (74%); mp 173-174° C.; MS (FAB) 419/421 (M++1); IR (KBr) 1631; 1H NMR (200 MHz, DMSO-d6) δ 7.88 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.17 (d, J=2.1 Hz, 2H), 7.02 (dd, J=8.9 Hz, 2.2 Hz, 1H), 6.98 (s, 1H), 6.66 (s, 1H), 4.19 (t, J=5.9 Hz, 2H), 3.79 (s, 6H), 3.64 (t, J=6.4 Hz, 2H), 2.26 (q, J=6.2 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].FC(I)(F)[C:9]([F:12])([F:11])[F:10].[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].[NH2:28][NH2:29]>CC#N.O.O.CCO>[CH3:1][N:2]([CH3:3])[C:4]1[NH:29][N:28]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: NN
Reactant: FC(F)(F)C(F)(F)I
Reactant: C#CCN(C)C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: CN(C)c1cc(C(F)(F)F)n[nH]1
Reaction time: 0.33 h
Yield: 18.1 %

Procedure:
To a solution of N,N-dimethylpropargyl amine (20 mmol) and perfluoroethyl iodide (20 mmol) in MeCN/H2O (35 mL, 4:3), cooled to 0° C., was added slowly a solution of Na2S2O4 (20 mmol) and NaHCO3 (20 mmol) in H2O (10 mL). After 20 minutes, volatile material was removed, and the residue was extracted with Et2O. The organic phase was washed with brine, dried over MgSO4, and evaporated to give the crude iodoalkene as a yellow oil (2.85 g, 43%). A mixture of the iodoalkene (8.5 mmol) and NH2NH2*H2O (42.5 mmol) in EtOH (13 mL,) was heated under reflux for 5 hours. The solvent was removed, and the residue was partitioned between NaHCO3 and CH2Cl2. The organic phase was washed with brine, dried over MgSO4, and evaporated to give 5-dimethylamino-3-trifluoromethylpyrazole (0.65 g, 40%).
Reaction SMILES: [Mg].[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.Cl>C1(C)C=CC=CC=1>[CH2:6]([O:2][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:17]2[CH2:18][CH2:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][CH:10]=3)[CH2:15][CH:16]=2)=[CH:9][CH:10]=1)[CH2:5][CH2:4][CH3:3]
Reactant: O=C1CCC(c2ccc(Br)cc2)CC1
Reactant: C1CCOC1
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Product: CCCCOCCc1ccc(C2=CCC(c3ccc(Br)cc3)CC2)cc1
Temperature: 110 °C

Procedure:
Metallic magnesium (6.9 g, 0.28 mol) was introduced into a completely dried 1 l three-neck flask and the inside of the vessel was completely dried by passing dry nitrogen gas through it, followed by adding anhydrous tetrahydrofuran (50 ml) and a trace of iodine. An anhydrous tetrahydrofuran solution (146 ml) of 4-brom-1-(β-butyloxyethyl)-benzene (X1V) (73 g, 0.28 mol) was gradually added with stirring, while the temperature was maintained at 30°~35° C., followed by further reaction at the same temperature for 1.5 hour. The reaction liquid was ice-cooled to reduce the inner temperature down to 5° C. or lower, followed by adding an anhydrous tetrahydrofuran solution (146 ml) of 4-(p-bromophenyl)-cyclohexanone (X111) (72 g, 0.28 mol) obtained in Step G, at such a rate that the inner temperature did not exceed 10° C. After reaction at room temperature for 30 minutes, a small amount of 6 N--HCl was added to make the contents weakly acidic, followed by adding toluene (200 ml), separating the toluene layer from the aqueous layer, subjecting the aqueous layer to extraction with toluene (50 ml), combining the toluene layers together, washing the combined layers with water and removing toluene by concentration of the layers. To the resulting residue were added toluene (200 ml) and potassium hydrogen sulfate (10 g) and the mixture was heated and placed under reflux at 110° C. for one hour. After cooling, the toluene solution was washed with water to make it neutral, followed by removing toluene by concentration of the solution. The resulting raw crystals were recrystallized from ethanol (200 ml) to obtain 1-[p-(β-butyloxyethyl)-phenyl]-4-(p-bromophenyl)-cyclohexene (XV) (57.5 g) having a melting point of 86.5°~89.5° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C1C=CC=CC=1>[CH3:18][S:19]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:21])=[O:20]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reaction time: 8 h
Yield: 95 %

Procedure:
Ethyl 2-hydroxyimino-2-cyanoacetate (28.4 g) and triethylamine (28.0 ml) are dissolved in benzene (150 ml). To the solution is added dropwise a solution of methanesulfonyl chloride (15.6 ml) in benzene (40 ml) with stirring under ice-cooling. After allowing to stand overnight, to the reaction mixture are added benzene (500 ml) and water (100 ml). The benzene layer is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the residue is washed well with ether and petroleum ether to give ethyl 2-methane-sulfonyloxyimino-2-cyanoacetate (41.8 g; 95%), melting point: 78°-81° C.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([S:18][CH2:19][CH3:20])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[S:18][CH2:19][CH3:20])[CH2:9][NH:8][CH2:16]2
Reactant: CCSc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CCSc1cc2c(cc1Cl)CNC2

Procedure:
Prepared in analogy to Example A3 (e) from 5-Chloro-6-ethylsulfanyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Off-white solid. MS (m/e): 216.2 ({37Cl}M+H+, 42%), 214.2 ({35Cl}M+H+, 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([N:6]1[CH:10]=[C:9]([Br:11])[C:8]([CH3:12])=[N:7]1)(=[O:5])=[O:4].[Cl:14][CH2:15][CH2:16][CH2:17]I>C(OCC)C.C(OCCCC)CCC.C1COCC1>[CH3:1][N:2]([CH3:13])[S:3]([N:6]1[C:10]([CH2:17][CH2:16][CH2:15][Cl:14])=[C:9]([Br:11])[C:8]([CH3:12])=[N:7]1)(=[O:4])=[O:5]
Reactant: ClCCCI
Reactant: Cc1nn(S(=O)(=O)N(C)C)cc1Br
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Solvent: CCOCC
Product: Cc1nn(S(=O)(=O)N(C)C)c(CCCCl)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a solution of 4-bromo-3-methyl-pyrazole-1-sulfonic acid dimethylamide (6.7 g, 25 mmol) in diethyl ether (75 mL) was added dropwise at −78° C. under N2 phenyl lithium (1.8 M, 14.6 mL, 26.3 mmol) in dibutyl ether. After warming to 0° C. for 15 m, the reaction mixture was re-cooled to −78° C. and a solution of 3-chloro-iodopropane (15.3 g, 75 mmol) in 20 mL THF was added dropwise. The reaction was warmed to room temperature and stirred for 3 h before quenching with a saturated aqueous solution of NH4Cl. The quenched reaction mixture was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified over normal phase silica starting with 5% EtOAc in heptane for 10 m and then increasing to 50% EtOAc in heptane for 20 m to give the desired product as a clear oil (3.85 g, 11.2 mmol) MS m/z 346.3 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]2[C:19]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]=1[CH2:13][CH2:14]O)(=[O:3])[CH3:2].C(N([CH2:31][CH3:32])CC)C.[CH3:33][S:34](Cl)(=O)=O.O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]2[C:19]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]=1[CH2:13][CH2:14][S:34][CH:33]([C:32]1[CH:31]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:11]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cccc2c(CCO)c(CCCOC(C)=O)oc12
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)COc1cccc2c(CCSC(c3ccccc3)c3ccccc3)c(CCCOC(C)=O)oc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Methyl (2-(3-acetoxypropyl)-3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (78 mg) was dissolved in dichloromethane (1 ml) and the obtained solution was cooled to 0° C. To this solution, triethylamine (0.02 ml) and methanesulfonyl chloride (0.047 ml) were added and the resulting mixture was stirred for 30 minutes. The reaction solution was poured into water (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in DMF (2 ml). To this solution, diphenylmethanethiol (89 mg) and potassium carbonate (37 mg) were added and the resultant was stirred at room temperature for 22 hours. The reaction mixture was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (83 mg, yield: 70%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]([CH3:31])([CH3:30])[CH2:10][C@@:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:13][CH2:12]1.Cl[C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[CH:40][N:41]=2)[N:38]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:8][C:9]([CH3:31])([CH3:30])[CH2:10][C@@:11]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:33]3[CH:34]=[CH:35][C:36]4[N:37]([CH:39]=[CH:40][N:41]=4)[N:38]=3)[CH2:19]2)[CH2:13][CH2:12]1
Reactant: Clc1ccc2nccn2n1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(c3ccc4nccn4n3)C2)C(=O)O1
Temperature: 160 °C
Yield: 10.1 %

Procedure:
The TFA salt of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (6 mg, 0.018 mmol), 6-chloroimidazo[1,2-b]pyridazine (6 mg, 2.15 equiv.), and i-Pr2NEt (30 μL, excess) were mixed with isopropanol (1 mL). The mixture was heated in a microwave oven at 160° C. for 2.5 h. After being cooled to rt, the mixture was filtered and purified by prep HPLC to afford the title compound (0.82 mg) as brown oil. LC-MS Method 1 tR=1.07 min., m/z=450 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:25])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6]([OH:25])=[O:24]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1C
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (1470 gms; 15 moles) were charged to a glass reactor equipped with a condenser, mechanical stirrer, thermometer, and addition funnel and cooled to about 5° C. Toluene (1380 gms; 15 moles) was then added over a two hour period while maintaining the temperature below 10° C. When the addition of toluene was complete, 831 gms (3 moles) oleic acid was incrementally added over a period of two hours. The reaction mixture was maintained below 10° C. for 1/2 hour and then allowed to rise to room temperature with continued stirring for 2 hours. Tolylstearic acid (1118.6 gms; 86.1% crude yield; acid value 154) was recovered and vacuum distilled.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][O:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:27])([F:28])[F:17])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Reactant: OCc1cccc(C(F)(F)F)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and (3-trifluoromethyl-phenyl)-methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=1[NH2:16].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:16][C:15]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:14]=2[F:13])=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: Nc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1F)Nc1cc(F)ccc1F
Temperature: 20 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (180 mg, 0.775 mmol) and 2,5-difluoroaniline (100 mg, 0.775 mmol) in DCM (20 mL) was added Et3N (0.324 mL, 2.324 mmol) and HATU (884 mg, 2.324 mmol) in portions. Then the mixture was stirred at 20° C. for 3 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. Then the crude product was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness. The crude product which was purified by silica column chromatography (PE/EA 100/1 to 10/1) to afford 2-(4-bromo-2-fluorophenyl)-N-(2,5-difluorophenyl)acetamide (103 mg, 0.276 mmol, 35.6% yield). 1H NMR: (400 MHz, CD3OD) δ 7.87-7.82 (m, 1H), 7.39-7.26 (m, 3H), 7.20-7.13 (m, 1H), 6.90-6.82 (m, 1H), 3.83 (s, 2H); ES-LCMS: m/z 343.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cc[nH]n1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Clc1ccc(C(c2ccc(Cl)cc2)c2cc[nH]n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 126.1 %

Procedure:
A solution of 0.638 g of α,α-bis(4-chlorophenyl)-1H-pyrazole-3-methanol in 15 ml of trifluoroacetic acid was cooled to 0° C. Under a nitrogen atmosphere, 0.464 g of triethylsilane in 1 ml of methylene chloride was added. After stirring for 1 hour at 0° C., the mixture was poured into water, treated with sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate extract was dried, filtered, and evaporated to provide 428 mg of the title product (base) as a colorless oil. The residue was dissolved in ether, dry hydrogen chloride was added, and the title product was recovered by filtration providing white crystals with a melting point of 155°-165° C.